AU2006271923A1 - Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity - Google Patents
Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity Download PDFInfo
- Publication number
- AU2006271923A1 AU2006271923A1 AU2006271923A AU2006271923A AU2006271923A1 AU 2006271923 A1 AU2006271923 A1 AU 2006271923A1 AU 2006271923 A AU2006271923 A AU 2006271923A AU 2006271923 A AU2006271923 A AU 2006271923A AU 2006271923 A1 AU2006271923 A1 AU 2006271923A1
- Authority
- AU
- Australia
- Prior art keywords
- exch
- aminothiocolchicine
- demethoxy
- meoh
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 230000001670 myorelaxant effect Effects 0.000 title claims description 10
- 239000003158 myorelaxant agent Substances 0.000 title claims description 6
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 4
- LEQAKWQJCITZNK-AXHKHJLKSA-N N-[(7S)-1,2-dimethoxy-10-(methylthio)-9-oxo-3-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide Chemical class C1([C@@H](NC(C)=O)CCC2=C3)=CC(=O)C(SC)=CC=C1C2=C(OC)C(OC)=C3O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LEQAKWQJCITZNK-AXHKHJLKSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 60
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000006111 contracture Diseases 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 206010062575 Muscle contracture Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 102000011714 Glycine Receptors Human genes 0.000 description 2
- 108010076533 Glycine Receptors Proteins 0.000 description 2
- -1 MeOH Chemical class 0.000 description 2
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960000287 thiocolchicoside Drugs 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000007125 Buchwald synthesis reaction Methods 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229930001910 pseudoalkaloid Natural products 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 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 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/248—Colchicine radicals, e.g. colchicosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
WO 2007/009772 PCT/EP2006/007108 THIOCOLCHICOSIDE ANALOGUES WITH MYORELAXANT AND ANTI-INFLAMMATORY ACTIVITY Field of the invention The present invention relates to 3-demethoxy-3-aminothiocolchicine derivatives with myorelaxant and anti-inflammatory activity. Technological background 5 Myorelaxant drugs share the property of reducing the muscle tone and are commonly used for alleviating pain due to tissue tension, such as muscle contractures. Muscle contractures characterize several pathologies of the locomotor apparatus and are one of the main factors responsible for the persistence of the 10 pain associated to these pathologies. Muscle contractures occur also in inflammatory-rheumatic and degenerative orthopedic pathologies and when they affect the joints, they cause not only pain, but also rigidity, which limit the mutual mobility of the joint ends and consequently the functionality of the affected part. For these reasons the study of molecules endowed with 15 myorelaxant and decontracting properties still raises remarkable interest from the clinical point of view. As it is known, colchicine is a pseudoalkaloid widely used for a long time in therapy for the treatment of gout. Also widely used in therapy is 3- demethyl-thiocoIchicine glucoside, known as thiocolchicoside (a colchicine 20 derivative in which the CIO bears a thiomethyl group and the hydroxy group at the 3- position is etherified with a glucose molecule), for the treatment of contractures an inflammatory conditions of skeleton muscles (Ortopedia e Traumatologia Oggi XII, n. 4. 1992). It has recently been demonstrated that thiocolchicoside's activity can be ascribed to its ability of interacting with the 25 strychnine-sensitive glycine receptors and therefore that compounds endowed npiF nF enlNFIRMATInN WO 2007/009772 PCT/EP2006/007108 2 with glycino-mimetic activity can be used in the rheumatologic-orthopedic field for their myorelaxant properties. Disclosure of the invention The present invention relates to 3-demethoxy-3-aminothiocolchicine 5 glycosyl derivatives of general formula (I) OH HO R HO O HN O - 0 (I) S in which R is hydrogen, methyl or hydroxymethyl. 10 Alpha and beta anomers of pentose and hexose D- and L- glycopyranosides of 3-demethoxy-3-aminothiocolchicine are therefore comprised in the compounds of formula (I). The compounds of the present invention are generally prepared by reaction of 3-demethoxy-3-aminothiocolchicine (II) 15
