WO2006024926A1 - Monosaccharide derivatives - Google Patents
Monosaccharide derivatives Download PDFInfo
- Publication number
- WO2006024926A1 WO2006024926A1 PCT/IB2005/002573 IB2005002573W WO2006024926A1 WO 2006024926 A1 WO2006024926 A1 WO 2006024926A1 IB 2005002573 W IB2005002573 W IB 2005002573W WO 2006024926 A1 WO2006024926 A1 WO 2006024926A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- aryl
- isopropylidene
- imino
- alkyl
- Prior art date
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- 150000002771 monosaccharide derivatives Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 238000000034 method Methods 0.000 claims abstract description 21
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 12
- 208000006673 asthma Diseases 0.000 claims abstract description 9
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims abstract description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 9
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 7
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 7
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 7
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 7
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 6
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 6
- 206010061218 Inflammation Diseases 0.000 claims abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 208000003251 Pruritus Diseases 0.000 claims abstract description 6
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 6
- 206010000496 acne Diseases 0.000 claims abstract description 6
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 70
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 48
- 125000003342 alkenyl group Chemical group 0.000 claims description 46
- 125000000304 alkynyl group Chemical group 0.000 claims description 46
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 36
- -1 heterocylyl Chemical group 0.000 claims description 33
- 150000001413 amino acids Chemical class 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 235000001014 amino acid Nutrition 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
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- 125000003545 alkoxy group Chemical group 0.000 claims description 18
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- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 15
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to monosaccharide derivatives as anti-inflammatory agents.
- the compounds disclosed herein can be useful for inhibition and prevention of inflammation and associated pathologies, including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection psoriasis, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis or allergic rhinitis.
- compositions containing the compounds disclosed herein and methods of treating bronchial asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis, allergic rhinitis and other inflammatory and/or autoimmune disorders, using the compounds are also provided.
- Inflammation is a key defense mechanism of the body that is activated as a result of tissue injury.
- the inflammatory process is self-containing, however, under certain pathophysiological conditions, the inflammatory process tends to perpetuate itself, giving rise to chronic inflammatory diseases like bronchial asthma, rheumatoid arthritis etc.
- cytokines IL-4, IL-5, IL-6, IL-8, IL-13, GM-CSF and TNFalpha
- chemokines and proteolytic enzymes chymase, tryptase
- Eosinophils infiltrate inflamed tissue following allergen - mast cell interaction in bronchial asthma and allergic rhinitis.
- U.S. Patent No. 6,329,344Bl discloses several monosaccharide derivatives described as cell adhesion inhibitors. It generally relates to substituted pentose and hexose monosaccharide derivatives, which are said to exhibit cell adhesion inhibitory and anti ⁇ inflammatory activities.
- U.S. Patent No. 6,590,085Bl discloses several monosaccharide derivatives described as inhibitors of cell adhesion and cell adhesion mediated pathologies, including inflammatory and autoimmune diseases.
- U.S. Patent Application US 2002/0173632 Al discloses furanose and amino furanose compounds said to be useful for rheumatoid, arthritis, immunomodulatory diseases inflammatory and proliferative diseases.
- 5,298,494 discloses derivatives of monosaccharides, which exhibit antiproliferative and/or anti-inflammatory activity and are described as useful for treating mammals having inflammatory disorders and/or autoimmune disorders.
- U.S. Patent No. 5,367,062 discloses derivatives of disubstituted and deoxydisubstituted ⁇ ,D- lyxofuranosides which reportedly exhibit significant anti-inflammatory and antiproliferative activity and are said to be useful for treating inflammatory and/or autoimmune disorders.
- 5,360,794 discloses deoxydisubstituted or dideoxy disubstituted derivatives of ⁇ -D-mannofuranoside and ⁇ -L-gulofuranosides, which are said to exhibit anti-inflammatory and antiproliferative activity.
- U. S Patent 4,996,195 discloses derivatives of ⁇ ,D-glucofuranose and ⁇ ,D-allofuranose described as useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
- U.S. Patent No. 5,010,058 discloses derivatives of 1,2-O-iso- ⁇ ropylidene- ⁇ -D-glucofuranose described as useful for treating animals and mammals with inflammatory and/or autoimmune disorders.
