HRP20140908T1 - Novi polimorfni oblici hidrokloridne soli 3-(1-{3-[5-(1-metil-piperidin-4ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila i postupci njihove proizvodnje - Google Patents
Novi polimorfni oblici hidrokloridne soli 3-(1-{3-[5-(1-metil-piperidin-4ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila i postupci njihove proizvodnje Download PDFInfo
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- HRP20140908T1 HRP20140908T1 HRP20140908AT HRP20140908T HRP20140908T1 HR P20140908 T1 HRP20140908 T1 HR P20140908T1 HR P20140908A T HRP20140908A T HR P20140908AT HR P20140908 T HRP20140908 T HR P20140908T HR P20140908 T1 HRP20140908 T1 HR P20140908T1
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- pyrimidin
- piperidin
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- 238000000034 method Methods 0.000 title claims 12
- 238000004519 manufacturing process Methods 0.000 title claims 10
- YHHHGHDGBUUWIS-UHFFFAOYSA-N 3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile;hydrochloride Chemical compound Cl.C1CN(C)CCC1COC1=CN=C(C=2C=C(CN3C(C=CC(=N3)C=3C=C(C=CC=3)C#N)=O)C=CC=2)N=C1 YHHHGHDGBUUWIS-UHFFFAOYSA-N 0.000 title claims 5
- 238000003756 stirring Methods 0.000 claims 34
- 239000002904 solvent Substances 0.000 claims 21
- 239000011877 solvent mixture Substances 0.000 claims 19
- 230000004048 modification Effects 0.000 claims 16
- 238000012986 modification Methods 0.000 claims 16
- KZVOMLRKFJUTLK-UHFFFAOYSA-N 3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile;hydrate;hydrochloride Chemical compound O.Cl.C1CN(C)CCC1COC1=CN=C(C=2C=C(CN3C(C=CC(=N3)C=3C=C(C=CC=3)C#N)=O)C=CC=2)N=C1 KZVOMLRKFJUTLK-UHFFFAOYSA-N 0.000 claims 15
- 150000001875 compounds Chemical class 0.000 claims 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 13
- 238000001914 filtration Methods 0.000 claims 13
- 239000012458 free base Substances 0.000 claims 13
- 239000007788 liquid Substances 0.000 claims 13
- 150000003839 salts Chemical class 0.000 claims 13
- 238000000926 separation method Methods 0.000 claims 13
- AHYMHWXQRWRBKT-UHFFFAOYSA-N tepotinib Chemical compound C1CN(C)CCC1COC1=CN=C(C=2C=C(CN3C(C=CC(=N3)C=3C=C(C=CC=3)C#N)=O)C=CC=2)N=C1 AHYMHWXQRWRBKT-UHFFFAOYSA-N 0.000 claims 12
- 206010028980 Neoplasm Diseases 0.000 claims 11
- 239000006185 dispersion Substances 0.000 claims 11
- 239000000243 solution Substances 0.000 claims 11
- 238000001035 drying Methods 0.000 claims 9
- 238000005406 washing Methods 0.000 claims 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- 201000011510 cancer Diseases 0.000 claims 6
- 238000001816 cooling Methods 0.000 claims 6
- 239000013078 crystal Substances 0.000 claims 6
- 239000003814 drug Substances 0.000 claims 6
- 238000010438 heat treatment Methods 0.000 claims 6
- 238000011534 incubation Methods 0.000 claims 6
- 239000007864 aqueous solution Substances 0.000 claims 5
- 238000002425 crystallisation Methods 0.000 claims 5
- 230000008025 crystallization Effects 0.000 claims 5
- 229940079593 drug Drugs 0.000 claims 5
- 238000002441 X-ray diffraction Methods 0.000 claims 4
- 239000013543 active substance Substances 0.000 claims 4
- 150000003841 chloride salts Chemical class 0.000 claims 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims 4
- 230000005855 radiation Effects 0.000 claims 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- 238000002156 mixing Methods 0.000 claims 3
- 238000011282 treatment Methods 0.000 claims 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims 2
- 206010005003 Bladder cancer Diseases 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 201000009030 Carcinoma Diseases 0.000 claims 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 206010060862 Prostate cancer Diseases 0.000 claims 2
- 206010039491 Sarcoma Diseases 0.000 claims 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 2
- 201000010881 cervical cancer Diseases 0.000 claims 2
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 230000005764 inhibitory process Effects 0.000 claims 2
- 208000032839 leukemia Diseases 0.000 claims 2
