WO2007009772A1 - Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity - Google Patents

Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity Download PDF

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WO2007009772A1
WO2007009772A1 PCT/EP2006/007108 EP2006007108W WO2007009772A1 WO 2007009772 A1 WO2007009772 A1 WO 2007009772A1 EP 2006007108 W EP2006007108 W EP 2006007108W WO 2007009772 A1 WO2007009772 A1 WO 2007009772A1
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exch
aminothiocolchicine
demethoxy
meoh
nmr
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PCT/EP2006/007108
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French (fr)
Inventor
Gabriele Fontana
Ezio Bombardelli
Antonella Riva
Paolo Morazzoni
Donato Pocar
Maria Luisa Gelmi
Guido Pontremoli
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Indena S.P.A.
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Priority to EP06762703A priority Critical patent/EP1907405A1/en
Priority to AU2006271923A priority patent/AU2006271923A1/en
Priority to NZ565265A priority patent/NZ565265A/en
Priority to MX2008000968A priority patent/MX2008000968A/en
Priority to CA002615860A priority patent/CA2615860A1/en
Priority to JP2008521882A priority patent/JP2009502755A/en
Priority to BRPI0613680-0A priority patent/BRPI0613680A2/en
Publication of WO2007009772A1 publication Critical patent/WO2007009772A1/en
Priority to IL188900A priority patent/IL188900A0/en
Priority to NO20080377A priority patent/NO20080377L/en

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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
    • C07H15/20—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

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  • the present invention relates to S-demethoxy-S-aminothiocolchicine derivatives with myorelaxant and anti-inflammatory activity.
  • Technological background 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 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 myorelaxant and decontracting properties still raises remarkable interest from the clinical point of view.
  • colchicine is a pseudoalkaloid widely used for a long time in therapy for the treatment of gout. Also widely used in therapy is
  • thiocolchicoside a colchicine derivative in which the C 10 bears a thiomethyl group and the hydroxy group at the 3- position is etherified with a glucose molecule
  • thiocolchicoside a colchicine derivative in which the C 10 bears a thiomethyl group and the hydroxy group at the 3- position is etherified with a glucose molecule
  • the present invention relates to 3-demethoxy-3-aminothiocolchicine glycosyl derivatives of general formula (I)
  • R is hydrogen, methyl or hydroxymethyl.
  • L- glycopyranosides of S-demethoxy-S-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)
  • R 2 is hydrogen, methyl, -CH 2 -O-R 3 ;
  • R 3 is hydrogen or a hydroxy-protecting group.
  • X groups fluorine and bromine are preferred.
  • protective groups the acetyl group is preferred.
  • 3-Demethoxy-3-aminothiocolchicine (II) is prepared from 3-O-demethylthiocolchicine triflate, tosylate or mesylate by Buchwald reaction as disclosed by Clark D. et al. in WO 00/35865.
  • 3-demethoxy-3-aminothiocolchicine is reacted with a 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.
  • the hydrolysis of the protecting groups can be carried out directly also on the reaction crude without recovery of the intermediates.
  • 3-demethoxy-3-aminothiocolchicine is reacted with a suitable glycoside in a polar protic solvent preferably selected from alcohols, such as MeOH, at 110 0 C, and with 150 watt power.
  • a suitable glycoside in a polar protic solvent preferably selected from alcohols, such as MeOH, at 110 0 C, and with 150 watt power.
  • the reaction is generally completed after 3 hours.
  • the compound of formula II proved to be active and therefore the invention relates also to the use of this compound for the preparation of medicaments with myorelaxant activity.
  • 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., Mack Pub., N. Y., U.S.A..
  • 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 melting points were measured using a Buchi 510 apparatus.
  • NMR spectra were obtained with a Bruker AC 500 instrumentation.
  • the IR spectra were obtained with a Jasco IR Report 100 spectrophotometer.
  • the reactions were carried out in a Milstone Micro SYNTH microwave oven.
  • Triflic anhydride (1.24 ml, 7.40 mmoles) was added under nitrogen atmosphere at 0 0 C to a solution of S-O-demethylthiocolchicine (2 g, 4.98 mmoles) and p-OMAP (1.77 g, 15.78 mmoles) in anhydrous CH 2 Cl 2 (50 mL).
  • the reaction mixture was stirred for 45 minutes at room temperature, then heated at 120 0 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 imino adduct was dissolved in MeOH (15 ml) at room temperature.
  • the solution was added with AcONa (509 mg, 6.21 mmoles) 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.
  • Method A A solution of 3-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 sealed tube at 8O 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 chromatography on silica gel (100: 1 to 100:5 CH 2 Cl 2 /MeOH) then crystallised from MeOH/ /Pr 2 O to obtain the desired compounds.
  • Method B A solution of 3-O-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 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).

