ITMI20000554A1 - Derivati di n-desacetiltiocolchicina e composizioni farmaceutiche cheli contengono - Google Patents
Derivati di n-desacetiltiocolchicina e composizioni farmaceutiche cheli contengono Download PDFInfo
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- ITMI20000554A1 ITMI20000554A1 IT2000MI000554A ITMI20000554A ITMI20000554A1 IT MI20000554 A1 ITMI20000554 A1 IT MI20000554A1 IT 2000MI000554 A IT2000MI000554 A IT 2000MI000554A IT MI20000554 A ITMI20000554 A IT MI20000554A IT MI20000554 A1 ITMI20000554 A1 IT MI20000554A1
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- derivatives
- thiocolchicine
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- pharmaceutical compositions
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- NUNCOHUMTCDISK-AWEZNQCLSA-N (7s)-7-amino-1,2,3-trimethoxy-10-methylsulfanyl-6,7-dihydro-5h-benzo[a]heptalen-9-one Chemical class C1([C@@H](N)CC2)=CC(=O)C(SC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC NUNCOHUMTCDISK-AWEZNQCLSA-N 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 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 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- LULCPJWUGUVEFU-UHFFFAOYSA-N Phthiocol Natural products C1=CC=C2C(=O)C(C)=C(O)C(=O)C2=C1 LULCPJWUGUVEFU-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 229960001338 colchicine Drugs 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- CMEGANPVAXDBPL-INIZCTEOSA-N n-[(7s)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(SC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC CMEGANPVAXDBPL-INIZCTEOSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 150000001279 adipic acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- -1 ampoules Substances 0.000 description 1
- 230000002634 anti-blastic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- RYPWQHONZWFXBN-UHFFFAOYSA-N dichloromethyl(methylidene)-$l^{3}-chlorane Chemical compound ClC(Cl)Cl=C RYPWQHONZWFXBN-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07C323/43—Y being a hetero atom
- C07C323/44—X or Y being nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo:
“DERIVATI DI N-DESACETILTIOCOLCHICINA E COMPOSIZIONI
FARMACEUTICHE CHE LI CONTENGONO”
La presente invenzione ha per oggetto derivati di N-desacetiltiocolchicina o del suo isostero di formula I
in cui:
n è un intero compreso tra 0 e 8;
Y è un gruppo CH2 oppure, quando n è 1 , può anche essere un gruppo di formula NH.
La colchicina e la tiocolchicina sono noti composti antiblastici capaci di destabilizzare i microtubuli per mezzo dell’interazione con la tubulina.
La colchicina è attualmente usata nella terapia della gotta e di stati infiammatori ad essa connessi ma il suo impiego è limitato alle fasi acute per una forte tossicità gastro-intestinale.
Sono stati studiati numerosi derivati di colchicina o tiocolchicina per un N-desacetil-tiocolchifina con N-idrossi-succinimide in presenza di ammine e di agenti condensanti quali dicicloesilcarbodiimmide (DCC), in un opportuno solvente aprotico, preferibilmente un idrocarburo clorurato (clofuro di. metilene, cloroformio). Gli stessi composti possono anche essere ottenuti come prodotti secondari della reazione fra N-idrossisuccinildiesteri di acidi bicarbossilici e N-desacetil-tiocolchicina.
L’attività di questi prodotti è stata verificata su un ampio numero di cellule tumorali e resistenti esprimenti il fenotipo MDR; questi composti sono risultati particolarmente attivi su diverse linee di colon sensibili esprimenti MDR. La tabella . riporta a titolo di esempio l’attività di questi due composti comparando l’attività biologica alla Tiocolchicina e al Taxolo come molecoje di riferimento.
TABELLA
Dai dati sopra riportati, risulta evidente l’elevata attività citotossica dei composti dell’invenzione nei confronti sia di linee cellulari sensibili sia a diverso grado di resistenza ai vari agenti antitumorali.
I composti dell’ invenzione sono pertanto utili nel trattamento di patologie su base proliferativa e in particolare di tumori di varia origine, di artrite reumatoide o di altre patologie deformanti in cui sia indicata un’azione antiproliferativa associata ad azione antiinfìammatoria.
