LEUCOMETYLTHIONIUM BIS(MESYLATE) COMPOUND, COMPOSITION COMPRISING IT, AND PROCESS FOR MANUFACTURING A PHARMACEUTICAL COMPOSITION COMPRISING SAID COMPOUND

Abstract

Compounds of general formula (1) where: each of R 1 and R 9 It is selected independently from: -H, C 1- 4 alkyl, C 2-4 alkenyl, and C 1- 4-halogenated alkyl; each of R 3NA and R 3NB It is selected independently from: -H, C 1-4 alkyl, C 2-4 alkenyl, and C 1-4 halogenated alkyl; each of R 7NA and R 7NB It is selected independently from: -H, C 1-4 alkyl, C 2-4 alkenyl, and C 1-4 halogenated alkyl; and where: each of R A and R B is selected independently from: C 1-4 alkyl, C 1-4 halogenated alkyl, and C 6-10 aril; or R A and R B They join together to form a group selected from: C 1- 6-al-kylene and C 6-10 arylene; and pharmaceutically acceptable salts thereof, which are useful in the treatment of, for example, Alzheimer's disease. Formulations of 3,7-diamino-10H-phenothiazinium salts.

Description

PHENOTHIAZINDIAMINUM SALTS AND THEIR USE technical field The invention relates generally to the field of phenothiazine compounds, in particular certain phenothiazindiaminium salts, including uses and formulations thereof. In some embodiments the invention relates to bis(sulfonic acid) salts of diaminophenothiazine compounds such as N,N,N',N'-tetramethyl-10H-phenothiazine-3,7diamine. The compounds of the invention are useful, for example, in the treatment of tauopathies such as Alzheimer's disease (AD). Background A number of patents and publications are cited herein for the purpose of more fully describing and disclosing the invention and the prior art to which the invention relates. Each of these references is hereby incorporated by reference in its entirety herein, to the same extent as if each individual reference were specifically and individually indicated as being incorporated by reference. Throughout this specification, including the claims that follow, unless the context otherwise requires, the word "comprise," and variations such as "comprise" and "comprising," shall be construed to imply the inclusion of a specified integer or step or group of specified integers or steps, but not the inclusion of any other integer or step or group of specified integers or steps. It should be noted that, as used in the specification and appended claims, the singular forms "a," "a," and "the" include the 1246454 of 249 referents in the plural unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like. Ranges are often expressed herein as between "about" a particular value, and / or "about" another particular value. When such a range is expressed, another embodiment includes between the particular value and / or the other particular value. Similarly, when values ​​are expressed as approximations, by use of the preceding word "approximately," it will be understood that the particular value forms another embodiment. All captions herein are included for convenience only, and should not be construed as limiting exposition in any way. Dementia conditions are often characterized by a progressive accumulation of intracellular and / or extracellular deposits of proteinaceous structures such as β-amyloid plaques and neurofibrillary tangles (MNFs) in the brains of affected patients. The appearance of these lesions correlates highly with pathologic neurofibrillary degeneration and brain atrophy, as well as cognitive impairment (see, e.g., Mukaetova-Ladinska, E.B. et al., 2000, Am. J. Pathol., Vol 157, No. 2, pages 623-636). In Alzheimer's disease, both neuritic plaques and MNFs contain paired helical filaments (HAFs), of which a major constituent is microtubule-associated protein tau (see, eg, Wischik et al., 1988, PNAS USA, Vol. 85, pages 4506-4510). The 1246454 of 249 plaques also contain extracellular β-amyloid fibrils that derive from abnormal amyloid precursor protein (APP) processing (see, eg, Kang et al., 1987, Nature, Vol. 325, p. 733). An article by Wischik et al. (in 'Neurobiology of Alzheimer's Disease', 2nd Edition, 2000, Eds. Dawbarn, D. and Allen, S.J., The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford) discusses in detail the putative role of tau protein in the pathogenesis of neurodegenerative dementias. The loss of the normal form of tau, the accumulation of pathological FHAs, and the loss of synapses in the medial-frontal cortex correlate with associated cognitive impairment. Furthermore, synapse loss and pyramidal cell loss both correlate with morphometric measures of tau-reactive neurofibrillary pathology, which parallels, at a molecular level, an almost complete redistribution of the tau protein pool from one cell to another. soluble form to a polymerized form (ie, FHAs) in Alzheimer's disease. Tau exists in isoforms generated by alternative splicing, which contain three or four copies of a repetitive sequence that corresponds to the microtubule-binding domain (see, eg, Goedert, M., et al., 1989, EMBO J., 8, pages 393-399; Goedert, M., et al., 1989, Neuron, Vol. 3, pages 519-526). The Tau of FHAs is proteolytically processed to a nuclear domain (see, for example, Wischik, C.M., et al., 1988, PNAS USA, Vol. 85, pages 4884-4888; Wischik et al., 1988, PNAS USA, 85, pages 4506-4510; Novak, M., et al., 1993, EMBO J., Vol. 12, pages 365-370) which is composed of