H
2 N 0 H N 11 0t s with a protected glycopyranoside of formula (III) R3 R2 0 R3,O 0 X R3, 20 wherein WO 2007/009772 PCT/EP2006/007108 3 X is OH, F, Cl, Br, I,
R
2 is hydrogen, methyl, -CH 2 -0-R 3 ;
R
3 is hydrogen or a hydroxy-protecting group. Among the X groups, fluorine and bromine are preferred. Among the 5 protective groups, the acetyl group is preferred. 3-Demethoxy-3-aminothiocolchicine (II) is prepared from 3-0-demethylthiocolchicine triflate, tosylate or mesylate by Buchwald reaction as disclosed by Clark D. et al. in WO 00/35865. In more detail, 3-demethoxy-3-aminothiocolchicine is reacted with a 10 suitable glycoside, optionally protected at the hydroxy residues. The reaction is carried out in polar protic solvents preferably selected from alcohols (MeOH) at a temperature ranging from 25'C to the boiling temperature of the solvent. The reaction is generally complete in a time ranging from 8 hours to 6 days. Where necessary, the hydrolysis of the protecting groups can be carried out directly 15 also on the reaction crude without recovery of the intermediates. Remarkable decrease in reaction times and increase in yields are observed when the reaction is carried out with microwaves. In more detail, 3-demethoxy-3-aminothiocolchicine is reacted with a suitable glycoside in a polar protic solvent preferably selected from alcohols, such as MeOH, at 1 10*C, 20 and with 150 watt power. The reaction is generally completed after 3 hours. The resulting products were tested in vitro by displacement tests to verify their affinity to strychnine-sensitive binding sites of rat spinal cord using [ 3 H]strychnine as ligand. The results suggest that the derivatives behave as allosteric compounds on the strychnine-sensitive glycine receptors of the 25 spinal cord. This interaction is an indication of the myorelaxant activity of the compounds of the invention (Cimino M. et al., Eur. J. Pharmacol. 1996, 318. 201-204; Balduini W. et al., Neuropharmacol. 2001, 40. 1044-1049). The compound of formula II proved to be active and therefore the WO 2007/009772 PCT/EP2006/007108 4 invention relates also to the use of this compound for the preparation of medicaments with myorelaxant activity. COMPOUND N FORMULA STRY 0
H
2 N ,, N 0 / 39.91 0.54
-
0 FW = 400 C21H24N204S HO H 0 HO N 2 OH " 10.55 0.35 O H -0 FW = 562 O C27H34N209S S HON N HO OH O H 4.22 0.44 1O -0 FW = 546 s C27H34N208S / HOH HO N / H OH | "N 4 0 3.25 0.57 A / N FW = 532 0 C26H32N208S S OH HO,O H 0 HO N 5 OH N 13.12 0.77 0 H FW =562 0 C27H34N209S S HO," HO N OH ""N 6 H 8.61 1.25 FW = 532 - 0 C26H32N208S S WO 2007/009772 PCT/EP2006/007108 5 The compounds of the invention can be formulated as pharmaceutical formulations intended for the oral, intravenous, intramuscular, transdermal and topical administration, with excipients and conventional methods, such as those reported in Remington's Pharmaceutical Sciences Handbook, XVII Ed., 5 Mack Pub., N.Y., U.S.A.. Among the excipients useful for the preparation of liposomial forms for the parenteral or topical administration, particularly preferred are natural and synthetic phospholipids. The doses can range from 5 to 50 mg a day depending on the disease and on the administration route. The invention will be now illustrated in more detail by means of some 10 examples. EXPERIMENTAL SECTION The melting points were measured using a Buchi 510 apparatus. The NMR spectra were obtained with a Bruker AC 500 instrumentation. The IR spectra were obtained with a Jasco IR Report 100 spectrophotometer. The 15 reactions were carried out in a Milstone Micro SYNTH microwave oven. [a] 25 D values were measured with a 343- PLUS Perkin-Helmer polarimeter. Example 1. 