A tale scopo, i composti I saranno somministrati sotto forma di composizioni farmaceutiche adatte alla somministrazione orale, parenterale, epicutanea o transdermica. A seconda della via di somministrazione, il dosaggio dei composti I potrà variare da 1 a 100mg/m di superficie corporea. La via di somministrazione preferita è quella orale.
Esempi di composizioni comprendono capsule, compresse, fiale, creme, soluzioni, granulari.
I seguenti Esempi illustrano l’invenzione in maggior dettaglio.
ESEMPIO 1
Preparazione del composto I in cui Y è CH2e n è 3.(Tiocol 39)
100 mg di N-desacetil tiocolchicina (P.M. = 373 g/mol, 0.27 mmoli) vengono sciolti in 6 mi di diossano anidro a temperatura ambiente sotto atmosfera di azoto. Si aggiungono 46 mg di acido adipico attivato come N-idrossi succinil diestere (P.M. = 340 g/mol, 0.135 mmoli), 40μ1 di trietilammina anidra (P.M. = 101 g/mol, d=0.726 g/ml, 0.27 mmoli).
Si lascia a temperatura ambiente sotto agitazione e sotto atmosfera di azoto per 48 ore (controllo in TLC: CHC13: MeOH = 95:5).
Si evapora il solvente. Il prodotto viene isolato in seguito a cromatografia flash su silice (eluente: CHC13 : MeOH = 75: 1).
Resa: 85%
ESEMPIO 2
Preparazione del composto 1 in cui Y è NH n è 1 (Tiocol 54)
A una soluzione di 1 g di Desacetil-tiocolchicina in 40 mi di CH2Cl2 anidro, si aggiungono 154 mg di N-idrossisuccinimmide, 276 mg di DCC e 476 μΐ di diisopropiletilammina.
Si lascia a ricadere e sotto azoto per almeno 2 giorni. Si controlla per TLC (CH2Cl2-EtOH-95/5) la reazione. Si concentra a piccolo volume e si riprende il residuo con Etil Acetato.
Si lascia cristallizzare il prodotto che viene ulteriormente purificato con flash cromatografia (eluente EtOAc - esano 7/3 oppure (CH2Cl2-EtOH=95/5). Si ottengono 500 mg di prodotto.
'H-NMR(DMSO-d6-300Mhz): 8,80 d; 7,82 br s; 7,75-7,60 S; 7,37;7,18; 6,59; 4,90 m; 4,66 m; 4,52 dd; 3,96 s ppm.
<13>C-NMR(CDCl3): 182,5; 181,9; 172,2; 158,0; 175,5; 157,1; 153,8; 153,7; 153; 152,3; 151,3, 151,2; 141,6; 141,5; 139,4; 139,3; 135,5; 135,5 d, 134,8; 134,7; 129,0; 128,4 (d).
MS(m/z) 866,4 [(M+Na)+J.
ESEMPIO 3
Preparazione del composto I in cui Y è CH2e n è 7 (Tiocol 33)
200 mg di N-desacetil tiocolchicina (P.M. = 373 g/mol, 0,54 mmoli) vengono sciolti in 12 mi di diossano anidro a temperatura ambiente sotto atmosfera di azoto. Si aggiungono 91 ,S mg di acido sebacico attivato come N-idrossi succinil diestere (P.M. = 396 g/moi, 0,27 mmoli), 75μ1 di trietilammina anidra (P.M. = 101 g/mol, d= 0,726 g/ml, 0,54 mmoli). Si lascia a temperatura ambiente sotto agitazione sotto atmosfera di azoto per 48 ore (controllo in TLC: CHCl3:MeOH = 95:5). Dopo 20 ore si scalda a 50 °C e la reazione è recuperata evaporando il solvente.
Il grezzo di reazione è purificato mediante cromatografia flash su silice (eluente: CHCl3:MeOH=40:l). Si ottengono 30 mg di una miscela del composto del titolo (con Rf:=0,3) e del composto dell’esempio 2.