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Abstract

The present invention relates to 3-demethoxy-3-aminothiocolchicine glycosyl derivatives of general formula (I) in which R is hydrogen, methyl or hydroxymethyl. The compounds of formula (I) have myorelaxant and anti-inflammatory activity.

Description

THIOCOLCHICOSIDE ANALOGUES WITH MYORELAXANT AND ANTI-INFLAMMATORY ACTIVITY
Field of the invention
The present invention relates to S-demethoxy-S-aminothiocolchicine derivatives with myorelaxant and anti-inflammatory activity.
Technological background 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 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 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-thiocolchicine glucoside, known as thiocolchicoside (a colchicine derivative in which the C10 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 strychnine-sensitive glycine receptors and therefore that compounds endowed 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 glycosyl derivatives of general formula (I)
Figure imgf000003_0001
in which
R is hydrogen, methyl or hydroxymethyl. Alpha and beta anomers of pentose and hexose D- and
L- glycopyranosides of S-demethoxy-S-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)
Figure imgf000003_0002
with a protected glycopyranoside of formula (III)
Figure imgf000003_0003
wherein X is OH, F, Cl, Br, I5
R2 is hydrogen, methyl, -CH2-O-R3;
R3 is hydrogen or a hydroxy-protecting group.
Among the X groups, fluorine and bromine are preferred. Among the protective groups, the acetyl group is preferred.
3-Demethoxy-3-aminothiocolchicine (II) is prepared from 3-O-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 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 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 1100C, 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 ^strychnine as ligand. The results suggest that the derivatives behave as allosteric compounds on the strychnine-sensitive glycine receptors of the 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 invention relates also to the use of this compound for the preparation of medicaments with myorelaxant activity.
Figure imgf000005_0001
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., 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 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 reactions were carried out in a Milstone Micro SYNTH microwave oven.
[tt]25° 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 atmosphere at 00C to a solution of S-O-demethylthiocolchicine (2 g, 4.98 mmoles) and p-OMAP (1.77 g, 15.78 mmoles) in anhydrous CH2Cl2 (50 mL).
Stirring was continued at O0C for 20 hours and then at room temperature for 3 hours. The reaction was monitored by TLC analysis (10: 1 CH2Cl2/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 CH2Cl2/MeOH mixture (increasing polarity gradient). The product (1.84 g, 70%) was obtained as yellow solid after crystallization from ethanol: mp 140-1420C; IR (Nujol) vmax 1667, 1620 cm"1; [α]25 D - 60° (c 0.9, CHCl3), 1H NMR (CDCl3): δ 7.94 (d, J = 7 Hz, IH), 7.44 (s, IH), 7.28. 7.09 (AB system, J = 10.4 Hz, IH), 6.84 (s, IH), 4.65-4.55 (m, IH), 4.05 (s, 3H), 3.68 (s, 3H), 2.63-2.54 (m, IH), 2.45 (s, 3H), 2.39-2.25 (m, 2H), 1.98 (s, 3H), 1.90-1.80 (m, 2H); 13C NMR (CDCl3): δ 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