- 230000004963 pathophysiological condition Effects 0.000 claims 2
- 230000004962 physiological condition Effects 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims 2
- FPYJSJDOHRDAMT-KQWNVCNZSA-N 1h-indole-5-sulfonamide, n-(3-chlorophenyl)-3-[[3,5-dimethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1h-pyrrol-2-yl]methylene]-2,3-dihydro-n-methyl-2-oxo-, (3z)- Chemical compound C=1C=C2NC(=O)\C(=C/C3=C(C(C(=O)N4CCN(C)CC4)=C(C)N3)C)C2=CC=1S(=O)(=O)N(C)C1=CC=CC(Cl)=C1 FPYJSJDOHRDAMT-KQWNVCNZSA-N 0.000 claims 1
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- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 102000001253 Protein Kinase Human genes 0.000 claims 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000006265 Renal cell carcinoma Diseases 0.000 claims 1
- 201000000582 Retinoblastoma Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
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- 208000024313 Testicular Neoplasms Diseases 0.000 claims 1
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- 208000002495 Uterine Neoplasms Diseases 0.000 claims 1
- 201000005969 Uveal melanoma Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 229910001514 alkali metal chloride Inorganic materials 0.000 claims 1
- 229910001617 alkaline earth metal chloride Inorganic materials 0.000 claims 1
- 239000012752 auxiliary agent Substances 0.000 claims 1
- 230000033228 biological regulation Effects 0.000 claims 1
- 210000000133 brain stem Anatomy 0.000 claims 1
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- 239000000969 carrier Substances 0.000 claims 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 1
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- 239000003085 diluting agent Substances 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
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- 239000000706 filtrate Substances 0.000 claims 1
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- 230000001404 mediated effect Effects 0.000 claims 1
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- 229910021381 transition metal chloride Inorganic materials 0.000 claims 1
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Claims (30)
1. 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid solvat isključujući 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrat kristalnu modifikaciju H2:
Oblik H2:
[image]
2. Spoj prema zahtjevu 1 naznačen time da je u svojim kristalnim modifikacijama.
3. 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid bezvodni.
4. Spoj prema zahtjevu 3 u svojoj kristalnoj modifikaciji A1, koji je naznačen time da XRD vrhovi obuhvaćaju 4,4°, 15.9° i 22,7° (u °2θ pomoću Cu-Kα1 zračenja, ± 0.1°).
5. Spoj prema bilo kojem zahtjevu od 3 do 4, koji je naznačen time da ima slijedeće XRD podatke:
Oblik A1:
[image]
6. 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrat isključujući 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrat kristalnu modifikaciju H2 prema zahtjevu 1:
Oblik H2:
[image]
7. Spoj prema zahtjevu 6 u svojoj kristalnoj modifikaciji H1, koji je naznačen time da XRD vrhovi obuhvaćaju 5,9°, 16,0° i 23,4° (u °2θ pomoću Cu-Kα1 zračenja, ± 0.1°).
8. Spoj prema bilo kojem zahtjevu od 6 do 7, koji je naznačen time da ima slijedeće XRD podatke:
Oblik H1:
[image]
9. Spoj prema zahtjevu 6 u svojoj kristalnoj modifikaciji NF3, koji je naznačen time da XRD vrhovi obuhvaćaju 9,9°, 15,7° i 24,1° (u °2θ pomoću Cu-Kα1 zračenja, ± 0.1°).
10. Spoj prema bilo kojem zahtjevu od 6, 9, koji je naznačen time da ima slijedeće XRD podatke:
Oblik NF3:
[image]
11. Spoj prema zahtjevu 3 u svojoj kristalnoj modifikaciji NF6, koji je naznačen time da XRD vrhovi obuhvaćaju 16,8°, 18.2° i 25,8° (u °2θ pomoću Cu-Kα1 zračenja, ± 0.1°).
12. Spoj prema bilo kojem zahtjevu od 3, 11, koji je naznačen time da ima slijedeće XRD podatke:
Oblik NF6:
[image]
13. Farmaceutski pripravak naznačen time da sadrži terapeutski učinkovitu količinu najmanje jednog spoja prema bilo kojem zahtjevu od 1 do 12.