3-0-Trifluoromethanesulfonyl-3-0 demethylthiocolchicine Triflic anhydride (1.24 ml, 7.40 mmoles) was added under nitrogen 20 atmosphere at 0*C to a solution of 3-0-demethylthiocolchicine (2 g, 4.98 mmoles) and p-DMAP (1.77 g, 15.78 mmoles) in anhydrous CH 2 Cl 2 (50 mL). Stirring was continued at 0 0 C for 20 hours and then at room temperature for 3 hours. The reaction was monitored by TLC analysis (10:1 25 CH 2 Cl 2 /MeOH, Rf: starting = 0.27, product = 0.38). After evaporation of the solvent, the residue was purified by column chromatography on a alumina using a CH 2 Cl 2 /MeOH mixture (increasing polarity gradient). The product (1.84 g, 70%) was obtained as yellow solid after crystallization from ethanol: WO 2007/009772 PCT/EP2006/007108 6 mp 140-142*C; IR (Nujol) vmax 1667, 1620 cm- ; [a] 2 5 D - 60' (c 0.9, CHCl 3 ), 'H NMR (CDC1 3 ): 8 7.94 (d, J = 7 Hz, 1H), 7.44 (s, 1H), 7.28. 7.09 (AB system, J = 10.4 Hz, 1H), 6.84 (s, 1H), 4.65-4.55 (in, 1H), 4.05 (s, 3H), 3.68 (s, 3H), 2.63-2.54 (in, 1H), 2.45 (s, 3H), 2.39-2.25 (in, 2H), 1.98 (s, 3H), 5 1.90-1.80 (in, 2H); 1 3 C NMR (CDCl 3 ): 8 181.8. 170.4. 160.3, 151.9, 151.0. 145.6, 142.4. 136.9, 135.3, 134.8. 134.7, 128.7, 126.6, 121.2, 116.9, 62.2, 62.0. 36.4. 29.7, 23.3, 15.6; MS m/z 533 (MH+). Example 2. 3-Demethoxy-3-aminothiocolchicine Cs 2
CO
3 (685 mg, 2.09 mmoles), Pd(OAc) 2 (68 mg, 0.29 mmoles), 10 (±)BINAP (290 mg, 0.44 mmoles) and the compound obtained in example I (800 mg, 1.48 mmoles) were loaded into a Schlenk round-bottom flask under nitrogen atmosphere. The mixture was heated at 40'C for 2 h under vacuum. After cooling, suitably degassed anhydrous toluene (3 ml) and then benzophenone imine (0.25 ml, 1.49 mmoles) were added. The round-bottom 15 flask was sealed with a rubber stopper and saturated with nitrogen. The reaction mixture was stirred for 45 minutes at room temperature, then heated at 120'C for 16 hours and monitored by TLC analysis (20:1 CH 2 Cl 2 /MeOH). The mixture was cooled to room temperature, diluted with AcOEt, filtered and concentrated under reduced pressure. The crude product containing the desired 20 imino adduct was dissolved in MeOH (15 ml) at room temperature. The solution was added with AcONa (509 mg, 6.21 moles) and NH 2 OH'HCl (323 mg, 4.65 mmoles). After 30 minutes, the mixture was diluted with
CH
2 Cl 2 (5 ml) and acidified to pH 2 with 2N HCl. The organic phase was separated, the aqueous phase was alkalinized with a 25% NaOH solution and 25 extracted with CH 2 Cl 2 (3x20 ml). The organic phase was dried over Na 2
SO
4 and concentrated under pressure to give the desired product (TLC 10:1.5
CH
2 Cl 2 /MeOH Rf 0.43) which was then crystallized from EtOH (373 mg, 60%): mp 280-282'C. [a] 25 D - 2920 (c 0.5, CHC1 3 ); IR (Nujol) Vmax 3340, WO 2007/009772 PCT/EP2006/007108 7 1667, 1620 cm-; IH NMR (CDC1 3 ): 5 7.38 (s, 1H), 7.33, 7.09 (AB system, J 10.2 Hz, 1H), 6.37 (s, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 2.45 (s, 3H), 2.40-2.24 (m, 2H), 2.00 (s, 3H), 1.89-1.81 (m, 2H); "C NMR (CDCl 3 ): 5 182.7, 170.2, 157.9, 152.4. 150.9, 141.0. 139.7, 139.5, 135.2, 134.8. 128.7, 127.1, 123.6, 5 110.8. 61.5, 61.0. 52.6, 36.7, 29.8. 23.1, 15.3; MS m/z 400.1 (MH+). Example 3. General procedure for the synthesis of 3--demethoxy-3 aminothiocolchicine glycosides Method A. A solution of 3-demethoxy-3-aminothiocolchicine (404 mg, 1 mmole) in MeOH (8.5 ml) was added with commercial glycopyranoside 10 (1 mole) and the mixture was heated in a sealed tube at 80 0 C for 6 days. The reaction was monitored by TLC analysis (10:1.5 CH 2 Cl 2 /MeOH). The solvent was evaporated under pressure and TLC analysis of the reaction crude revealed the presence of the starting reagent (8-10%) and of an isomeric mixture of aminoglycosides which was separated through column 15 chromatography on silica gel (100:1 to 100:5 CH 2 Cl 2 /MeOH) then crystallised from MeOH/iPr 2 O to obtain the desired compounds. Method B. A solution of 3-0-demethoxy-3-aminothiocolchicine (404 mg, 1 mmole) in MeOH (8.5 ml), was added with commercial glycopyranoside (1 mmole) and the mixture was heated in a microwave oven 20 for 4 hours at 1 10 0 C and 150 watt. The reaction was monitored by TLC analysis (10:1.5 CH 2 Cl 2 /MeOH). The solvent was removed under pressure and TLC analysis of the reaction crude revealed the presence of traces of the starting reagent and of an isomeric mixture of aminoglycosides which was separated by column chromatography on silica gel (100:1 to 100:5 25 CH 2 Cl 2 /MeOH) and recrystallized from MeOH/iPr 2 O to obtain the desired compounds. The following table reports the yields and diastereoselection of the processes.