Cs2CO3 (685 mg, 2.09 mmoles), Pd(OAc)2 (68 mg, 0.29 mmoles), (±)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 400C 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 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 1200C for 16 hours and monitored by TLC analysis (20: 1 CH2Cl2/MeOH). The mixture was cooled to room temperature, diluted with AcOEt, filtered and concentrated under reduced pressure. The crude product containing the desired imino adduct was dissolved in MeOH (15 ml) at room temperature. The solution was added with AcONa (509 mg, 6.21 mmoles) and NH2OH HCl (323 mg, 4.65 mmoles). After 30 minutes, the mixture was diluted with CH2Cl2 (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 extracted with CH2Cl2 (3x20 ml). The organic phase was dried over Na2SO4 and concentrated under pressure to give the desired product (TLC 10: 1.5 CH2Cl2/MeOH Rf 0.43) which was then crystallized from EtOH (373 mg, 60%): mp 280-2820C. [α]25 D - 292° (c 0.5, CHCl3); IR (Nujol) vmax 3340, 1667, 1620 cm'1; 1H NMR (CDCl3): δ 7.38 (s, IH), 7.33, 7.09 (AB system, J = 10.2 Hz, IH), 6.37 (s, IH), 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); 13C NMR (CDCl3): δ 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, 1 10.8. 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 (1 mmole) and the mixture was heated in a sealed tube at 8O0C for 6 days. The reaction was monitored by TLC analysis (10:1.5 CH2Cl2/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 chromatography on silica gel (100: 1 to 100:5 CH2Cl2/MeOH) then crystallised from MeOH/ /Pr2O to obtain the desired compounds.
Method B. A solution of 3-O-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 for 4 hours at 1 100C and 150 watt. The reaction was monitored by TLC analysis (10: 1.5 CH2Cl2/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 CH2Cl2/MeOH) and recrystallized from MeOH//Pr2O to obtain the desired compounds.
The following table reports the yields and diastereoselection of the processes.
Figure imgf000009_0001
Example 4. 3-7V-α-D-Glucopyranosyl-3-O-demethoxy-3- aminothiocolchicine
TLC Rf 0.30 (5: 1 CH2Cl2MeOH). IR (Nujol) vmax 1667, 1620 cm"1; 1H
NMR (DMSO): δ 8.63 (d, J - 7.6 Hz, IH, exch), 7.25, 7.18 (AB system, J = 10.3 Hz, 2H), 7.01 (s, IH), 6.76 (s, IH), 5.58 (d, J = 3.8 Hz, IH, exch), 5.36
(bs, IH, exch), 5.22 (bs, IH, exch), 4.91 (dd, J = 5.0. 3.8 Hz, IH), 4.41-4.35
(m, IH), 3.83 (s, 3H), 3.73-3.64 (m, IH), 3.64-3.57 (m, IH), 3.51 (s, 3H),
3.50-3.40 (m, IH), 3.19-3.10 (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); 13C NMR (DMSO): δ 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. S-Λ'-β-D-Glucopyranosyl-S-O-demethoxy-S- aminothiocolchicine TLC Rf 0.37 (5: 1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm'1; 1H
NMR (DMSO): δ 8.63 (d, J = 7.6 Hz, IH, exch), 7.26, 7.15 (AB system, J = 10.3 Hz, 2H), 7.01 (s, IH), 6.48 (s, IH), 5.78 (d, J = 6.5 Hz, IH, 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), 3.73-3.64 (m, IH), 3.64-3.57 (m, IH), 3.52 (s, 3H), 3.50-3.40 (m, IH), 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); 13C 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, 23.3, 14.8; MS m/z 563.2 (MH+).