a phase-shifted version of the repetitive domain; only three repeats are involved in the stable tau-tau interaction (see, for example, Jakes, R., et al., 1991, EMBO 1246454 of 249 J., Vol. 10, pages 2725-2729). Once formed, FHA-type tau aggregates act as seeds for further capture and provide a target for proteolytic processing of full-length tau protein (see, eg, Wischik et al., 1996, PNAS USA , Vol. 93, pages 11213-11218). The phase change observed in the repetitive domain of the tau that was incorporated into the FHAs suggests that the repetitive domain undergoes a conformational change induced during its incorporation into the filament. During the onset of AD, it is believed that this conformational change may be initiated by the binding of tau to a pathological substrate, such as damaged or mutated membrane proteins (see, e.g., Wischik, C.M., et al., 1997, in “Microtubule-associated proteins: modifications in disease”, Eds. Avila, J., Brandt, R. and Kosik, K. S. (Harwood Academic Publishers, Amsterdam) pages 185-241). In the course of their formation and accumulation, FHAs first assemble to form amorphous aggregates within the cytoplasm, probably from early tau oligomers that become truncated prior to, or in the course of, FHA assembly (see , for example, Mena, R., et al., 1995, Acta Neuropathol., Vol. 89, pages 50-56 Mena, R., et al., 1996, Acta Neuropathol., Vol. 641). These filaments then go on to form classical intracellular MNFs. In this state, FHAs consist of a core of truncated tau and a diffuse outer shell containing full-length tau (see, eg, Wischik et al., 1996, PNAS USA, Vol. 93, pages 11213-11218). The assembly process is exponential, consuming the cellular pool of normal functional tau and inducing the synthesis of 1246454 of 249 new tau to counteract the deficit (see, eg, Lai, R.Y.K., et al., 1995, Neurobiology of Aging, Vol. 16, No. 3, pages 433-445). Eventually, functional impairment of the neuron progresses to the point of cell death, leaving behind an extracellular MNF. Cell death is highly correlated with the number of extracellular MNFs (see, for example, Wischik et al., in Neurobiology of Alzheimer's Disease, 2nd Edition, 2000, Eds. Dawbarn, D. and Allen, S.J., The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford). As the tangles exit the extracellular space, there is a progressive loss of the diffuse outer covering of the neuron with a corresponding loss of N-terminal tau immunoreactivity, but with preservation of core-associated tau immunoreactivity of FHAs (see, for eg, Bondareff, W. et al., 1994, J. Neuropath.Exper.Neurol., Vol. 53, No. 2, pages 158-164). Diaminophenothiazine Compounds Methithionium Chloride (MTC) (also known as Methylene Blue (MB); methylthionine chloride; tetramethylthionine chloride; 3,7-bis(dimethylamino)phenothiazin-5-io chloride; C.I. Basic Blue 9; tetramethylthionine chloride ; 3,7-bis(dimethylamino) phenazathionino chloride; Swiss blue; C.I. 52015; C.I. Solvent Blue 8; aniline violet; and Urolene Blue®) is a tricyclic organic compound of low molecular weight (319.86), soluble in water, with the following formula: 1246454 of 249 Methithionium Chloride (MTC) is a well-known phenothiazine dye and redox indicator and has also been used as an optical probe for biophysical systems, as an intercalator in nanoporous materials, as a redox mediator, and in photoelectrochromic imaging. Methithioninium Chloride (MTC) and other diaminophenothiazines have been described as inhibitors of protein aggregation in diseases in which proteins aggregate pathologically. In particular, diaminophenothiazines including MTC have been shown to inhibit tau protein aggregation and structure disruption of FHAs, and reverse the proteolytic stability of the FHA core (see, eg, WO 96 / 30766, Hofmann-La Roche ). Said compounds were disclosed for use in the treatment or prophylaxis of different diseases, including Alzheimer's disease. WO2007 / 110630 (WisTa Laboratories Ltd) also discloses certain specific MTC-related diaminophenothiazine compounds, including ETC, DEMTC, DMETC, DEETC, MTZ, ETZ, MTI, MTILHI, ETI, ETLHI, MTN, and ETN, that are useful. as drugs, for example in the treatment of Alzheimer's disease. In addition, WO 2005 / 030676 (The University Court of the University of Aberdeen) discusses radiolabelled phenothiazines, and their use in the diagnosis and 1246454 of 249 therapy, for example, of tauopathies. Methithionium chloride (MTC) has also been exposed for other medical uses. For example, it is currently used to treat methemoglobinemia (a disorder that occurs when the blood cannot deliver oxygen to parts of the body that need it). MTC is also used as a medicinal stain (for example, to stain certain parts of the body before or during surgery); diagnostic (eg, as an indicator dye to detect certain compounds present in urine); mild urinary antiseptic; mucosal surface stimulant; treatment and prevention for kidney stones; and in the diagnosis and treatment of melanoma. MTC has been used to treat malaria, either individually (see, for example, Guttmann, P. and Ehrlich, P., 1891, "Uber die wirkung des methyleneblau bei malaria," Berl. Klin. Woschenr., Vol. 28 , pages 953-956) or in combination with chloroquine (see, for example, Schirmer, H., et al., 2003, “Methylene blue as an antimalarial agent,” Redox Report, Vol. 8, pages 272-275; Rengelshausen, J ., et al., 2004, “Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria,” European Journal of Clinical Pharmacology, Vol. 60, pages 709-715). MTC (better named Virostat®, from Bioenvision Inc., New York) has also shown potent virucidal activity in vitro. Specifically Virostat® is effective against viruses such as HIV and West Nile Virus in laboratory tests. Virostat® is also currently in clinical trials for the treatment of chronic Hepatitis C, a viral infection of the liver. The virus, HCV, is a leading cause of acute hepatitis and chronic liver disease, including cirrhosis and liver cancer. 