WO 2007/009772 PCT/EP2006/007108 8 Method A Method B Name FORMULA Yield a/p Yield a/p HO HO4,, 3-N-D- H 0 glucopyranosyl-3-0- HO NN demethoxy-3- H 34 20:80 58 20:80 aminothiocolchicine -0 / FW =5620 C27H34N209S S HO"- ' HN 3-N-L-fucopyranosyl- N 3-0-demethoxy-3- HO OH H 35 1:99 58 1:99 aminothiocolchicine FW=546 C27H34N208S / HO N 3-N-D-xylopyranosyl- 6 H N" 3-0-demethoxy-3- O r- 34 30:70 55 30:70 aminothiocolchicine 1 / FW=532 0 C26H32N208S S OH HO,,, O 3-N-D- H 0 mannopyranosyl-3- HO OH N N O-demethoxy-3- O H 36 1:99 60 1:99 aminothiocolchicine / FW =562 0 C27H34N209S S HO 3-N-D- HO N arabinopyranosyl-3- O H 38 45:55 60 45:55 0-demethoxy-3- I / aminothiocolchicine FW = 532 0 C26H32N208S S 0::XH 0 HO' O 3-N-D-Iyxopyranosyl- HO H N 3-0-demethoxy-3- O H 37 40:60 60 40:60 aminothiocolchicine -0 FW=532 0 C26H32N208S S HO 3-N-L- HO,- N0 ramnopyranosyl-3-0- H"35 99:1 60 99:1 N 0 demethoxy-3- 0 / 36 aminothiocolchicine o FW =546.64 s C27H34N208S WO 2007/009772 PCT/EP2006/007108 9 Example 4. 3-N-a-D-Glucopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC Rf 0.30 (5:1CH 2 Cl 2 /MeOH). IR (Nujol) vmax 1667, 1620 cm-1; 'H NMR (DMSO): 8 8.63 (d, J = 7.6 Hz, 1H, exch), 7.25, 7.18 (AB system, J = 5 10.3 Hz, 2H), 7.01 (s, 1H), 6.76 (s, iH), 5.58 (d, J= 3.8 Hz, 1H, exch), 5.36 (bs, 1H, exch), 5.22 (bs, 1H, exch), 4.91 (dd, J= 5.0. 3.8 Hz, 1H), 4.41-4.35 (m, 1H), 3.83 (s, 3H), 3.73-3.64 (m, IH), 3.64-3.57 (m, 1H), 3.51 (s, 3H), 3.50-3.40 (m, 1H), 3.19-3.10 (m, 2H), 2.55-2.45 (m, 1H), 2.41 (s, 3H), 2.23 2.15 (m, 1H), 2.07-1.95 (m, 1H), 1.87-1.78 (m, 1H), 1.81 (s, 3H); 13C NMR 10 (DMSO): 8 181.6, 169.0. 157.0. 152.0. 150.1, 141.7, 138.9, 138.6, 135.2, 134.2, 128.4. 127.2, 122.3, 108.1, 85.5, 78.1, 77.9, 73.3, 70.8. 61.5, 60.9, 60.9, 51.9, 36.3, 29.9, 22.9, 14.8; MS m/z 563.2 (MH*). Example 5. 3-N- -D-Glucopyranosyl-3-O-demethoxy-3 aminothiocolchicine 15 TLC Rf 0.37 (5:1 CH 2 Cl 2 /MeOH). IR (Nujol) Vmax 1667, 1620 cm 1 ; IH NMR (DMSO): 6 8.63 (d, J= 7.6 Hz, IH, exch), 7.26, 7.15 (AB system, J= 10.3 Hz, 2H), 7.01 (s, 1H), 6.48 (s, 1H), 5.78 (d, J= 6.5 Hz, 1H, exch), 5.19 (d, J= 10.2 Hz, iH, exch), 5.18 (d, J= 4.6 Hz, iH, exch), 5.04 (d, J= 3.8 Hz, iH, exch), 4.41-4.35 (m, iH), 4.34 (dd, J = 8.1, 6.5 Hz, IH), 3.79 (s, 3H), 20 3.73-3.64 (m, 1H), 3.64-3.57 (m, iH), 3.52 (s, 3H), 3.50-3.40 (m, 1H), 3.32-3.23 (m, 2H), 2.55-2.45 (m, iH), 2.41 (s, 3H), 2.23-2.15 (m, iH), 2.07-1.95 (m, iH), 1.87-1.78 (m, iH), 1.81 (s, 3H); 1C NMR (DMSO) 181.6, 169.0. 157.0. 152.0. 150.1, 141.7, 138.9, 138.6, 135.2, 134.2, 128.4. 127.2, 122.3, 108.1, 85.5, 78.1, 77.9, 73.3, 70.8. 