14. Farmaceutski pripravak prema zahtjevu 13 naznačen time da dodatno sadrži barem jedan dodatni spoj odabran iz skupine koja sadrži fiziološki prihvatljive pomoćne tvari, pomoćna sredstva, adjuvante, sredstva za razrjeđivanje, nosače i/ili dodatne farmaceutski aktivne tvari koje su različite od spojeva prema bilo kojem zahtjevu od 1 do 12.
15. Medikament naznačen time da sadrži barem jedan spoj prema bilo kojem zahtjevu od 1 do 12 ili farmaceutski pripravak prema bilo kojem zahtjevu od 13 do 14.
16. Medikament prema zahtjevu 15 naznačen time da je za uporabu kod liječenja i/ili profilakse fizioloških i/ili patofizioloških stanja, koja su uzrokovana, posredovana i/ili koja se šire inhibicijom, regulacijom i/ili modulacijom transdukcije signala kinaza, naročito inhibicijom tirozin kinaza, poželjno Met-kinaze.
17. Medikament prema zahtjevu 15 naznačen time da je za uporabu kod liječenja i/ili profilakse fizioloških i/ili patofizioloških stanja odabranih iz skupine koju čine: "rak, tumor, maligni tumori, benigni tumori, solidni tumori, sarkomi, karcinomi, hiperproliferativni poremećaji, karcinoidi, Ewingovi sarkomi, Kapozijevi sarkomi, tumori mozga, tumori koji potječu iz mozga i/ili živčanog sustava i/ili moždanih ovojnica, gliomi, glioblastomi, neuroblastomi, rak želuca, rak bubrega, karcinomi stanica bubrega, rak prostate, karcinomi prostate, tumori vezivnog tkiva, sarkomi mekog tkiva, tumori gušterače, tumori jetre, tumori glave, tumori vrata, rak grkljana, rak jednjaka, rak štitnjače, osteosarkomi, retinoblastomi, timomi, rak testisa, rak pluća, adenokarcinom pluća, karcinom pluća malih stanica, karcinomi bronha, rak dojke, karcinomi dojki, rak crijeva, tumori debelog crijeva, karcinomi debelog crijeva, karcinomi rektuma, ginekološki tumori, tumori jajnika, uterine rak, rak grlića maternice, karcinomi vrata maternice, rak tijela maternice, karcinomi sluznice maternice, karcinomi endometrija, rak mokraćnog mjehura, rak urogenitalnog trakta, rak mokraćnog mjehura, rak kože, epitelni tumori, karcinom skvamoznog epitela, bazaliomi, spinaliomi, melanomi, intraokularni melanomi, leukemija, monocitna leukemija, kronična leukemija, kronična mijeloična leukemija, kronična limfatična leukemija, akutne leukemije, akutna mijeloična leukemija, akutna limfatična leukemija i/ili limfomi".
18. Medikament prema bilo kojem zahtjevu 15 do 17, naznačen time da navedeni medikament sadrži najmanje jednu dodatnu farmakološki aktivnu tvar.
19. Medikament prema bilo kojem zahtjevu 15 do 17, naznačen time da se medikament primjenjuje prije i/ili tijekom i/ili nakon tretmana sa najmanje jednom dodatnom farmakološki aktivnom tvari.
20. Komplet naznačen time da sadrži terapeutski učinkovitu količinu najmanje jednog spoja prema bilo kojem zahtjevu od 1 do 12 i/ili najmanje jednog farmaceutskog pripravka prema bilo kojem zahtjevu od 13 do 14 i terapeutski učinkovitu količinu najmanje jedne dodatne farmakološki aktivne tvari različite od spojeva prema bilo kojem zahtjevu od 1 do 12.
21. Postupak za proizvodnju kristalne modifikacije A1 prema bilo kojem zahtjevu od 4 do 5 naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u otapalu ili smjesi otapala, poželjno 2-propanolu, proizvoljno uz miješanje,
(b) pretvaranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u odgovarajuću hidrokloridnu sol dodavanjem eterne otopine klorovodične kiseline, proizvoljno uz miješanje,
(c) grijanje dobivene disperzije ili otopine iz koraka (b) na povišenoj temperaturi T1, poželjno 30° C do 95° C, poželjnije 50° C, proizvoljno uz miješanje, te miješanje do početka kristalizacije i nastavak miješanja kod sobne temperature sve do okončanja postupka kristalizacije,
(d) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorida bezvodnog pomoću separacije kruto-tekuće, poželjno filtracijom, proizvoljno uz naknadno ispiranje sa otapalom ili smjesom otapala, poželjno eterom, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T2, poželjno 30° C do 95° C, poželjnije 70° C.