- WO 93/13117 and U.S. Patent No. 5,360,792 discloses 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen containing heterocycle described as useful as antiproliferative and anti-inflammatory compounds.
- WO 94/28910 discloses 5,6- dideoxy-5 -amino derivatives of idose and 6-deoxy-6-amino derivatives of glucose, which are said to exhibit immunomodulatory, anti-inflammatory and anti-proliferative activity.
- WO 94/11381 discloses derivatives of pentose monosaccharides described as anti ⁇ proliferative and anti inflammatory compounds. Summary of the Invention
- Monosaccharide derivatives which can be used for the inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection or psoriasis are provided.
- Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides of these compounds having the same type of activity are also provided.
- compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis, allograft rejection, psoriasis inflammatory bowel disease, ulcerative colitis, acne, atherosclerosis, cancer, pruritis and allergic rhinitis are also provided.
- X can be O, or NH.
- Ri can be hydrogen or methyl.
- R 2 and R3 can together form a five-membered acetal, wherein the carbon joining the oxygens is substituted with R 1 and R m
- R4 can be hydrogen, or OR 0 (wherein R c is selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl). Also, when R 4 is OR c , R 3 and R 0 may together form an acetal (wherein the acetal is as defined earlier) and then R 2 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl.
- alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t- butyl, n-hexyl, n-decyl, tetradecyl, and the like.
- alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
- alkynyl unless and otherwise specified refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms.
- cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the definition.
- Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cycloocryl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo [2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
- alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
- aralkyl refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is as defined below.
- alkyl is the same as defined above
- aryl is as defined below.
- the examples of aralkyl groups are benzyl and the like.
- aryloxy denotes the group O-aryl wherein aryl is the same as defined above.
- the substituents are attached to the ring atom, be it carbon or heteroatom.
- heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
- the substituents are attached to the ring atom, be it carbon or heteroatom.
- the heterocyclyl ring may optionally contain one or more olefmic bond(s).
- heterocyclyl groups include tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl.
- Heteroarylalkyl refers to alkyl-heteroaryl groups linked through the alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier.
- Heterocyclylalkyl refers to alkyl-heterocyclyl groups linked through the alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
- leaving group generally refers to groups that exhibit the properties of being labile under the defined synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of such leaving groups include but are not limited to, halogen (F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
- activated derivative of a carboxylic acid refers to the corresponding acyl halide (e.g., acid fluoride, acid chloride and acid bromide), corresponding activated esters (e.g. nitro phenyl ester, the ester of 1- hydroxybenzotriazole or the ester of hydroxysuccinimide, HOSu) or a mixed anhydride for example anhydride with ethyl chloroformate and other conventional derivatives within the skill of the art.
- acyl halide e.g., acid fluoride, acid chloride and acid bromide
- activated esters e.g. nitro phenyl ester, the ester of 1- hydroxybenzotriazole or the ester of hydroxysuccinimide, HOSu
- a mixed anhydride for example anhydride with ethyl chloroformate and other conventional derivatives within the skill of the art.
- protecting groups refers to moieties which have the property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective groups in Organic Synthesis", 2 nd Ed, John Wiley and Sons, New York, N. Y., which is incorporated herein by reference.
- carboxylic protecting groups amino protecting groups or hydroxy protecting group employed is not critical, so long as the derivatised moieties are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
- amino acid refers to both natural and unnatural amino acids.
- natural amino acid represents the twenty-two naturally-occurring amino acids glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, trytophan, cysteine, proline, proline, histidine, aspartic acid, asparagines, glutamic acid, glutamine, ⁇ -carboxyglutamic acid, arginine, ornithine and lysine in their L form.
- unnatural amino acid is intended to represent the 'D' form of the twenty-two naturally-occurring amino acids described above.
- unnatural amino acid includes homologues of the natural amino acids, and synthetically modified forms of the natural amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogues of naturally occurring peptides, including D and L forms.
- the synthetically modified forms include amino acids having alkylene chains shortened or lengthened by up to two carbon atoms, amino acids comprising optionally substituted aryl groups, and amino acids comprising halogenated groups, for example halogenated alkyl and aryl groups.