61.5, 60.9, 60.9, 51.9, 36.3, 29.9, 25 23.3, 14.8; MS m/z 563.2 (MH*). Example 6. 3-N-a-D-Arabinopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC Rf 0.37 (5:1 CH 2 Cl 2 /MeOH). IR (Nujol) vmax 1667, 1620 cm 1 ; 'H WO 2007/009772 PCT/EP2006/007108 10 NMR (DMSO): 5 8.59 (d, J= 8.7 Hz, 1H exch), 7.25, 7.18 (AB system, J= 10.4 Hz, 1H), 7.01 (s, 1H), 6.49 (s, 1H), 6.01 (d, J= 9.8 Hz, 1H exch), 5.77 (d, J= 6.1 Hz, 1H exch), 5.48 (d, J= 4.2 Hz, 1H exch), 5.29 (d, J= 4.4 Hz, 1H exch), 4.93 (dd, J = 9.8. 3.5 Hz, 1H), 4.41-4.32 (m, 1H), 3.78 (m, 3H), 5 3.68-3.64 (m, 1H), 3.62-3.57 (m, 3H), 3.52 (s, 3H), 3.46-3.37 (m, 1H), 2.55 2.48 (m, 1H), 2.41 (s, 3H), 2.21-2.16 (m, 1H), 2.05-1.98 (m, 1H), 1.86-1.78 (m, 1H), 1.85 (s, 3H); 3 C NMR (DMSO) d 181.6, 168.9, 157.2, 152.2, 150.4. 141.9, 141.0. 138.7, 135.4. 134.2, 128.3, 127.2, 122.4. 107.4. 81.6, 73.5, 70.5, 68.2, 65.7, 61.1, 60.9, 51.9, 36.3, 29.9, 23.3, 22.7, 14.8; MS m/z 533.3 (MH*). 10 Example 7. 3-N- -D-Arabinopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC Rf 0.30 (5:1 CH 2 Cl 2 /MeOH). IR (Nujol) vmax 1667, 1620 cm; IH NMR (DMSO):5 8.56 (d, J= 7.7 Hz, 1H exch), 7.26, 7.18 (AB system, J= 10.5 Hz, 1H), 7.01 (s, 1H), 6.45 (s, 1H), 6.21 (d, J= 8.3 Hz, 1H exch), 5.57 15 (d, J= 9.2 Hz, 1H exch), 5.51 (d, J= 5.6 Hz, 1H exch), 4.61 (dd, J= 8.3, 4.8 Hz, 1H), 4.57 (d, J = 6.1 Hz, 1H exch), 4.41-4.32 (m, 1H), 3.80 (s, 3H), 3.68-3.64 (m, 1H), 3.62-3.57 (m, 3H), 3.52 (s, 3H), 3.46-3.37 (m, 1H), 2.55-2.48 (m, 1H), 2.41 (s, 3H), 2.21-2.16 (m, 1H), 2.05-1.98 (m, 1H), 1.86 1.78 (m, 1H), 1.84 (s, 3H); 13 C NMR (DMSO) 5 181.6, 168.9, 157.2, 152.2, 20 150.4. 141.9, 141.0. 138.7, 135.4. 134.2, 128.3 127.2, 122.4. 107.4. 81.6, 73.5, 70.5, 68.2, 65.7, 61.1, 60.9, 51.9, 36.3, 29.9, 23.3, 22.7, 14.8; MS m/z 533.3 (MH+). Example 8. 3-N- a-D-Lyxopyranosyl-3-0-demethoxy-3 aminothiocolchicine 25 TLC Rf 0.37 (5:1 CH 2 Cl 2 /MeOH). IR (Nujol) Vmax 1667, 1620 cm~-; H NMR (DMSO): 5 8.58 (d, J= 7.6 Hz, 1H, exch), 7.26, 7.17 (AB system, J= 10.7 Hz, 2H), 7.03 (s, 1H), 6.45 (s, 1H), 5.68 (d, J= 7.1 Hz, 1H exch), 5.18 (d, J= 4.5 Hz, 1H exch), 4.95 (d, J= 3.9 Hz, 1H exch), 4.83 (d, J= 7.1 Hz, WO 2007/009772 PCT/EP2006/007108 11 1H exch), 4.72 (dd, J = 8.4. 7.1 Hz, 1H), 4.40-4.36 (m, 1H), 3.81 (s, 3H), 3.75-3.72 (m, 2H), 3.52 (s, 3H), 3.55-3.51 (m, 1H), 20-3.16 (m, 1H), 3.18 3.15 (m, 1H), 2.56-2.48 (m, 1H), 2.41 (s, 3H), 2.24-2.15(m, 1H), 2.07-1.95 (m, 2H), 1.86-1.78 (m, 1H), 1.84 (s, 3H); 3 C NMR (DMSO) d 181.6, 168.9, 5 157.1, 151.9, 150.2, 141.7, 141.0. 138.7, 135.2, 134.2, 128.4. 127.2, 122.1, 106.4. 82.1, 71.2, 70.1, 67.8. 63.6, 60.8. 60.7, 51.9, 36.3, 29.9, 23.3, 22.9, 14.8; MS m/z 533.3 (MH+). Example 9. 