Example 6. 3-./V-α-D-Arabinopyranosyl-3-0-demethoxy-3- aminothiocolchicine
TLC Rf 0.37 (5 : 1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm"1; 1H NMR (DMSO): δ 8.59 (d, J = 8.7 Hz, IH exch), 7.25, 7.18 (AB system, J =
10.4 Hz, IH), 7.01 (s, IH), 6.49 (s, IH), 6.01 (d, J = 9.8 Hz, IH exch), 5.77 (d, J = 6.1 Hz, IH exch), 5.48 (d, J = 4.2 Hz, IH exch), 5.29 (d, J = 4.4 Hz, IH exch), 4.93 (dd, J = 9.8. 3.5 Hz, IH), 4.41-4.32 (m, IH), 3.78 (m, 3H), 3.68-3.64 (m, IH), 3.62-3.57 (m, 3H), 3.52 (s, 3H), 3.46-3.37 (m, IH), 2.55- 2.48 (m, IH), 2.41 (s, 3H), 2.21-2.16 (m, IH), 2.05- 1.98 (m, IH), 1.86- 1.78 (m, IH), 1.85 (s, 3H); 13C 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+). Example 7. 3-7V-β-D-Arabinopyranosyl-3-0-demethoxy-3- aminothiocolchicine
TLC R/ 0.30 (5 : 1 CH2Cl2MeOH). IR (Nujol) vmax 1667, 1620 cm-1; 1H NMR (DMSO):δ 8.56 (d, J = 7.7 Hz, IH exch), 7.26, 7.18 (AB system, J =
10.5 Hz, IH), 7.01 (s, IH), 6.45 (s, IH), 6.21 (d, J = 8.3 Hz, IH exch), 5.57 (d, J = 9.2 Hz, IH exch), 5.51 (d, J = 5.6 Hz, IH exch), 4.61 (dd, J = 8.3, 4.8
Hz, IH), 4.57 (d, J = 6.1 Hz, IH exch), 4.41-4.32 (m, IH), 3.80 (s, 3H), 3.68-3.64 (m, IH), 3.62-3.57 (m, 3H), 3.52 (s, 3H), 3.46-3.37 (m, IH), 2.55-2.48 (m, IH), 2.41 (s, 3H), 2.21-2.16 (m, IH), 2.05- 1.98 (m, IH), 1.86- 1.78 (m, IH), 1.84 (s, 3H); 13C NMR (DMSO) δ 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+).
Example 8. 3-7V- α-D-Lyxopyranosyl-3-0-demethoxy-3- aminothiocolchicine TLC R/ 0.37 (5 : 1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm"1; 1H
NMR (DMSO): δ 8.58 (d, J = 7.6 Hz, IH, exch), 7.26, 7.17 (AB system, J = 10.7 Hz, 2H), 7.03 (s, IH), 6.45 (s, IH), 5.68 (d, J = 7.1 Hz, IH exch), 5.18 (d, J = 4.5 Hz, IH exch), 4.95 (d, J = 3.9 Hz, IH exch), 4.83 (d, J = 7.1 Hz, IH exch), 4.72 (dd, J = 8.4. 7.1 Hz, IH), 4.40-4.36 (m, IH), 3.81 (s, 3H), 3.75-3.72 (m, 2H), 3.52 (s, 3H), 3.55-3.51 (m, IH), 20-3.16 (m, IH), 3.18- 3.15 (m, IH), 2.56-2.48 (m, IH), 2.41 (s, 3H), 2.24-2.15(m, IH), 2.07-1.95 (m, 2H), 1.86-1.78 (m, IH), 1.84 (s, 3H); 13C NMR (DMSO) d 181.6, 168.9, 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. 3-7V-β-D-Lyxopyranosyl-3-0-demethoxy-3- aminothiocolchicine TLC Rf 0.30 (5: 1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm"1; 1H
NMR (DMSO): δ 8.59 (d, J = 7.3 Hz, IH, exch), 7.25, 7.15 (AB system, J = 10.4 Hz, 2H), 7.03 (s, IH), 6.48 (s, IH), 6.13 (d, J= 8.9 Hz, H, exch), 5.06 (d, J = 5.5 Hz, IH exch), 4.90 (dd, J = 8.9, 2.7 Hz, IH), 4.86 (d, J = 4.5 Hz, IH exch), 4.40-4.36 (m, IH), 3.82-3.79 (m, 2H), 3.79 (s, 3H), 3.62-3.58 (m, IH), 3.52 (s, 3H), 3.55-3.51 (m, IH), 3.49-3.46 (m, IH), 3.18-3.15 (m, IH), 2.56- 2.48 (m, IH), 2.41 (s, 3H), 2.24-2.15(m, IH), 2.07-1.95 (m, 2H), 1.86-1.78 (m, IH), 1.84 (s, 3H); 13C NMR (DMSO) δ: 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+). Example 10. 3-7V-α-D-Xylopyranosyl-3-0-demethoxy-3- aminothiocolchicine