- the term "unnatural amino acids" as used herein also represents beta amino acids.
- peptide refers to a molecule comprising a series of amino acids linked through amide bonds.
- Dipeptides comprise 2 amino acids
- tripeptides comprise peptides having 3 amino acids
- tetrapeptide refers to peptides having four amino acids, wherein the term amino acid is as defined earlier.
- the compounds disclosed herein contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. AU such isomeric forms of these compounds are expressly included herein.
- Each stereogenic carbon may be of the R or S configuration.
- the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention.
- amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are envisioned as part of the • disclosure. Detailed Description of the Invention
- the compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, particular compounds may be prepared, for example, by generally following the reaction scheme as depicted below.
- the compounds disclosed herein include both the syn and anti isomers either as pure isomers or as a mixture(s) thereof.
- the compounds of Formula VT can be prepared following Scheme I.
- a compound of Formula II (wherein Ri, R 2 , R 3 and R 4 are the same as defined earlier) may be oxidized to furnish a compound of Formula III, which can react with hydroxylamine hydrochloride to furnish a compound of Formula IV, which can be reacted with compound of Formula V (wherein R f and R q are the same as defined earlier) to yield a compound of Formula VI.
- the oxidation of the compound of Formula II to form a compound of Formula III can be carried out in an organic solvent, for example, dichloromethane, diethyl ether, or tetrahydrofuran, in the presence of oxidizing agents, such as pyridinium chlorochromate, pyridinium dichromate, dimethylsulphoxide with either oxalyl chloride or trifluoroacetic anhydride or acetic anhydride, or periodinane.
- an organic solvent for example, dichloromethane, diethyl ether, or tetrahydrofuran
- the condensation of the compound of Formula III with hydroxy lamine hydrochloride to yield a compound of Formula IV can be carried out in an organic solvent, for example, ethanol, methanol, propanol or isopropyl alcohol, in the presence of a organic base, for example, pyridine, diisopropylethylamine, or triethylamine.
- a organic base for example, pyridine, diisopropylethylamine, or triethylamine.
- reaction of compound of Formula IV with a compound of Formula V to yield a compound of Formula VI can be carried out in the presence of an organic solvent, for example, dichloromethane, dichloroethane, chloroform or carbontetrachloride.
- organic solvent for example, dichloromethane, dichloroethane, chloroform or carbontetrachloride.
- Example 1 Synthesis of l-0-Dodecyl-2,3-0-isopropylidene-5,6-dideoxy-5- ⁇ [f2-fluoro- phenylVaminoi-carbonyloxyl-imino- ⁇ -D-mannofuranoside (Compound No. 1)
- Step a Synthesis of l-O-Dodecyl-ZjS-O-isopropylidene-Sj ⁇ -dideoxy-S-oxo- ⁇ -D- mannofuranoside
- Step b Synthesis of l-0-Dodecyl-2,3-0-isopropyIidene-5,6-dideoxy -5-hydroxy- imino- ⁇ -D-mannofuranoside
- Step c Synthesis of l-0-Dodecyl-2,3-0-isopropyIidene-5,6-dideoxy-5- ⁇ [(2-fluoro- phenyI)-amino]-carbonyloxy ⁇ -imino- ⁇ -D-mannofuranoside (Compound No. 1)
- LTB4 leukotriene B4
- Venous blood was collected from healthy human donors using heparin as an anti ⁇ coagulant.
- Neutrophils were isolated from freshly drawn blood after dextran sedimentation and ficoll separation (Eur J Biochem. 169, 175, 1987).
- 180 ⁇ l of the of neutrophil suspension (0.2xl0 6 cells/ml) was taken and added 19 ⁇ L of Hank's Buffer salt solution along with 1 ⁇ L of the test drug (200 times concentrated) in a 24-well plate and incubated at 37°C for lhour. 3 minutes before the end of test compound incubation, 0.25 niM Ca +4 VMg +"1" were added.
- phosphate buffer saline PBS
- DTT 200 ⁇ M
- ATP 100 ⁇ M
- calcium chloride 100 ⁇ M
- test drug 200 times concentrated
- 4 ⁇ l of recombinant 5-Lox 3 units/ ⁇ l
- the reaction is initiated by adding 1 ⁇ l of ImM freshly prepared arachidonic acid and increase in absorbance is monitored at 236 nm for 10 min.
