NZ565265A

NZ565265A - Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity

Info

Publication number: NZ565265A
Application number: NZ565265A
Authority: NZ
Inventors: Gabriele Fontana; Ezio Bombardelli; Antonella Riva; Paolo Morazzoni; Donato Pocar; Maria Luisa Gelmi; Guido Pontremoli
Original assignee: Indena Spa
Priority date: 2005-07-22
Filing date: 2006-07-20
Publication date: 2010-01-29
Also published as: EP1907405A1; IL188900A0; JP2009502755A; AU2006271923A1; RU2008102251A; BRPI0613680A2; MX2008000968A; CN101228175A; KR20080036585A; WO2007009772A1; ITMI20051418A1; CA2615860A1; NO20080377L

Abstract

The disclosure relates to compounds of the general formula (I) wherein R is hydrogen, methyl or hydroxymethyl. These compounds of formula (I) have myorelaxant and anti-inflammatory activity.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 565265 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-thiocolchicine glucoside, known as thiocolchicoside (a colchicine 20 derivative in which the Ci0 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 COPIE DE CONFIRMATION WO 2007/009772 565265 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 glycosyl derivatives of general formula (I) in which R is hydrogen, methyl or hydroxymethyl. 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) oh (II) with a protected glycopyranoside of formula (III) r3 r2 r3' (III) wherein WO 2007/009772 PCT/EP2006/007108 3 X is OH, F, CI, Br, I, R2 is hydrogen, methyl, -CH2-0-R3; R3 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-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 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 110°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 [3H]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 1 -o vh h Wa fw = 400 l c21h24n204s 39.91 ±0.54 2 ""i ho,. aq hc/V^n k oh li /•"' n /0 Li fw = 562 ° c27h34n209s 10.55 ± 0.35 3 /~°\ h 9\ ho-/ y— )—( ] T /'"n ho oh a^a J h 'Tqo fw = 546 \ c27h34n208s z55 4.22 ± 0.44 4 hov~o "h 0h fth'n^ i J ( \° fw = 532 c26h32n208s 3.25 ± 0.57 5 .oh ho, i oh | /"'n ?VV4k ' wA fw = 562 ^==^"0 c27h34n209s 13.12 ± 0.77 6 hov^o oh i n J h °Tq fw = 532 c26h32n208s yS 8.61 ± 1.25 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. [c]25D 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-O-demethylthiocolchicine (2 g, 4.98 mmoles) and />-DMAP (1.77 g, 15.78 mmoles) in anhydrous CH2C12 (50 mL). Stirring was continued at 0°C for 20 hours and then at room temperature for 3 hours. The reaction was monitored by TLC analysis (10:1 25 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 C^CVMeOH 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"1; [<x]25D - 60° (c 0.9, CHC13), 'H NMR (CDCI3): 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 (m, 1H), 4.05 (s, 3H), 3.68 (s, 3H), 2.63-2.54 (m, 1H), 2.45 (s, 3H), 2.39-2.25 (m, 2H), 1.98 (s, 3H), 5 1.90-1.80 (m, 2H); 13C NMR (CDC13): 5 181.8. 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), 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 CH2Cl2/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 mmoles) and NH2OH HCI (323 mg, 4.65 mmoles). After 30 minutes, the mixture was diluted with CH2CI2 (5 ml) and acidified to pH 2 with 2N HC1. The organic phase was separated, the aqueous phase was alkalinized with a 25% NaOH solution and 25 extracted with CH2CI2 (3x20 ml). The organic phase was dried over Na2S04 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 280-282°C. [a]25D - 292° (c 0.5, CHC13); IR (Nujol) vmax 3340, WO 2007/009772 PCT/EP2006/007108 7 1667, 1620 on1; lH NMR (CDC13): 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); 13C NMR (CDC13): 8 182.7, 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 mmole) and the mixture was heated in a sealed tube at 80°C for 6 days. The reaction was monitored by TLC analysis (10:1.5 CH2Cl2/Me0H). 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 CH2Cl2/Me0H) then crystallised from Me0H//Pr20 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 110°C 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 25 CH2Cl2/MeOH) and recrystallized from Me0H/z'Pr20 to obtain the desired compounds. The following table reports the yields and diastereoselection of the processes. WO 2007/009772 565265 8 PCT/EP2006/007108 Name FORMULA Method A Method B Yield a/p Yield a/p 3-jV-d- glucopyranosyl-3-O- demethoxy-3- aminothiocolchicine 6h jl it /■"■n ?"VvV fw = 562 c27h34n209s 34 20:80 58 20:80 3-jV-l-fucopyranosyl- 3-<9-demethoxy-3- aminothiocolchicine )~°\ H H°vrNrY~>-»)_ ho oh h TTrxo fw = 546 \ c27h34n208s / 35 1:99 58 1:99 3-jV-d-xylopyranosyl- 3-0-demethoxy-3- aminothiocolchicine h0v~0 h 0H JL X /""nv 9' " ' ( i° fw = 532 c26h32n208s s 34 30:70 55 30:70 3-JV-d- mannopyranosyl-3-O-demethoxy-3 -aminothiocolchicine v: oh 1 >■■" n ?VyV fw = 532 ^^^o c27h34n209s 36 1:99 60 1:99 3-A-d- arabinopyranosyl-3- O-demethoxy-3- aminothiocolchicine HO"^o h0'rayy^ k oh 1 n .asa / h fw = 532 \° c26h32n208s 38 45:55 60 45:55 3-7V-d-lyxopyranosy]- 3-0-demethoxy-3- aminothiocolchicine no^o •"VWa °k oh n ?WH "° Li fw = 532 c26h32n208s 37 40:60 60 40:60 3-N-l- ramnopyranosyl-3-O- demethoxy-3- aminothiocolchicine "°A H0" \ ^ oh T if V"N ■Tci0 fw =546.64 s c27h34n208s ' 35 99:1 60 99:1 WO 2007/009772 PCT/EP2006/007108 9 Example 4. 