22. Postupak za proizvodnju kristalne modifikacije H1 prema bilo kojem zahtjevu od 7 do 8 naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u otapalu ili smjesi otapala, poželjno u vodi, proizvoljno uz miješanje,
(b) pretvaranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u odgovarajuću hidrokloridnu sol dodavanjem vodene otopine klorovodične kiseline, proizvoljno uz miješanje, (c1) zagrijavanje nastale disperzije iz koraka (b) na povišenoj temperaturi T1, poželjno 30°C do 95° C, poželjnije 60° C, proizvoljno uz miješanje, te (i) hlađenje dobivene otopine, poželjno na 10° C do 40° C, poželjnije na 35° C, proizvoljno uz miješanje, koncentriranje otopine do početka kristalizacije i daljnje hlađenje, poželjno na 0° C do 25° C, proizvoljno uz miješanje, ili (ii) separaciju kruto-tekuće, poželjno uz filtriranje da se dobije otopina, inkubiranje otopine kod sobne temperature do početka kristalizacije i njeno dodatno inkubiranje na sobnoj temperaturi, jedan ili više sati ili dana, proizvoljno uz miješanje, ili
(c2) inkubaciju dobivene disperzije iz koraka (b) u ultrazvučnoj kupelji do dobivanja bistre otopine, separacijom kruto-tekuće, poželjno uz filtriranje nastale otopine i njeno inkubiranje tijekom jednog ili više sati ili dana kod sobne temperature, proizvoljno uz miješanje,
(d) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrata uz separaciju kruto-tekuće, poželjno uz filtraciju, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno u vodi, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T2, poželjno 30° C do 95° C, poželjnije 70° C.
23. Postupak za proizvodnju kristalne modifikacije H1 prema bilo kojem zahtjevu od 7 do 8 naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorida bezvodnog u otapalu ili smjesi otapala, poželjno u vodi, proizvoljno uz miješanje,
(b) inkubaciju dobivene disperzije iz koraka (a) na sobnoj temperaturi, jedan ili više sati ili dana, proizvoljno uz miješanje,
(c) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrata uz separaciju kruto-tekuće, poželjno uz filtraciju, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno u vodi, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T, poželjno 30° C do 95° C, poželjnije 70° C.
24. Postupak za proizvodnju kristalne modifikacije NF3 prema bilo kojem zahtjevu od 9 do 10 naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrata u otapalu ili smjesi otapala, poželjno metanolu ili etanolu, proizvoljno uz miješanje,
(b) inkubaciju dobivene disperzije iz koraka (a) kod povišene temperature T1, poželjno 30° C do 95° C, poželjnije 40° C, tijekom jednog ili više sati ili dana, proizvoljno uz miješanje, te proizvoljno uz njeno hlađenje na sobnu temperaturu, proizvoljno uz miješanje,
(c) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrata sa separacijom kruto-tekuće, poželjno filtracijom, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno etanolu, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T2, poželjno 30° C do 95° C, poželjnije 70° C.
25. Postupak za proizvodnju kristalne modifikacije NF3 prema bilo kojem zahtjevu od 9 do 10 naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u otapalu ili smjesi otapala, poželjno u vodi, proizvoljno uz miješanje,
(b) pretvaranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u odgovarajuću hidrokloridnu sol dodavanjem vodene otopine klorovodične kiseline, proizvoljno uz miješanje,
(c) zagrijavanje nastale disperzije iz koraka (b) na povišenoj temperaturi T1, poželjno 30° C do 95° C, poželjnije 60° C, proizvoljno uz miješanje, proizvoljno uz separaciju kruto-tekuće, poželjno uz filtriranje da se dobije otopina, te inkubaciju otopine kod sobne temperature do početka kristalizacije i daljnju inkubaciju na sobnoj temperaturi, jedan ili više sati ili dana, proizvoljno uz miješanje,
(d) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrata uz separaciju kruto-tekuće, poželjno uz filtraciju, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno u vodi, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T2, poželjno 30° C do 95° C, poželjnije 70° C.