TLC Rf 0.30 (5: 1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm"1; 1H NMR (DMSO): δ 8.65-8.56 (m, IH exch), 7.25, 7.17 (AB system, J= 10.6 Hz, 2H), 7.02 (s, IH), 6.55 (s, IH), 5.46 (d, J = 5.9 Hz, IH exch), 5.32 (d, J = 5.6 Hz, IH exch), 5.21 (bs, IH exch), 5.05 (d, J = 5.4 Hz, IH exch), 4.88 (dd, J = 5.9, 3.8 Hz, IH), 4.42-4.35 (m, IH), 3.82 (s, 3H), 3.70-3.50 (m, 2H), 3.51 (s, 3H), 3.40-3.30 (m, IH), 3.30-3.20 (m, 2H), 2.57-2.50 (m, IH), 2.50 (s, 3H), 2.21-2.12 (m, IH), 2.07-1.97 (m, IH), 1.86-1.78 (m, IH), 1.85 (s, 3H), 13C NMR (DMSO) δ 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. 3-7V-β-D-Xylopyranosyl-3-O-demethoxy-3- aminothiocolchicine
TLC R/ 0.37 (5: 1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm-1; 1H NMR (DMSO) δ 8.65-8.56 (m, IH exch), 7.25, 7.17 (AB system, J= 10.6 Hz, 2H), 7.02 (s, IH), 6.46 (s, IH), 5.81 (d, J = 7.2 Hz, IH exch), 5.52 (t, J = 5.3 Hz, 0.06H6T exch), 5.11 (bs, 2H exch), 4.99 (d, J = 4.8 Hz, IH exch), 4.42-4.35 (m, IH), 4.41 (dd, J= 7.8. 7.2 Hz, IH), 3.79 (s, 3H), 3.70-3.50 (m, 2H), 3.49 (s, 3H), 3.40-3.30 (m, IH), 3.30-3.20 (m, 2H), 2.57-2.50 (m, IH), 2.50 (s, 3H), 2.21-2.12 (m, IH), 2.07-1.97 (m, IH), 1.86-1.78 (m, IH), 1.84 (s, 3H); 13C NMR (DMSO) δ 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, 61.0. 51.9, 36.3, 29.8. 22.9, 14.8; MS m/z 533.3 (MH+).
Example 12. 3-7V-α-L-Rhamnopyranosyl-3-O-demethoxy-3- aminothiocolchicine
TLC R/ 0.30 (10:2 CH2Cl2-MeOH). Mp 185-188°C; [α]25 D- 299° (c 0.4. MeOH); IR (Nujol) vmax 1667, 1620 cm"1; 1H-NMR (DMSO) λ 8.58 (d, J= 7.3 Hz, 1H exch), 7.27, 7.14 (AB system, J = 10.5 Hz, 2H), 7.02 (s, IH), 6.49 (s, IH), 5.64 (d, J = 9.8 Hz, IH exch), 5.12 (d, J= 4.4 Hz, IH exch), 4.84 (d, J = 10.2 Hz, IH exch), 4.79 (brs, 2H exch), 4.41-4.38 (m, IH), 3.80 (s, 3H), 3.79-3.78 (m, IH), 3.51 (s, 3H), 3.45-3.15 (m, 3H), 2.55-2.47 (m, IH), 2.40 (s, 3H), 2.22-2.17 (m, IH), 2.06-1.97 (m, IH). 1.85 (s, 3H), 1.84-1.81 (m, IH), 1.11 (d, J = 5.6 Hz, 3H); 13C NMR (DMSO): δ 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+). Example 13. 3-iV-β-D-Mannopyranosyl-3-O-demethoxy-3- aminothiocolchicine
TLC Rf 0.21 (10:2 CH2Cl2-MeOH). M.p. 165-1670C; [α]25 D -395° (c 0.44. MeOH); IR (Nujol) vmax 1667, 1620 cm-1; 1H NMR (DMSO) λ 8.59 (d, J = 7.5 Hz, IH, exch), 7.25, 7.16 (AB system, J = 10.3 Hz, 2H), 7.01 (s, IH), 6.48 (s, IH), 5.72 (d, J = 10.0 Hz, IH, exch), 5.13 (d, J = 5.2 Hz, IH, exch), 4.80 (d, J = 5.4 Hz, IH, exch), 4.82 (d, J = 10 Hz, IH), 4.76 (d, J= 5.0 Hz, IH, exch), 4.43 (t, J = 6.1 Hz, IH, exch), 4.42-4.33 (m, IH), 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, IH), 2.52-2.45 (m, IH), 2.42 (s, 3H), 2.20-2.15 (m, IH), 2.05-1.98 (m, IH), 1.84-1.78 (m, IH), 1.86 (s, 3H); 13C NMR (DMSO) δ 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. Example 14. 3-Λ^-β-L-Fucopyranosyl-3-O-demethoxy-3- aminothiocolchicine
TLC R/ 0.30 (5: 1 CH2Cl2/MeOH). M.p. 185-188°C; [α]25 D -299° (c 0.4. MeOH); IR (Nujol) vmax 1667, 1620 cm"1; 1H-NMR (DMSO): δ 8.60 (d, J = 7.3 Hz, IH exch), 7.26, 7.17 (AB system, J = 10.3 Hz, 2H), 7.02 (s, IH), 6.46 (s, IH), 5.65 (d, J = 6.6 Hz, IH exch), 4.94 (d, J = 6.6 Hz, IH exch), 4.74 (d, J = 5.5 Hz, IH exch), 4.40 (d, J = 5.1 Hz, IH exch), 4.40-4.35 (m, IH), 4.36 (dd, J = 8.6, 6.6 Hz, IH), 3.81 (s, 3H), 3.75-3.65 (m, IH), 3.70-3.38 (m, 5H), 3.65-3.50 (m, 2H), 3.51 (s, 3H), 3.50-3.40 (m, IH), 2.55-2.47 (m, IH), 2.40 (s, 3H), 2.22-2.17 (m, IH), 2.06-1.97 (m, IH). 1.88-1.78 (m, IH), 1.84 (s, 3H), 1.10 (d, J = 6.1 Hz, 3H); 13C NMR (DMSO): δ 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