ESEMPIO 4
Preparazione del composto I in cui Y è CH2 e n è 0 (Tiocol 43)
Metodologia A
190 mg di N-desacetil tiocolchicina (P.M. =373 g/mol, 0,512 mmoli) vengono sciolti in 6 mL di diossano anidro a temperatura ambiente sotto atmosfera di azoto. Si aggiungono 80 mg di acido succinico attivato come N-idrossi succimi diestere (P.M. = 312 g/mol, 0,256 mmoli), 70 μΐ di trietilammina anidra (P.M. = 101 g/mol, d=0,726 g/ml, 0,512mmoli).
Si lascia a temperatura ambiente sotto agitazione e sotto atmosfera di azoto per 48 ore (controllo in TLC: CHC13: MeOH = 95:5).
Si evapora il solvente. Si riprende con AcOET per eliminare la N-desacetil tiocolchicina residua e la trietilammina (il prodotto risulta insolubile).
Resa: 45%
Metodologia B
100 mg di N-desacetil-N-succinil-tiocolchicina (P.M. =473 g/mol, 0,21 mmoli) vengono sciolti in 8mL di CH2Cl2 anidro a temperatura ambiente sotto atmosfera di azoto. Si aggiungono 93 mg di BOP (P.M. = 442,3 g/mol, 0,21 mmoli), 60 μΐ di trietilammina anidra (P.M. = 101 g/mol, d=0,726 g/ml, 0,42 mmoli). Dopo 10 minuti si aggiungono 80 mg di N-desacetil tiocolchicina (P.M. = 101 g/mol, d=0,726 g/ml, 0,42 mmoli).
Si lascia a temperatura ambiente sotto agitazione e sotto atmosfera di azoto per 48 ore (controllo in TLC: CHCl3: MeOH = 95:5).
Si evapora il solvente. Si riprende con AcOET per eliminare la N-desacetil tiocolchicina residua e la trietilammina (il prodotto risulta insolubile).
Resa: 45%
Claims (5)
- RIVENDICAZIONI 1. Composti di formula Iin cui: n è un intero compreso tra 0 e 8; Y è un gruppo CH2 oppure, quando n è 1, può anche essere un gruppo di formula NH.
- 2. Composti secondo la rivendicazione 1 in cui Y è CH2.
- 3. Composizioni secondo la rivendicazione 1 in cui Y è NH.
- 4. Composizioni farmaceutiche contenenti un composto delle rivendicazioni 1-3.
- 5. Uso dei composti delle rivendicazioni 1-3 per la preparazione di medicamenti per il trattamento di tumori e di artrite reumatoide.
Priority Applications (24)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI000554A IT1318401B1 (it) | 2000-03-17 | 2000-03-17 | Derivati di n-desacetiltiocolchicina e composizioni farmaceutiche cheli contengono. |
| CA002403110A CA2403110C (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| RU2002124524/04A RU2257379C2 (ru) | 2000-03-17 | 2001-03-12 | Производные n-деацетилтиоколхицина и содержащие их фармацевтические композиции |
| DE60139306T DE60139306D1 (de) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchin-derivate und diese enthaltende arzneimittel |
| DK01921326T DK1263719T3 (da) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchin-derivater og farmaceutiske sammensætninger indeholdende disse. |
| KR1020027011947A KR100761577B1 (ko) | 2000-03-17 | 2001-03-12 | Ｎ-데아세틸티오콜히친 유도체 및 그를 함유한 약제학적조성물 |
| CNB018064833A CN1169788C (zh) | 2000-03-17 | 2001-03-12 | N-脱乙酰基硫代秋水仙素衍生物及包含其的药物组合物 |
| SK1310-2002A SK287108B6 (sk) | 2000-03-17 | 2001-03-12 | N-Deacetyltiokolchicínové deriváty, farmaceutický prostriedok s ich obsahom a ich použitie |
| HU0300557A HU228790B1 (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| IL15171501A IL151715A0 (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| JP2001567693A JP4614608B2 (ja) | 2000-03-17 | 2001-03-12 | Ｎ−デアセチルチオコルヒチン誘導体及びそれを含有する医薬組成物 |
| PL357375A PL201575B1 (pl) | 2000-03-17 | 2001-03-12 | Pochodne N-deacetylotiokolchicyny i kompozycje farmaceutyczne je zawierające |