3-N- -D-Lyxopyranosyl-3-O-demethoxy-3 aminothiocolchicine 10 TLC Rf 0.30 (5:1 CH 2 Cl 2 /MeOH). IR (Nujol) Vmax 1667, 1620 cm~ 1 ; 'H NMR (DMSO): 5 8.59 (d, J= 7.3 Hz, 1H, exch), 7.25, 7.15 (AB system, J= 10.4 Hz, 2H), 7.03 (s, 1H), 6.48 (s, 1H), 6.13 (d, J= 8.9 Hz, H, exch), 5.06 (d, J= 5.5 Hz, 1H exch), 4.90 (dd, J= 8.9, 2.7 Hz, 1H), 4.86 (d, J= 4.5 Hz, 1H exch), 4.40-4.36 (m, 1H), 3.82-3.79 (m, 2H), 3.79 (s, 3H), 3.62-3.58 (m, 1H), 15 3.52 (s, 3H), 3.55-3.51 (m, 1H), 3.49-3.46 (m, 1H), 3.18-3.15 (m, 1H), 2.56 2.48 (m, 1H), 2.41 (s, 3H), 2.24-2.15(m, 1H), 2.07-1.95 (m, 2H), 1.86-1.78 (m, 1H), 1.84 (s, 3H); 13 C NMR (DMSO) 8: 181.6, 169.0. 157.1, 152.0. 150.3, 141.7, 141.0. 138.9, 135.2, 134.3, 128.4. 127.2, 122.2, 107.4. 81.6, 73.6, 71.5, 68.0. 65.5, 61.0. 60.9, 51.9, 36.2, 29.8. 23.3, 22.9, 14.8; MS m/z 533.3 (MH+). 20 Example 10. 3-N-a-D-Xylopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC R 0.30 (5:1 CH 2 C1 2 /MeOH). IR (Nujol) vmax 1667, 1620 cm-I; 'H NMR (DMS0): a 8.65-8.56 (m, 1H exch), 7.25, 7.17 (AB system, J= 10.6 Hz, 2H), 7.02 (s, 1H), 6.55 (s, 1H), 5.46 (d, J= 5.9 Hz, 1H exch), 5.32 (d, J= 5.6 25 Hz, 1H exch), 5.21 (bs, 1H exch), 5.05 (d, J= 5.4 Hz, 1H exch), 4.88 (dd, J= 5.9, 3.8 Hz, 1H), 4.42-4.35 (m, 1H), 3.82 (s, 3H), 3.70-3.50 (m, 2H), 3.51 (s, 3H), 3.40-3.30 (m, 1H), 3.30-3.20 (m, 2H), 2.57-2.50 (m, 1H), 2.50 (s, 3H), 2.21-2.12 (m, 1H), 2.07-1.97 (m, 1H), 1.86-1.78 (m, 1H), 1.85 (s, 3H), "C WO 2007/009772 PCT/EP2006/007108 12 NMR (DMSO) 5 181.6, 168.9, 157.2, 151.8. 150.1, 141.5, 138.8. 135.4. 134.4. 128.3, 127.2, 123.1, 108.0. 81.7, 77.2, 71.1, 67.8. 66.1, 60.9, 51.9, 36.3, 29.8. 23.3, 14.8; MS m/z 533.3 (MH+). Example 11. 3-N- -D-Xylopyranosyl-3-0-demethoxy-3 5 aminothiocolchicine TLC Rf 0.37 (5:1 CH 2 Cl 2 /MeOH). IR (Nujol) vmax 1667, 1620 cm'; IH NMR (DMSO) 5 8.65-8.56 (m, 1H exch), 7.25, 7.17 (AB system, J= 10.6 Hz, 2H), 7.02 (s, 1H), 6.46 (s, 1H), 5.81 (d, J= 7.2 Hz, 1H exch), 5.52 (t, J= 5.3 Hz, 0.06H 6 'f exch), 5.11 (bs, 2H exch), 4.99 (d, J = 4.8 Hz, 1H exch), 10 4.42-4.35 (m, 1H), 4.41 (dd, J= 7.8. 7.2 Hz, 1H), 3.79 (s, 3H), 3.70-3.50 (m, 2H), 3.49 (s, 3H), 3.40-3.30 (m, 1H), 3.30-3.20 (m, 2H), 2.57-2.50 (m, 1H), 2.50 (s, 3H), 2.21-2.12 (m, 1H), 2.07-1.97 (m, 1H), 1.86-1.78 (m, 1H), 1.84 (s, 3H); "C NMR (DMSO) 5 181.6, 168.9, 157.1, 151.9, 150.2, 141.4. 138.7, 135.2, 134.2, 128.3, 127.2, 122.3, 107.5, 85.7, 77.4. 72.9, 70.2, 66.6, 61.1, 15 61.0. 51.9, 36.3, 29.8. 22.9, 14.8; MS m/z 533.3 (MH*). Example 12. 