1. Compounds of general formula (I)
Figure imgf000015_0001
wherein
R is hydrogen, methyl or hydroxymethyl.
2. A compound selected from: S-N-D-xylopyranosyl-S-O-demethoxy-S-aminothiocolchicine; 3-N-D-glucopyranosyl-3-O-demethoxy-3-aminothiocolchicine;
S-N-D-mannopyranosyl-S-O-demethoxy-S-aminothiocolchicine;
S-N-D-arabinopyranosyl-S-O-demethoxy-S-aminothiocolchicine;
3-N-D-lyxopyranosyl-3-0-demethoxy-3-aminothiocolchicine;
S-N-L-rhamnopyranosyl-S-O-demethoxy-S-aminothiocolchicine; 3-N-L-fucopyranosyl-3-O-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.
5. Use of the compound of formula (II)
Figure imgf000015_0002
for the preparation of medicaments with myorelaxant activity.
PCT/EP2006/007108 2005-07-22 2006-07-20 Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity WO2007009772A1 (en)

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WO2010138670A3 (en) * 2009-05-27 2011-03-24 Mutual Pharmaceutical Company, Inc. Thiocolchicine derivatives, method of making and methods of use thereof
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EP0870761A1 (en) * 1997-04-11 1998-10-14 INDENA S.p.A. Thiocolchicine derivatives with antiinflammatory and muscle relaxant activities
WO2004111068A1 (en) * 2003-06-06 2004-12-23 Indena S.P.A. Colchicoside analogues

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EP0870761A1 (en) * 1997-04-11 1998-10-14 INDENA S.p.A. Thiocolchicine derivatives with antiinflammatory and muscle relaxant activities
WO2004111068A1 (en) * 2003-06-06 2004-12-23 Indena S.P.A. Colchicoside analogues

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WO2010138670A3 (en) * 2009-05-27 2011-03-24 Mutual Pharmaceutical Company, Inc. Thiocolchicine derivatives, method of making and methods of use thereof

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