- a plot of absorbance verses time curve is prepared and area under curve (AUC) is computed for each well. Percent inhibition of AUC for different treatments is calculated with respect to the difference between the Arachidonic acid stimulated and negative control values, to compute IC 50 values.
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US6329344B1 (en) * | 1998-10-22 | 2001-12-11 | Ranbaxy Laboratories Limited | Derivatives of monosaccharides as cell adhesion inhibitors |
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US5298494A (en) * | 1989-01-09 | 1994-03-29 | Greenwich Pharmaceuticals Incorporated | Monosaccharides having anti-proliferation and anti-inflammatory activity, compositions and uses thereof |
US4996195A (en) * | 1989-01-09 | 1991-02-26 | Greenwich Pharmaceuticals Inc. | Derivatives of α,D-glucofuranose or α,D-allofuranose and intermediates for preparing these derivatives |
US5010058A (en) * | 1989-06-22 | 1991-04-23 | 501 Greenwich Pharmaceuticals Incorporated | 3,5,6-substituted derivatives of 1,2-O-isopropylidene-α,D-glucofuranose and intermediates for preparing these derivatives |
US5360792A (en) * | 1991-12-20 | 1994-11-01 | Greenwich Pharmaceuticals Incorporated | Anti-proliferative and anti-inflammatory compounds: 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen-containing heterocycle at the 5- or 6-position bound through the nitrogen atom |
US5360794A (en) * | 1992-08-03 | 1994-11-01 | Medicarb Inc. | Disubstituted and deoxy disubstituted derivatives of α-D-mannofuranosides and β-L-gulofuranosides having anti-inflammatory and anti-proliferative activity |
US5367062A (en) * | 1992-08-21 | 1994-11-22 | Medicarb Inc. | Disubstituted and deoxydisubstituted derivatives of α-d-lyxofuranosides having anti-inflammatory and anti-proliferative activity |
IN190975B (en) * | 1999-01-15 | 2003-09-06 | Ranbaxy Lab Ltd | |
US6794497B2 (en) * | 2001-01-22 | 2004-09-21 | Warner-Lambert Company | Aminofuranose compounds |
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2005
- 2005-08-31 WO PCT/IB2005/002573 patent/WO2006024926A1/en active Application Filing
- 2005-08-31 US US11/574,465 patent/US20090221515A1/en not_active Abandoned
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US6329344B1 (en) * | 1998-10-22 | 2001-12-11 | Ranbaxy Laboratories Limited | Derivatives of monosaccharides as cell adhesion inhibitors |
Non-Patent Citations (6)
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CHANDRASEKHAR, S. ET AL: "Caveat in alkylative fragmentation of aldehyde tosylhydrazones of cyclic ethers", TETRAHEDRON LETTERS, vol. 39, 1998, pages 6535 - 6538, XP002358582 * |
FERNANDEZ, R. ET AL: "Stereoselective nucleophilic formylation and cyanation of alpha-alkoxy- and alpha-aminoaldehydes", JOURNAL OF ORGANIC CHEMISTRY, vol. 66, no. 15, 2001, pages 5201 - 5207, XP002358583 * |
HORTON, D. ET AL: "Ethynylation of 1,2-O-isopropylidene-alpha-D-xylo- pentodialdose derivatives. A synthetic route to uronic acids", CARBOHYDRATE RESEARCH, vol. 14, 1970, pages 159 - 171, XP002358585 * |
PAULSEN, H. ET AL: "Synthese von 1,5-Didesoxy-1,5-imino-D-galactit", CHEMISCHE BERICHTE, vol. 113, 1980, pages 2601 - 2608, XP008056829 * |
TARASCONI, P. ET AL: "Synthesis, spectroscopic characterization and biological properties of new natural aldehydes thiosemicarbazones", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 8, 2000, pages 157 - 162, XP002358584 * |
TURK, C. ET AL: "Synthesis of 4- and 5-(s-triazolo[4,3-b]pyridazinyl-3)- substituted cyclic polyols", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 35, 1998, pages 513 - 518, XP002358581 * |
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