(e) dispergiranje dobivenih suhih kristala iz koraka (d) u otapalu ili smjesi otapala, poželjno u metanolu ili etanolu, te inkubaciju dobivene disperzije na sobnoj temperaturi, jedan ili više sati ili dana, proizvoljno uz miješanje,
(f) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid hidrata uz separaciju kruto-tekuće, poželjno uz filtraciju, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno u etanolu, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T3, poželjno 30° C do 95° C, poželjnije 70° C.
26. Postupak za proizvodnju kristalne modifikacije H2 od 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrata
Oblik H2:
[image]
naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u otapalu ili smjesi otapala, poželjno u acetonu, proizvoljno uz miješanje, te proizvoljno zagrijavanje nastale disperzije na povišenoj temperaturi T1, poželjno 30° C do 95° C, poželjnije 60° C, proizvoljno uz miješanje,
(b) pretvaranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u odgovarajuću hidrokloridnu sol dodavanjem vodene otopine klorovodične kiseline, proizvoljno uz miješanje, zagrijavanje nastale disperzije na povišenoj temperaturi T2, poželjno 30° C do 95° C, poželjnije 60° C, tijekom jedne ili više minuta ili sati, poželjno 30 min, proizvoljno uz miješanje, te proizvoljno uz dodavanje dodatnog otapala ili smjese otapala, poželjno u vodi, proizvoljno uz miješanje,
(c) hlađenje disperzije iz koraka (b) do sobne temperature, proizvoljno uz miješanje, te uz njeno inkubiranje na sobnoj temperaturi, jedan ili više sati ili dana, proizvoljno uz miješanje,
(d) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrata uz separaciju kruto-tekuće, poželjno uz filtraciju, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno s acetonom ili THF, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T3, poželjno 30° C do 95° C, poželjnije 50° C.
27. Postupak za proizvodnju kristalne modifikacije H2 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrata
Oblik H2:
[image]
naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u otapalu ili smjesi otapala, poželjno u vodi, proizvoljno uz miješanje,
(b) pretvaranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u odgovarajuću hidrokloridnu sol dodavanjem vodene otopine klorovodične kiseline, proizvoljno uz miješanje, zagrijavanje nastale disperzije na povišenoj temperaturi T1, poželjno 30° C do 100° C, poželjnije 80° C do 100° C, proizvoljno uz miješanje, te uz separaciju kruto-tekuće, poželjno uz njenu filtraciju da se dobije otopina,
(c) ponovno zagrijavanje dobivenog filtrata iz koraka (b) na povišenoj temperaturi T2, poželjno 30° C do 100° C, poželjnije 78° C do 85° C, proizvoljno uz miješanje, te naknadno hlađenje, poželjno na 0° C do 40° C, poželjnije na 0° C do 27° C, tijekom jednog ili više sati ili dana, proizvoljno uz miješanje, i proizvoljno daljnje hlađenje, poželjno na 0° C do 25° C, poželjnije na 20° C, proizvoljno uz miješanje,
(d) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrata sa separacijom kruto-tekuće, poželjno filtracijom, proizvoljno uz ispiranje s otapalom ili smjesom otapala, poželjno u vodi, THF ili acetone, i proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T3, poželjno 30° C do 95° C, poželjnije 50° C do 55° C.
28. Postupak prema bilo kojem zahtjevu od 26 do 27, naznačen time da se u koraku (b) 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril (slobodna baza) ili jedna ili više njegovih soli pretvara u odgovarajuću hidrokloridnu sol dodavanjem jedne ili više kloridnih soli odabranih iz skupine koju čine: "kloridna sol alkalijskog metala, kloridna sol zemnoalkalijskog metala, sol amonijevog klorida, kvaterna organska sol amonijevog klorida, kloridna sol tranzicijskog metala".
29. Postupak za proizvodnju kristalne modifikacije H2 od 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrata
Oblik H2:
[image]
naznačen time da sadrži korak:
(a) re-kristalizacije 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorid monohidrata iz otapala ili smjese otapala, proizvoljno uz miješanje.
