WO2007009772A1 - Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity - Google Patents
Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity Download PDFInfo
- Publication number
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- exch
- aminothiocolchicine
- demethoxy
- meoh
- nmr
- Prior art date
Links
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
Definitions
- 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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- 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)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0613680-0A BRPI0613680A2 (en) | 2005-07-22 | 2006-07-20 | thiocolchicoside analogues, pharmaceutical compositions and their uses |
CA002615860A CA2615860A1 (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
NZ565265A NZ565265A (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
EP06762703A EP1907405A1 (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
AU2006271923A AU2006271923A1 (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
JP2008521882A JP2009502755A (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with muscle relaxant and anti-inflammatory effects |
MX2008000968A MX2008000968A (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity. |
IL188900A IL188900A0 (en) | 2005-07-22 | 2008-01-21 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
NO20080377A NO20080377L (en) | 2005-07-22 | 2008-01-21 | Thiocochicoside analogues with myorelaxative and anti-inflammatory activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2005A001418 | 2005-07-22 | ||
IT001418A ITMI20051418A1 (en) | 2005-07-22 | 2005-07-22 | ANALOGUES OF THIOILCYCOSIDE WITH HYDRO-LASER ACTIVITY AND ANTI-INFLAMMATORY |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007009772A1 true WO2007009772A1 (en) | 2007-01-25 |
Family
ID=37420844
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2006/007108 WO2007009772A1 (en) | 2005-07-22 | 2006-07-20 | Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1907405A1 (en) |
JP (1) | JP2009502755A (en) |
KR (1) | KR20080036585A (en) |
CN (1) | CN101228175A (en) |
AU (1) | AU2006271923A1 (en) |
BR (1) | BRPI0613680A2 (en) |
CA (1) | CA2615860A1 (en) |
IL (1) | IL188900A0 (en) |
IT (1) | ITMI20051418A1 (en) |
MX (1) | MX2008000968A (en) |
NO (1) | NO20080377L (en) |
NZ (1) | NZ565265A (en) |
RU (1) | RU2008102251A (en) |
WO (1) | WO2007009772A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010138670A3 (en) * | 2009-05-27 | 2011-03-24 | Mutual Pharmaceutical Company, Inc. | Thiocolchicine derivatives, method of making and methods of use thereof |
JP2012503801A (en) * | 2008-09-24 | 2012-02-09 | マイクロソフト コーポレーション | Object detection and user settings |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2526086A2 (en) * | 2010-01-22 | 2012-11-28 | Mutual Pharmaceutical Company, Inc. | Thiocolchicine and colchicine analogs, methods of making and methods of use thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
-
2005
- 2005-07-22 IT IT001418A patent/ITMI20051418A1/en unknown
-
2006
- 2006-07-20 NZ NZ565265A patent/NZ565265A/en unknown
- 2006-07-20 RU RU2008102251/04A patent/RU2008102251A/en not_active Application Discontinuation
- 2006-07-20 MX MX2008000968A patent/MX2008000968A/en unknown
- 2006-07-20 AU AU2006271923A patent/AU2006271923A1/en not_active Abandoned
- 2006-07-20 KR KR1020087001654A patent/KR20080036585A/en not_active Application Discontinuation
- 2006-07-20 EP EP06762703A patent/EP1907405A1/en not_active Withdrawn
- 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 CA CA002615860A patent/CA2615860A1/en not_active Abandoned
- 2006-07-20 WO PCT/EP2006/007108 patent/WO2007009772A1/en not_active Application Discontinuation
- 2006-07-20 JP JP2008521882A patent/JP2009502755A/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
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012503801A (en) * | 2008-09-24 | 2012-02-09 | マイクロソフト コーポレーション | Object detection and user settings |
WO2010138670A3 (en) * | 2009-05-27 | 2011-03-24 | Mutual Pharmaceutical Company, Inc. | Thiocolchicine derivatives, method of making and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
RU2008102251A (en) | 2009-07-27 |
NO20080377L (en) | 2008-02-01 |
CN101228175A (en) | 2008-07-23 |
JP2009502755A (en) | 2009-01-29 |
AU2006271923A1 (en) | 2007-01-25 |
ITMI20051418A1 (en) | 2007-01-23 |
BRPI0613680A2 (en) | 2011-01-25 |
IL188900A0 (en) | 2008-04-13 |
EP1907405A1 (en) | 2008-04-09 |
MX2008000968A (en) | 2008-03-26 |
CA2615860A1 (en) | 2007-01-25 |
NZ565265A (en) | 2010-01-29 |
KR20080036585A (en) | 2008-04-28 |
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