3-N-a-L-Rhamnopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC Rf 0.30 (10:2 CH 2 Cl 2 -MeOH). Mp 185-188'C; [a] 25 D - 2990 (c 0.4. MeOH); IR (Nujol) vmax 1667, 1620 cm'; 'H-NMR (DMS0) X 8.58 (d, J= 7.3 20 Hz, 'H exch), 7.27, 7.14 (AB system, J= 10.5 Hz, 2H), 7.02 (s, 1H), 6.49 (s, 1H), 5.64 (d, J= 9.8 Hz, 1H exch), 5.12 (d, J= 4.4 Hz, 1H exch), 4.84 (d, J= 10.2 Hz, 1H exch), 4.79 (brs, 2H exch), 4.41-4.38 (m, 1H), 3.80 (s, 3H), 3.79-3.78 (m, 1H), 3.51 (s, 3H), 3.45-3.15 (m, 3H), 2.55-2.47 (m, 1H), 2.40 (s, 3H), 2.22-2.17 (m, 1H), 2.06-1.97 (m, 1H). 1.85 (s, 3H), 1.84-1.81 (m, 1H), 25 1.11 (d, J = 5.6 Hz, 3H); 1 3 C NMR (DMSO): 5 182.00. 169.39, 157.51, 152.33, 150.61, 140.77, 139.01, 135.59, 134.64. 128.75, 127.58. 122.62, 108.07, 94.92, 80.94. 74.94. 73.39, 72.75, 71.88. 61.37, 61.22, 36.68. 29.87, 23.31, 22.95, 18.88; MS m/z 547.2 (MH+).
WO 2007/009772 PCT/EP2006/007108 13 Example 13. 3-N-$-D-Mannopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC Rf 0.21 (10:2 CH 2 Cl 2 -MeOH). M.p. 165-167'C; [a] 25 ' -3950 (c 0.44. MeOH); IR (Nujol) Vmax 1667, 1620 cm' ; 'H NMR (DMSO) X 8.59 5 (d, J= 7.5 Hz, 1H, exch), 7.25, 7.16 (AB system, J= 10.3 Hz, 2H), 7.01 (s, 1H), 6.48 (s, 1H), 5.72 (d, J= 10.0 Hz, 1H, exch), 5.13 (d, J= 5.2 Hz, 1H, exch), 4.80 (d, J= 5.4 Hz, 1H, exch), 4.82 (d, J= 10 Hz, 1H), 4.76 (d, J= 5.0 Hz, 1H, exch), 4.43 (t, J= 6.1 Hz, 1H, exch), 4.42-4.33 (m, 1H), 3.49 (s, 3H), 3.83 (s, 3H), 3.77-3.52 (m, 3H), 3.49-3.35 (m, 2H), 3.29-3.15 (m, 1H), 10 2.52-2.45 (m, 1H), 2.42 (s, 3H), 2.20-2.15 (m, 1H), 2.05-1.98 (m, 1H), 1.84-1.78 (m, 1H), 1.86 (s, 3H); "C NMR (DMSO) 6 181.6, 169.0. 157.1, 152.0. 150.1, 140.4. 138.8. 138.6, 135.2, 134.3, 128.4. 127.2, 122.3, 108.2, 94.5, 78.5, 74.9, 71.3, 67.9, 67.6, 61.6, 60.9, 60.8. 51.9, 36.2, 29.9, 23.3, 14.8; MS m/z 563.2 (MH+). In admixture with 10% of the conformational isomer. 15 Example 14. 3-N- -L-Fucopyranosyl-3-0-demethoxy-3 aminothiocolchicine TLC Rf 0.30 (5:1 CH 2 C1 2 /MeOH). M.p. 185-188'C; [a] 25 D 299o (c 0.4. MeOH); IR (Nujol) Vmax 1667, 1620 cm-1; 'H-NMR (DMSO): 5 8.60 (d, J= 7.3 Hz, 1H exch), 7.26, 7.17 (AB system, J= 10.3 Hz, 2H), 7.02 (s, 1H), 6.46 20 (s, 1H), 5.65 (d, J= 6.6 Hz, 1H exch), 4.94 (d, J= 6.6 Hz, 1H exch), 4.74 (d, J= 5.5 Hz, 1H exch), 4.40 (d, J= 5.1 Hz, 1H exch), 4.40-4.35 (m, 1H), 4.36 (dd, J= 8.6, 6.6 Hz, 1H), 3.81 (s, 3H), 3.75-3.65 (m, 1H), 3.70-3.38 (m, 5H), 3.65-3.50 (m, 2H), 3.51 (s, 3H), 3.50-3.40 (m, 1H), 2.55-2.47 (m, 1H), 2.40 (s, 3H), 2.22-2.17 (m, 1H), 2.06-1.97 (m, 1H). 1.88-1.78 (m, 1H), 1.84 (s, 25 3H), 1.10 (d, J = 6.1 Hz, 3H); 1 3 C NMR (DMSO): 8 181.62, 168.98. 157.03, 152.00. 150.18. 141.71, 138.74. 138.65, 135.21, 134.21, 128.36, 127.21, 122.06, 107.38. 85.38. 74.61, 71.91, 70.99, 70.14. 60.97, 60.91, 51.88. 36.32, 29.96, 23.29, 17.29, 14.82; MS m/z 547.2 (MH+).