30. Postupak za proizvodnju kristalne modifikacije NF6 prema bilo kojem zahtjevu od 11 do 12 naznačen time da sadrži korake:
(a) dispergiranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u otapalu ili smjesi otapala, poželjno u acetonu, proizvoljno uz miješanje,
(b) pretvaranje 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila (slobodna baza) ili jedne ili više njegovih soli u odgovarajuću hidrokloridnu sol dodavanjem vodene otopine klorovodične kiseline, proizvoljno uz miješanje,
(c) izoliranje istaloženog 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitril hidroklorida bezvodnog uz separaciju kruto-tekuće, poželjno uz filtraciju, proizvoljno uz naknadno ispiranje sa otapalom ili smjesom otapala, te proizvoljno uz naknadno sušenje, po mogućnosti in vacuo, proizvoljno na povišenoj temperaturi T2, poželjno 30° C do 95° C, poželjnije 65° C.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP09000140 | 2009-01-08 | ||
PCT/EP2009/008684 WO2010078897A1 (en) | 2009-01-08 | 2009-12-04 | Novel polymorphic forms of 3-(1-{3-[5-(1-methyl-piperidin-4ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride salt and processes of manufacturing thereof |
Publications (1)
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HRP20140908T1 true HRP20140908T1 (hr) | 2014-11-07 |
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HRP20140908AT HRP20140908T1 (hr) | 2009-01-08 | 2014-09-23 | Novi polimorfni oblici hidrokloridne soli 3-(1-{3-[5-(1-metil-piperidin-4ilmetoksi)-pirimidin-2-il]-benzil}-6-okso-1,6-dihidro-piridazin-3-il)-benzonitrila i postupci njihove proizvodnje |
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US (3) | US8710058B2 (hr) |
EP (1) | EP2373640B1 (hr) |
JP (2) | JP5719781B2 (hr) |
KR (2) | KR101829595B1 (hr) |
CN (1) | CN102272121B (hr) |
AR (1) | AR074996A1 (hr) |
AU (1) | AU2009336839B2 (hr) |
BR (1) | BRPI0922642B8 (hr) |
CA (4) | CA2749012C (hr) |
CL (1) | CL2011001356A1 (hr) |
CO (1) | CO6400191A2 (hr) |
CY (1) | CY1115631T1 (hr) |
DK (1) | DK2373640T3 (hr) |
EA (1) | EA019342B1 (hr) |
EC (1) | ECSP11011248A (hr) |
ES (1) | ES2522629T3 (hr) |
HK (1) | HK1164856A1 (hr) |
HR (1) | HRP20140908T1 (hr) |
IL (1) | IL213829A0 (hr) |
MX (3) | MX350894B (hr) |
MY (1) | MY160017A (hr) |
NZ (1) | NZ594404A (hr) |
PE (2) | PE20141317A1 (hr) |
PL (1) | PL2373640T3 (hr) |
PT (1) | PT2373640E (hr) |
SG (2) | SG10201504735QA (hr) |
SI (1) | SI2373640T1 (hr) |
SM (1) | SMT201400161B (hr) |
TW (1) | TWI475997B (hr) |
UA (1) | UA106220C2 (hr) |
WO (1) | WO2010078897A1 (hr) |
ZA (1) | ZA201105782B (hr) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
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MX350894B (es) * | 2009-01-08 | 2017-09-22 | Merck Patent Gmbh * | Nuevas formas polimorficas de sal de clorhidrato de 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoxi)-pirimidin-2-il]-bencil} -6-oxo-1,6-dihidro-piridazin-3-il)-benzonitrilo y sus procesos de preparacion. |
BR112014022266A2 (pt) * | 2012-03-19 | 2021-09-08 | Merck Patent Gmbh | Combinação de um derivado de 6-oxo-1,6-di-hidro-piridazina tendo atividade anticâncer com outros compostos antitumor |
AU2013339823B2 (en) * | 2012-11-02 | 2018-01-04 | Merck Patent Gmbh | A 6-oxo-1,6-dihydro-pyridazine derivative for the use for the treatment of hepatocellular carcinoma (HCC) |
EP3091980A1 (en) * | 2014-01-07 | 2016-11-16 | Merck Patent GmbH | A 6-oxo-1,6-dihydro-pyridazine derivative for the use for the treatment of renal cell carcinoma (rcc) |
