GB2005003634 METHODS OF CHEMICAL SYNTHESIS AND PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)

1. (WO2006032879) METHODS OF CHEMICAL SYNTHESIS AND PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)

Latest bibliographic data on file with the International Bureau

Pub. No.:		WO/2006/032879		International Application No.:		PCT/GB2005/003634
Publication Date:		30.03.2006		International Filing Date:		21.09.2005

IPC:

C07D 279/18 (2006.01), A61K 31/54 (2006.01), A61P 25/28 (2006.01), A61P 35/00 (2006.01)

Applicants:

WISTA LABORATORIES LTD. [SG/SG]; 51 Ayer Rajah Crescent, #07-01/02, Singapore 139948 (SG) (For All Designated States Except US).
STOREY, John, Mervyn, David [GB/GB]; (GB) (For US Only).
SINCLAIR, James, Peter [GB/GB]; (GB) (For US Only).
MARSHALL, Colin [GB/GB]; (GB) (For US Only).
TAN, Han Wan [MY/SG]; (SG) (For US Only).
WISCHIK, Claude, Michel [FR/GB]; (GB) (For US Only)

Inventors:

STOREY, John, Mervyn, David; (GB).
SINCLAIR, James, Peter; (GB).
MARSHALL, Colin; (GB).
TAN, Han Wan; (SG).
WISCHIK, Claude, Michel; (GB)

Agent:

WYTENBURG, Wilhelmus; Mewburn Ellis LLP, York House, 23 Kingsway, London Greater London WC2B 6HP (GB)

Priority Data:

0421234.6	23.09.2004	GB
0503343.6	17.02.2005	GB
PCT/GB2005/003441	07.09.2005	GB

Title

(EN) METHODS OF CHEMICAL SYNTHESIS AND PURIFICATION OF DIAMINOPHENOTHIAZINIUM COMPOUNDS INCLUDING METHYLTHIONINIUM CHLORIDE (MTC)
(FR) PROCEDES DE SYNTHESE CHIMIQUE ET DE PURIFICATION DE COMPOSES DIAMINOPHENOTHIAZINIUM RENFERMANT DU CHLORURE DE METHYLTHIONINIUM (MTC)

Abstract:

(EN)This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7 diamino-phenothiazin-5-ium compounds (referred to herein as 'diaminophenothiazinium compounds') including Methythioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: nitrosylation (NOS); nitrosyl reduction (NR); thiosulfonic acid formation (TSAF); oxidative coupling (OC); Cr(VI) reduction (CR); isolation and purification of zwitterionic intermediate (IAPOZI); ring closure (RC); chloride salt formation (CSF); one of: sulphide treatment (ST); dimethyldithiocarbamate treatment (DT); carbonate treatment (CT); ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction (OE); and recrystallisation (RX). The present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment and diagnosis, etc., for example, for tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral diseases, bacterial diseases, or protozoal diseases. Wherein: each of R¹ and R⁹ is independently selected from:-H; C_1-4alkenyl; and halogenated C_1-4akyl; each of R^3NA and R^3NBis independently selected from: C_1-4alkyl; C₂-₄alkenyl; and halogenated C_4-1alkyl; each of R^7NA and R^7NB is independently selected from: C_1-4alkyl; C_2-4alkenyl; and halogenated C_1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality.
(FR)L'invention concerne en règle générale le domaine de la synthèse chimique et de la purification, et plus précisément des procédés de synthèse et de purification de certains composés de 3,7 diamino-phénothiazin-5-ium (que l'on appellera 'composés diaminophénothiazinium') renfermant du chlorure de méthythioninium (MTC) (connu sous le nom de bleu de méthylène). Selon une variante, le procédé comprend les étapes suivantes, dans cet ordre: nitrosylation (NOS); réduction de nitrosyle (NR); formation d'acide thiosulfonique (TSAF); couplage oxydatif (OC); réduction de Cr(VI) (CR); isolation et purification d'intermédiaire zwittérionique (IAPOZI); fermeture de chaîne (RC); formation de sel chlorure (CSF); au choix, l'une des opérations suivantes: traitement sulphure (ST); traitement diméthyldithiocarbamate (DT); traitement carbonate (CT); traitement acide éthylènediaminetétraacétique (EDTAT); extraction organique (OE); et recristallisation (RX). On décrit aussi des composés résultants (pureté élevée), des compositions qui les renferment (par exemple, comprimés, capsules), et leur utilisation dans le cadre de procédés d'inactivation de pathogènes, ou de traitement médical et de diagnostic, etc., par exemple pour les tauopathies, la maladie d'Alzheimer (AD), le cancer de la peau, le mélanome, les maladies virales, bactériennes ou protozoaires.

Designated States:

AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW.
African Regional Intellectual Property Org. (ARIPO) (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Organization (EAPO) (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM)
European Patent Office (EPO) (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT, RO, SE, SI, SK, TR)
African Intellectual Property Organization (OAPI) (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).

Publication Language:	English (EN)
Filing Language:	English (EN)