3-7V-a-D-Glucopyranosyl-3-0-demethoxy-3- aminothiocolchicine TLC Rf 0.30 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm-1; 'H NMR (DMSO): 8 8.63 (d, J = 7.6 Hz, IH, exch), 7.25, 7.18 (AB system, J = 5 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, 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 10 (DMSO): 5 181.6, 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-A'-P-D-Glucopyranosyl-S-O-demethoxy-S- aminothiocolchicine 15 TLC Rf 0.37 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm-1; ]H NMR (DMSO): 8 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), 20 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, 25 23.3, 14.8; MS m/z 563.2 (MH+). Example 6, 3-7V-<x-D-Arabinopyranosyl-3-0-demethoxy-3-aminothiocolchicinc TLC Rf 0.37 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm-1; JH WO 2007/009772 PCT/EP2006/007108 10 NMR (DMSO): 8 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), 5 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); ,3C 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. 3-7V-P-D-Arabinopyranosyl-3-0-demethoxy-3- aminothiocolchicine TLC Rf 0.30 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm'1; 'H NMR (DMSO):8 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 15 (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) 8 181.6, 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 CH2Cl2/MeOH). IR (Nujol) vraax 1667, 1620 cm-1; *H ;NMR (DMSO): 8 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, .7=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, ;WO 2007/009772 PCT/EP2006/007108 ;11 ;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); l3C 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. 3-7V-P-D-Lyxopyranosyl-3-0-demethoxy-3- ;aminothiocolchicine 10 TLC fly 0.30 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm-1; !H ;NMR (DMSO): 5 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), 15 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) 5: 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-Af-a-D-Xylopyranosyl-3-0-demethoxy-3- ;aminothiocolchicine ;TLC Rf 0.30 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm-1; ]H NMR (DMSO): 5 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 25 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 ;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-/V-P-D-Xylopyranosyl-3-0-demethoxy-3- ;5 aminothiocolchicine ;TLC Rf 0.37 (5:1 CH2Cl2/MeOH). IR (Nujol) vmax 1667, 1620 cm'1; *H NMR (DMSO) 8 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, 0.06H6'f exch), 5.11 (bs, 2H exch), 4.99 (d, J = 4.8 Hz, IH exch), 10 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) 8 181.6, 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-iV-a-L-Rhamnopyranosyl-3-0-demethoxy-3-aminothiocolchicine TLC fly0.30 (10:2 CH2Cl2-MeOH). Mp 185-188°C; [a]25D- 299° (c 0.4. MeOH); IR (Nujol) vmax 1667, 1620 cm"1; 'H-NMR (DMSO) 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, 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), 25 1.11 (d, J = 5.6 Hz, 3H); 13C NMR (DMSO): 8 182.00. 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+). </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 2007/009772 PCT/EP2006/007108 13 Example 13. 3-/V-P-D-Mannopyranosyl-3-0-demethoxy-3-aminothiocolchicine TLC Rf 0.21 (10:2 CH2Cl2-MeOH). M.p. I65-167°C; [a]25D -395° (c 0.44. MeOH); IR (Nujol) vmax 1667, 1620 cm-1; *H NMR (DMSO) X 8.59 5 (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), 10 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) 8 181.6, 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. S-A^P-L-Fucopyranosyl-S-O-demethoxy-S- aminothiocolchicine TLC Rf 0.30 (5:1 CH2Cl2/MeOH). M.p. 185-188°C; [a]25° -299° (c 0.4. MeOH); IR (Nujol) vmax 1667, 1620 cm'1; 'H-NMR (DMSO): 8 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 20 (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, 25 3H), 1.10 (d, J = 6.1 Hz, 3H); ,3C 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+). wo 2007/009772 565265 14 pct/ep2006/007108 CLAIMS

1. Compounds of general formula (I) oh HO^ A. M yV h ho s (I) wherein R is hydrogen, methyl or hydroxymethyl.

2. A compound selected from: 3-jV-D-xylopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-Af-D-glucopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-iV-D-mannopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-7V-D-arabinopyranosyl-3-Odemethoxy-3-aminothiocolchicine; 3 -7V-D-lyxopyranosyl-3-0-demethoxy-3-aminothiocolchicine; 3-TV-L-rhamnopyranosyl-3-O-demethoxy-3-aminothiocolchicine; 3 -7V-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.

5. Use of the compound of formula (II) o h2n 0 / s (II) WO 2007/009772 565265 PCT/EP2006/007108 15 for the preparation of medicaments with myorelaxant activity. </div>