CN106999493A (zh) | 2014-12-12 | 2017-08-01 | 默克专利股份公司 | 具有抗癌活性的6‑氧代‑1,6‑二氢‑哒嗪衍生物与egfr抑制剂的组合 |
CA2981627C (en) * | 2015-04-03 | 2024-02-20 | Suixiong Cai | Solid pharmaceutical formulation of parp inhibitors and the use thereof |
WO2016192831A1 (en) | 2015-05-29 | 2016-12-08 | Merck Patent Gmbh | Compositions of anions and cations with pharmacological activity |
KR20180092096A (ko) | 2017-02-08 | 2018-08-17 | 에이비온 주식회사 | 트리아졸로 피라진 유도체의 신규한 다형체 및 이의 제조 방법 |
US11465986B2 (en) | 2018-04-26 | 2022-10-11 | Fujian Akeylink Biotechnology Co., Ltd. | Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor |
RS64906B1 (sr) * | 2019-07-10 | 2023-12-29 | Merck Patent Gmbh | Farmaceutski preparat |
WO2022063869A2 (en) | 2020-09-24 | 2022-03-31 | Merck Patent Gmbh | Compounds for the treatment of viral infections |
KR102489160B1 (ko) | 2021-05-26 | 2023-01-18 | 주식회사 이노큐어테라퓨틱스 | 피페리딘디온 유도체 |
WO2022250350A1 (ko) | 2021-05-26 | 2022-12-01 | 주식회사 이노큐어테라퓨틱스 | 피페리딘디온 유도체 |
WO2022253935A1 (en) | 2021-06-04 | 2022-12-08 | Merck Patent Gmbh | Compounds for the treatment of glioblastoma |
CN114394957B (zh) * | 2021-12-24 | 2023-05-09 | 武汉九州钰民医药科技有限公司 | Met抑制剂盐酸特泊替尼的制备方法 |
KR20230155324A (ko) | 2022-05-03 | 2023-11-10 | 주식회사 이노큐어테라퓨틱스 | 피페리딘디온 유도체 |
CN116768868B (zh) * | 2023-08-15 | 2023-12-08 | 云南省药物研究所 | 一种哒嗪酮硫代衍生物及其制备方法和应用 |
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US7169932B2 (en) * | 2001-06-11 | 2007-01-30 | Pfizer Inc. | HIV protease inhibitors, compositions containing the same, their pharmaceutical uses, material for their synthesis |
US7094909B2 (en) * | 2001-06-11 | 2006-08-22 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis |
CA2536135C (en) * | 2003-08-19 | 2012-05-22 | Boehringer Ingelheim International Gmbh | Multivitamin syrup for children or young adults |
WO2005026114A1 (en) * | 2003-09-17 | 2005-03-24 | Pfizer Inc. | Hiv protease inhibitors, compositions containing the same and their pharmaceutical uses |
TW200616634A (en) * | 2004-10-01 | 2006-06-01 | Bristol Myers Squibb Co | Crystalline forms and process for preparing spiro-hydantoin compounds |
MX2007004783A (es) * | 2004-10-21 | 2007-05-11 | Pfizer | Inhibidores de la proteasa del virus de la hepatitis c, y composiciones y tratamientos que los usan. |
CN101052633A (zh) * | 2004-11-02 | 2007-10-10 | 辉瑞大药厂 | 制备吲唑化合物的方法 |
KR20070058690A (ko) * | 2004-11-02 | 2007-06-08 | 화이자 인코포레이티드 | 인다졸 화합물의 제조방법 |
DE102005057924A1 (de) * | 2005-12-05 | 2007-06-06 | Merck Patent Gmbh | Pyridazinonderivate |
AU2007243466B2 (en) * | 2006-04-26 | 2012-01-19 | F. Hoffmann-La Roche Ag | Phosphoinositide 3-kinase inhibitor compounds and pharmaceutical compositions containing them |
US7820812B2 (en) * | 2006-07-25 | 2010-10-26 | Abbott Laboratories | Methods of manufacturing crystalline forms of rapamycin analogs |
US7812032B2 (en) * | 2006-07-25 | 2010-10-12 | Abbott Laboratories | Crystalline forms of rapamycin analogs |
DE102007032507A1 (de) | 2007-07-12 | 2009-04-02 | Merck Patent Gmbh | Pyridazinonderivate |
MX350894B (es) * | 2009-01-08 | 2017-09-22 | Merck Patent Gmbh * | Nuevas formas polimorficas de sal de clorhidrato de 3-(1-{3-[5-(1-metil-piperidin-4-ilmetoxi)-pirimidin-2-il]-bencil} -6-oxo-1,6-dihidro-piridazin-3-il)-benzonitrilo y sus procesos de preparacion. |
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