HRP20191100T1 - Postupci kemijske sinteze i pročišćavanja diaminofenotiazinskih spojeva uključujući metiltioninijev klorid (mtc) - Google Patents
Postupci kemijske sinteze i pročišćavanja diaminofenotiazinskih spojeva uključujući metiltioninijev klorid (mtc) Download PDFInfo
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- HRP20191100T1 HRP20191100T1 HRP20191100TT HRP20191100T HRP20191100T1 HR P20191100 T1 HRP20191100 T1 HR P20191100T1 HR P20191100T T HRP20191100T T HR P20191100TT HR P20191100 T HRP20191100 T HR P20191100T HR P20191100 T1 HRP20191100 T1 HR P20191100T1
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- Prior art keywords
- optionally substituted
- disubstituted
- amino
- purity
- phenothiazine
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- 238000000034 method Methods 0.000 title claims 6
- 238000000746 purification Methods 0.000 title claims 3
- 238000003786 synthesis reaction Methods 0.000 title claims 3
- KPYHKEZPEDJERZ-UHFFFAOYSA-N 10h-phenothiazine-1,2-diamine Chemical class C1=CC=C2NC3=C(N)C(N)=CC=C3SC2=C1 KPYHKEZPEDJERZ-UHFFFAOYSA-N 0.000 title 1
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 title 1
- 229960000907 methylthioninium chloride Drugs 0.000 title 1
- -1 diaminophenothiazine compound Chemical class 0.000 claims 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 14
- 150000003841 chloride salts Chemical class 0.000 claims 11
- 238000006798 ring closing metathesis reaction Methods 0.000 claims 11
- 238000005691 oxidative coupling reaction Methods 0.000 claims 9
- 230000015572 biosynthetic process Effects 0.000 claims 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims 6
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 6
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 claims 5
- 208000024827 Alzheimer disease Diseases 0.000 claims 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 4
- 150000003863 ammonium salts Chemical class 0.000 claims 4
- 239000011651 chromium Substances 0.000 claims 4
- 239000010949 copper Substances 0.000 claims 4
- 239000012535 impurity Substances 0.000 claims 4
- 239000011572 manganese Substances 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 4
- 239000003960 organic solvent Substances 0.000 claims 4
- 239000007800 oxidant agent Substances 0.000 claims 4
- ALJHHTHBYJROOG-UHFFFAOYSA-N 7-(dimethylamino)phenothiazin-3-one Chemical compound C1=CC(=O)C=C2SC3=CC(N(C)C)=CC=C3N=C21 ALJHHTHBYJROOG-UHFFFAOYSA-N 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 3
- 238000000605 extraction Methods 0.000 claims 3
- 230000009635 nitrosylation Effects 0.000 claims 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 208000005176 Hepatitis C Diseases 0.000 claims 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical group O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- 208000034799 Tauopathies Diseases 0.000 claims 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims 2
- 241000710886 West Nile virus Species 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 2
- 229910052782 aluminium Inorganic materials 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 claims 2
- 239000007900 aqueous suspension Substances 0.000 claims 2
- 230000001580 bacterial effect Effects 0.000 claims 2
- 229910052793 cadmium Inorganic materials 0.000 claims 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 2
- 229910052804 chromium Inorganic materials 0.000 claims 2
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims 2
- 229910052802 copper Inorganic materials 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 238000002955 isolation Methods 0.000 claims 2
- 229910052748 manganese Inorganic materials 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 229910052750 molybdenum Inorganic materials 0.000 claims 2
- 239000011733 molybdenum Substances 0.000 claims 2
- 229910052759 nickel Inorganic materials 0.000 claims 2
- 230000003647 oxidation Effects 0.000 claims 2
- 238000007254 oxidation reaction Methods 0.000 claims 2
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 201000000849 skin cancer Diseases 0.000 claims 2