| PT01921326T PT1263719E (pt) | 2000-03-17 | 2001-03-12 | Derivados de n-deacetiltiocolchicina e composições farmacêuticas contendo os mesmos |
| EP01921326A EP1263719B1 (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchine derivatives and pharmaceutical compositions containing them |
| ES01921326T ES2327386T3 (es) | 2000-03-17 | 2001-03-12 | Derivados de n-desacetiltiocolchicina y composiciones farmaceuticas que los contienen. |
| PCT/EP2001/002739 WO2001068597A1 (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| CZ20023083A CZ303386B6 (cs) | 2000-03-17 | 2001-03-12 | N-deacetylthiokolchicinové deriváty |
| AU4834101A AU4834101A (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| SI200130931T SI1263719T1 (sl) | 2000-03-17 | 2001-03-12 | Derivati n-deacetiltiokolhina in farmacevtski sestavki, ki jih vsebujejo |
| AU2001248341A AU2001248341B2 (en) | 2000-03-17 | 2001-03-12 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| US10/210,035 US6627774B2 (en) | 2000-03-17 | 2002-08-02 | N-deacetylthiocolchicine derivatives and pharmaceutical compositions containing them |
| IL151715A IL151715A (en) | 2000-03-17 | 2002-09-12 | History of N-de-acetylthiocolciccin and pharmaceutical preparations containing them |
| NO20024354A NO329428B1 (no) | 2000-03-17 | 2002-09-12 | N-deacetyltiocolchicin-derivater, farmasoytiske sammensetninger inneholdende dem og anvendelse derav |
| HK03104265A HK1052168A1 (en) | 2000-03-17 | 2003-06-16 | N-deacetylthiocolchincine derivatives and pharmaceutical compositions containing them. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI000554A IT1318401B1 (it) | 2000-03-17 | 2000-03-17 | Derivati di n-desacetiltiocolchicina e composizioni farmaceutiche cheli contengono. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI20000554A0 ITMI20000554A0 (it) | 2000-03-17 |
| ITMI20000554A1 true ITMI20000554A1 (it) | 2001-09-17 |
| IT1318401B1 IT1318401B1 (it) | 2003-08-25 |
Family
ID=11444502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT2000MI000554A IT1318401B1 (it) | 2000-03-17 | 2000-03-17 | Derivati di n-desacetiltiocolchicina e composizioni farmaceutiche cheli contengono. |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6627774B2 (it) |
| EP (1) | EP1263719B1 (it) |
| JP (1) | JP4614608B2 (it) |
| KR (1) | KR100761577B1 (it) |
| CN (1) | CN1169788C (it) |
| AU (2) | AU4834101A (it) |
| CA (1) | CA2403110C (it) |
| CZ (1) | CZ303386B6 (it) |
| DE (1) | DE60139306D1 (it) |
| DK (1) | DK1263719T3 (it) |
| ES (1) | ES2327386T3 (it) |
| HK (1) | HK1052168A1 (it) |
| HU (1) | HU228790B1 (it) |
| IL (2) | IL151715A0 (it) |
| IT (1) | IT1318401B1 (it) |
| NO (1) | NO329428B1 (it) |
| PL (1) | PL201575B1 (it) |
| PT (1) | PT1263719E (it) |
| RU (1) | RU2257379C2 (it) |
| SI (1) | SI1263719T1 (it) |
| SK (1) | SK287108B6 (it) |
| WO (1) | WO2001068597A1 (it) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6825236B2 (en) * | 2003-04-14 | 2004-11-30 | California Pacific Medical Center | Colchicine derivatives |
| ITMI20040164A1 (it) * | 2004-02-03 | 2004-05-03 | Indena Spa | Derivati di n.deacetiltiocolchicina loro uso e formulazioni farmaceutiche che li contengono |
| EP2896412A1 (en) * | 2005-02-18 | 2015-07-22 | Abraxis BioScience, LLC | Drugs with improved hydrophobicity for incorporation in medical devices |