Claims (5)
1. Compounds of general formula (I) OH HO R HO HN -- "N 0 H 5 0 5 /S (I) wherein R is hydrogen, methyl or hydroxymethyl.
2. A compound selected from:
3-N-D-xylopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 10 3-N-D-glucopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-N-D-mannopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-N-D-arabinopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-N-D-lyxopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-N-L-rhamnopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 15 3-N-L-fucopyranosyl-3-0-demethoxy-3-aminothiocolchicine. 3. Pharmaceutical compositions comprising a compound of claim 1 or 2 in admixture with acceptable carriers and/or excipients.
4. Use of the compounds of claims 1 and 2 for the preparation of medicaments with myorelaxant and anti-inflammatory activity. 20
5. Use of the compound of formula (II) 0 H 2 N H H 10 - 0 S WO 2007/009772 PCT/EP2006/007108 15 for the preparation of medicaments with myorelaxant activity.
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| ITMI2005A001418 | 2005-07-22 | ||
| PCT/EP2006/007108 WO2007009772A1 (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
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- 2006-07-20 BR BRPI0613680-0A patent/BRPI0613680A2/en not_active IP Right Cessation
- 2006-07-20 CN CNA2006800267270A patent/CN101228175A/en active Pending
- 2006-07-20 KR KR1020087001654A patent/KR20080036585A/en not_active Withdrawn
- 2006-07-20 EP EP06762703A patent/EP1907405A1/en not_active Withdrawn
- 2006-07-20 JP JP2008521882A patent/JP2009502755A/en not_active Ceased
- 2006-07-20 CA CA002615860A patent/CA2615860A1/en not_active Abandoned
- 2006-07-20 WO PCT/EP2006/007108 patent/WO2007009772A1/en not_active Ceased
-
2008
- 2008-01-21 IL IL188900A patent/IL188900A0/en unknown
- 2008-01-21 NO NO20080377A patent/NO20080377L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1907405A1 (en) | 2008-04-09 |
| IL188900A0 (en) | 2008-04-13 |
| JP2009502755A (en) | 2009-01-29 |
| RU2008102251A (en) | 2009-07-27 |
| BRPI0613680A2 (en) | 2011-01-25 |
| NZ565265A (en) | 2010-01-29 |
| MX2008000968A (en) | 2008-03-26 |
| CN101228175A (en) | 2008-07-23 |
| KR20080036585A (en) | 2008-04-28 |
| WO2007009772A1 (en) | 2007-01-25 |
| ITMI20051418A1 (en) | 2007-01-23 |
| CA2615860A1 (en) | 2007-01-25 |
| NO20080377L (en) | 2008-02-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1 | Application lapsed section 142(2)(a) - no request for examination in relevant period |