- KIEOKOFEPABQKJ-UHFFFAOYSA-N sodium dichromate Chemical compound [Na+].[Na+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KIEOKOFEPABQKJ-UHFFFAOYSA-N 0.000 claims 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims 2
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims 2
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 claims 2
- 230000003612 virological effect Effects 0.000 claims 2
- 241000711549 Hepacivirus C Species 0.000 claims 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 239000008280 blood Substances 0.000 claims 1
- 210000004369 blood Anatomy 0.000 claims 1
- 239000002775 capsule Substances 0.000 claims 1
- WIVXEZIMDUGYRW-UHFFFAOYSA-L copper(i) sulfate Chemical compound [Cu+].[Cu+].[O-]S([O-])(=O)=O WIVXEZIMDUGYRW-UHFFFAOYSA-L 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 244000052769 pathogen Species 0.000 claims 1
- 230000001717 pathogenic effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims 1
- 235000009518 sodium iodide Nutrition 0.000 claims 1
- 235000010288 sodium nitrite Nutrition 0.000 claims 1
- 229910052979 sodium sulfide Inorganic materials 0.000 claims 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims 1
- 235000019345 sodium thiosulphate Nutrition 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
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Claims (13)
1. Diaminofenotiazinski spoj visoke čistoće koji je predstavljen sljedećom formulom:
naznačen time, da je njegova visoka čistoća okarakterizirana čistoćom većom od 98% i jednim ili više od sljedećih svojstava:
manje od 2% Azura B kao nečistoća;
manje od 0,13% Metilen-ljubičastog Bernthsena (MVB) kao nečistoća;
čistoća elemenata bolja nego kod graničnih vrijednosti Europske Farmakopeje (EP) od 100 μg/g aluminija (Al), 10 μg/g kroma (Cr), 10 μg/g cinka (Zn), 10 μg/g bakra (Cu), 100 μg/g željeza (Fe), 10 μg/g mangana (Mn), 10 μg/g nikla (Ni), 10 μg/g molibdena (Mo), 1 μg/g kadmija (Cd), 1 μg/g kositra (Sn), i
10 μg/g olova (Pb).
2. Diaminofenotiazinski spoj visoke čistoće prema zahtjevu 1, naznačen time, da se može dobiti putem postupka sinteze koji obuhvaća sljedeće korake, po redu:
oksidacijsko spajanje (OC), u kojem se tiosulfonska kiselina-S-{2-(amino)-3-(opcionalno supstituirani)-5-(disupstituirani-amino)-fenil}ester, 4, oksidacijski spaja na N,N-disupstituirani-3-opcionalno supstituirani-anilin, 5, uporabom oksidacijskog sredstva koje jest ili obuhvaća Cr(VI), kako bi se dobio [4-{2-(tiosulfat)-4-(disupstituirani amino)-6-(opcionalno supstituirani)-fenil-imino}-3-(opcionalno supstituirani)-cikloheksa-2,5-dieniliden]-N,N-disupstituirani amonij, 6:
izolacija i pročišćavanje cviterionskog intermedijera (IAPOZI), gdje se izolira i pročišćava navedeni [4-{2-(tiosulfat)-4-(disupstituirani amino)-6-(opcionalno supstituirani)-fenil-imino}3-(opcionalno supstituirani)-cikloheksa-2,5-dieniliden]-N,N-disupstituirani amonij, 6;
zatvaranje prstena (RC), gdje se navedeni izolirani i pročišćeni [4-{2-(tiosulfat)-4-(disupstituirani amino)-6-(opcionalno supstituirani)-fenil-imino}-3-(opcionalno
supstituirani)-cikloheksa-2,5-dieniliden]-N,N-disupstituirani amonij, 6,
podvrgava zatvaranju prstena (RC) kako bi se dobila 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ijeva sol, 7:
dok nadalje obuhvaća, nakon spomenutog koraka zatvaranja prstena (RC), sljedeći dodatni korak:
tvorba kloridne soli (CSF) u kojoj navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ijeva sol, 7, reagira s kloridom, kako bi se dobila 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ij-kloridna sol, 8:
gdje nadalje obuhvaća, nakon spomenutog koraka tvorbe kloridne soli (CSF), sljedeći dodatni korak:
sulfidna obrada (ST) u kojoj se navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ij-kloridna sol, 8, obrađuje sa sulfidom;
te nadalje obuhvaća uzastopni sljedeći dodatni korak:
organska ekstrakcija (OE) u kojoj se navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ij-kloridna sol, 8, u vodenoj otopini ili suspenziji, obrađuje s (primjerice, ispire s) organskim otapalom;
pri čemu navedeno organsko otapalo koje se koristi u navedenoj organskoj ekstrakciji (OE) jest diklorometan (CH2Cl2, DCM).