| DK2301531T3 (en) * | 2005-02-18 | 2018-07-30 | Abraxis Bioscience Llc | COMBINATIONS AND WAYS FOR ADMINISTRATING THERAPEUTIC SUBSTANCES AND COMBINATION THERAPY |
| WO2008027055A1 (en) * | 2006-08-31 | 2008-03-06 | Abraxis Bioscience, Llc | Methods of inhibiting angiogenesis and treating angiogenesis-associated diseases |
| US20080280987A1 (en) * | 2006-08-31 | 2008-11-13 | Desai Neil P | Methods of inhibiting angiogenesis and treating angiogenesis-associated diseases |
| MX2011009452A (es) * | 2009-03-13 | 2011-11-29 | Abraxis Bioscience Llc | Terapia de combinacion con derivados tiocolchicina. |
| EP2924022A1 (en) * | 2014-03-27 | 2015-09-30 | INDENA S.p.A. | Amorphous form of a thiocolchicine derivative |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1359637A (fr) * | 1962-10-29 | 1964-04-30 | Roussel Uclaf | Dérivés de la cochicine et de la thiocolchicine et procédé de préparation |
| US4533675A (en) | 1984-04-17 | 1985-08-06 | The United States Of America As Represented By The Department Of Health And Human Services | Carbamates of colchicine for treatment of gout |
| DE68927479T2 (de) * | 1988-05-02 | 1997-04-03 | Phanos Tech Inc | Verbindungen, zusammensetzungen und verfahren zum binden von bio-affektions-substanzen an oberflächenmembranen von bioteilchen |
| US5433675A (en) * | 1993-11-29 | 1995-07-18 | Excelermatic Inc. | Traction roller transmission |
| IT1276996B1 (it) * | 1995-06-27 | 1997-11-04 | Indena Spa | Derivati della colchicina, loro uso e formulazioni che li contengono |
| IT1283110B1 (it) * | 1996-06-07 | 1998-04-07 | Indena Spa | Composti a scheletro colchicinico,loro uso come farmaci e composizioni che li contengono |
-
2000
- 2000-03-17 IT IT2000MI000554A patent/IT1318401B1/it active
-
2001
- 2001-03-12 AU AU4834101A patent/AU4834101A/xx active Pending
- 2001-03-12 EP EP01921326A patent/EP1263719B1/en not_active Expired - Lifetime
- 2001-03-12 KR KR1020027011947A patent/KR100761577B1/ko active IP Right Grant
- 2001-03-12 ES ES01921326T patent/ES2327386T3/es not_active Expired - Lifetime
- 2001-03-12 JP JP2001567693A patent/JP4614608B2/ja not_active Expired - Lifetime
- 2001-03-12 IL IL15171501A patent/IL151715A0/xx active IP Right Grant
- 2001-03-12 CA CA002403110A patent/CA2403110C/en not_active Expired - Lifetime
- 2001-03-12 CZ CZ20023083A patent/CZ303386B6/cs not_active IP Right Cessation
- 2001-03-12 RU RU2002124524/04A patent/RU2257379C2/ru active
- 2001-03-12 CN CNB018064833A patent/CN1169788C/zh not_active Expired - Lifetime
- 2001-03-12 AU AU2001248341A patent/AU2001248341B2/en not_active Expired
- 2001-03-12 PL PL357375A patent/PL201575B1/pl unknown
- 2001-03-12 HU HU0300557A patent/HU228790B1/hu unknown
- 2001-03-12 SI SI200130931T patent/SI1263719T1/sl unknown
- 2001-03-12 DK DK01921326T patent/DK1263719T3/da active
- 2001-03-12 SK SK1310-2002A patent/SK287108B6/sk not_active IP Right Cessation
- 2001-03-12 WO PCT/EP2001/002739 patent/WO2001068597A1/en active IP Right Grant
- 2001-03-12 DE DE60139306T patent/DE60139306D1/de not_active Expired - Lifetime
- 2001-03-12 PT PT01921326T patent/PT1263719E/pt unknown
-
2002
- 2002-08-02 US US10/210,035 patent/US6627774B2/en not_active Expired - Lifetime
- 2002-09-12 IL IL151715A patent/IL151715A/en unknown
- 2002-09-12 NO NO20024354A patent/NO329428B1/no not_active IP Right Cessation
-
2003
- 2003-06-16 HK HK03104265A patent/HK1052168A1/xx not_active IP Right Cessation
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