3. Diaminofenotiazinski spoj visoke čistoće prema zahtjevu 2, naznačen time, da:
navedeno oksidacijsko sredstvo za spomenuti korak oksidacijskog spajanja (OC) je Na2Cr2O7;
navedeni korak oksidacijskog spajanja (OC) se provodi pod kiselim uvjetima;
navedeni korak zatvaranja prstena (RC) se postiže putem obrade s Cu(II)-sulfatom; i
korak zatvaranja prstena (RC) se provodi pod kiselim uvjetima.
4. Diaminofenotiazinski spoj visoke čistoće prema zahtjevu 2 ili 3, naznačen time, da se može dobiti putem postupka sinteze koji obuhvaća sljedeće korake, po redu:
nitrozilacija (NOS) u kojoj se N,N-disupstituirani-3-opcionalno supstituirani anilin, 1, 4-nitrozilira kako bi dobio navedeni N,N-disupstituirani-3-opcionalno supstituirani-4-nitrozil-anilin, 2:
nitrozilna redukcija (NR) u kojoj se N,N-disupstituirani-3-opcionalno supstituirani-4-nitrozil-anilin, 2, reducira kako bi stvorio navedeni N,N-disupstituirani-1,4-diamino-5-opcionalno supstituirani benzen, 3:
tvorba tiosulfonske kiseline (TSAF), u kojoj se navedeni N,N-disupstituirani-1,4-diamino-5-opcionalno supstituirani benzen, 3, oksidira u prisutnosti tiosulfata, kako bi se dobio spomenuti tiosulfonska kiselina-S-{2-(amino)-3-(opcionalno supstituirani)-5-(disupstituirani-amino)-fenil}ester, 4:
oksidacijsko spajanje (OC) u kojem se tiosulfonska kiselina-S-{2-(amino)-3-(opcionalno supstituirani)-5-(disupstituirani-amino)-fenil}ester, 4, oksidacijski spaja na N,N-disupstituirani-3-opcionalno supstituirani-anilin, 5, uporabom oksidacijskog sredstva koje jest ili obuhvaća Cr(VI), kako bi se dobio [4-{2-(tiosulfat)-4-(disupstituirani amino)-6-(opcionalno supstituirani)-fenil-imino}-3-(opcionalno supstituirani)-cikloheksa-2,5-dieniliden]-N,N-disupstituirani amonij, 6:
Cr(VI) redukcija (CR) u kojoj se produkt iz koraka oksidacijskog spajanja (OC)
obrađuje kako bi pretvorio rezidualni Cr(VI) u Cr(III);
izolacija i pročišćavanje cviterionskog intermedijera (IAPOZI), gdje se izolira i pročišćava navedeni [4-{2-(tiosulfat)-4-(disupstituirani amino)-6-(opcionalno supstituirani)-fenil-imino}-3-(opcionalno supstituirani)-cikloheksa-2,5-dieniliden]-N,N-disupstituirani amonij, 6;
zatvaranje prstena (RC), gdje se navedeni izolirani i pročišćeni [4-{2-(tiosulfat)-4-(disupstituirani amino)-6-(opcionalno supstituirani)-fenil-imino}-3-(opcionalno supstituirani)-cikloheksa-2,5-dieniliden]-N,N-disupstituirani amonij, 6, podvrgava zatvaranju prstena kako bi se dobila 3,7-bis(disupstituirani-amino)-1.9-(opcionalno supstituirana)-fenotiazin-5-ijeva sol, 7:
tvorba kloridne soli (CSF), u kojoj navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ijeva sol, 7, reagira s kloridom, kako bi se dobila 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ij-kloridna sol, 8:
sulfidna obrada (ST) u kojoj se navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ij-kloridna sol, 8, obrađuje sa sulfidom;
organska ekstrakcija (OE) u kojoj se navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirana)-fenotiazin-5-ij-kloridna sol, 8, u vodenoj otopini ili suspenziji, obrađuje s (primjerice, ispire s) organskim otapalom,
pri čemu navedeno organsko otapalo je diklorometan (CH2Cl2, DCM);
rekristalizacija (RX) u kojoj se navedena 3,7-bis(disupstituirani-amino)-1,9-(opcionalno supstituirani)-fenotiazin-5-ij-kloridna sol, 8, rekristalizira.
5. Diaminofenotiazinski spoj visoke čistoće prema zahtjevu 4, naznačen time, da:
je spomenuta obrada za pretvaranje rezidualnog Cr(VI) u Cr(III), obrada sa sredstvom za redukciju koji je odabran od natrijevog hidrosulfita, etanola i natrijevog jodida;
spomenuti tiosulfat jest ili obuhvaća Na2S2O3;
navedena oksidacija u spomenutom koraku tvorbe tiosulfonske kiseline (TSAF), vrši se putem reakcije sa sredstvom za oksidaciju koje jest ili obuhvaća Na2Cr2O7;
navedena redukcija u spomenutom koraku nitrozilne redukcije (NR), vrši se putem reakcije sa sredstvom za redukciju koji jest ili obuhvaća metalno željezo;
navedena nitrozilacija se provodi uporabom natrijevog nitrita;
je klorid koji se upotrebljava u navedenoj tvorbi kloridne soli (CSF), klorovodična kiselina ili natrijev klorid; i
je navedeni sulfid koji se upotrebljava u spomenutoj sulfidnoj obradi (ST), natrijev sulfid.
6. Diaminofenotiazinski spoj visoke čistoće prema bilo kojem od zahtjeva 1 do 5, naznačen time, da ima manje od 2% Azura B kao nečistoća.
7. Diaminofenotiazinski spoj visoke čistoće prema bilo kojem od zahtjeva 1 do 6, naznačen time, da ima manje od 0,13% MVB kao nečistoća.
8. Diaminofenotiazinski spoj visoke čistoće prema bilo kojem od zahtjeva 1 do 7, naznačen time, da ima čistoću elemenata bolju nego kod graničnih vrijednosti Europske Farmakopeje (EP) od 100 μg/g aluminija (Al), 10 μg/g kroma (Cr), 10 μg/g cinka (Zn), 10 μg/g bakra (Cu), 100 μg/g željeza (Fe), 10 μg/g mangana (Mn), 10 μg/g nikla (Ni), 10 μg/g molibdena (Mo), 1 μg/g kadmija (Cd), 1 μg/g kositra (Sn), i 10 μg/g olova (Pb).
9. Farmaceutska tableta ili kapsula, naznačena time, da obuhvaća od 20 do 300 mg ili od 30 do 200 mg diaminofenotiazinskog spoja visoke čistoće prema bilo kojem od zahtjeva 1 do 8, i farmaceutski prihvatljiv nosač, razrjeđivač ili pomoćnu tvar.
10. Diaminofenotiazinski spoj visoke čistoće prema bilo kojem od zahtjeva 1 do 8, naznačen time, da se upotrebljava u postupku liječenja ljudskog ili životinjskog tijela pomoću terapije.
11. Diaminofenotiazinski spoj visoke čistoće prema bilo kojem od zahtjeva 1 do 8, naznačen time, da se upotrebljava u postupku liječenja virusne, bakterijske ili protozoalne bolesti, tauopatije, Alzheimerove bolesti (AD), raka kože, melanoma, hepatitisa C, HIV-a ili virusa Zapadnog Nila.
12. Uporaba diaminofenotiazinskog spoja visoke čistoće prema bilo kojem od zahtjeva 1 do 8, naznačena time, da je za proizvodnju lijeka za liječenje virusne, bakterijske ili protozoalne bolesti, tauopatije, Alzheimerove bolesti (AD), raka kože, melanoma, hepatitisa C, HIV-a ili virusa Zapadnog Nila.
13. Postupak deaktiviranja patogena u uzorku, naznačen time, da obuhvaća uvođenje u uzorak diaminofenotiazinskog spoja visoke čistoće prema bilo kojem od zahtjeva 1 do 8, te izlaganje uzorka utjecaju svjetlosti, opcionalno se kod uzorka radi o krvi ili plazmi.
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| GBGB0421234.6A GB0421234D0 (en) | 2004-09-23 | 2004-09-23 | Methods of chemical synthesis |
| GB0503343A GB0503343D0 (en) | 2005-02-17 | 2005-02-17 | Methods of chemical synthesis |
| GB2005003441 | 2005-09-07 | ||
| EP10010049.4A EP2322517B1 (en) | 2004-09-23 | 2005-09-21 | Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (mtc) |
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