1246454 of 249 MTC, when combined with light, can also prevent nucleic acid (DNA or RNA) replication. Plasma, platelets, and red blood cells do not contain nuclear DNA or RNA. When MTC is introduced into plasma components, it crosses bacterial cell walls or the viral membrane and then moves into the nucleic acid structure. When activated by light, the compound binds to the nucleic acid of the viral or bacterial pathogen, preventing DNA or RNA replication. Because MTC can inactivate pathogens, it has the potential to reduce the risk of transmission of pathogens that would remain undetected in tests. Oral and parenteral formulations of MTC have been commercially available in the United States, usually under the name Urolene Blue®. Reduced (“leuco”) forms MTC, a phenothiazine-5-io salt, can be considered as an "oxidized form" relative to the corresponding 10H-phenothiazine compound, N,N,N',N'-tetramethyl-10H-phenothiazine-3,7-diamine, which can be considered as a "reduced form": reduced formoxidized form (MTC) I I N i I Cl© 1246454 of 249 The "reduced form" (or "leuco form") is known to be unstable and can be rapidly and easily oxidized to the corresponding "oxidized" form. May et al. (Am J Physiol Cell Physiol, 2004, Vol. 286, pages C1390C1398) have shown that human erythrocytes sequentially deplete and uptake MTC; that MTC itself is not taken up by cells; that it is the reduced form of MTC that crosses the cell membrane; that the rate of uptake is enzyme dependent; and that both MTC and reduced MTC are concentrated in cells (reduced MTC re-equilibrates once inside the cell to form MTC). MTC and similar drugs are taken up in the intestine and enter the bloodstream. Unabsorbed drug filters through the alimentary canal to the distal intestine. An important unwanted side effect is the effect of the unabsorbed drug on the distal gut, eg sensitization of the distal gut and / or the antimicrobial effects of the unabsorbed drug on the distal gut flora, both leading to diarrhoea. Therefore, it is desirable to minimize the amount of drug that leaks into the distal intestine. By increasing drug uptake in the gut (ie, by increasing drug bioavailability), dosage can be reduced, and unwanted side effects, such as diarrhea, can be alleviated. Since it is the reduced form of MTC itself that is taken up by cells, it may be desirable to administer the reduced form to patients. This may also reduce safety in the rate limiting enzyme reduction step. 1246454 of 249 WO 02 / 055720 (The University Court of the University of Aberdeen) discloses the use of the reduced forms of certain diaminophenothiazines for the treatment of protein aggregation diseases, mainly tauopathies. WO2007 / 110627 (WisTa Laboratories Ltd) discloses certain 3,7-diamino-10H-phenothiazinium salts, which are effective as drugs or prodrugs for the treatment of diseases including Alzheimer's disease. These compounds are also in the "reduced" or "leuco" form when considered with respect to MTC. These include the following salts: H 1 x N^ / A Me^ JL .Me z N S Ns Me Me HCl HCl N,N,N',N'-tetramethyl10H-phenothiazine-3,7-diaminium di(chloride), (LMT.2HCl) H 1 Nx / X Me^ / L „.Me _ N S NC Me Me HBr HBr N,N,N',N'-tetramethyl10H-phenothiazine-3,7-diaminium di(bromide), (LMT.2HBr) H 1 N Me^ / -Lx .-Me N S NC Me Me HI HI N,N,N',N'-tetramethyl10H-phenothiazine-3,7-diaminium di(iodide), (LMT.2HI) Although it provides certain advantages over the use of MTC, the synthesis of LMT.2HCl under certain conditions can result in CHaCl trapped within 1246454 of 249 of the glass. Therefore it needs to be removed because CH3Cl is toxic and its levels need to be kept below safe levels. Furthermore LMT.2HBr contains bromide ions. In principle this is less desirable because bromide is toxic either at high levels or with chronic dosage or at low levels it can cause side effects in patients such as confusion. Therefore it can be seen that the provision of other salts of methylthioninium compounds, having one or more desirable properties over and above those already known, would be a contribution to the art. Furthermore, the provision of new formulations of methylthioninium compounds that improve stability, absorption, and / or otherwise improve their efficacy as therapeutic agents would be a contribution to the art. Synthesis of the invention These inventors have now identified a new class of stable phenothiazindiaminium compounds having improved properties compared to previously discussed diaminophenothiazine compounds and salts. The properties of the compounds are described herein below, where it can be seen that in preferred embodiments the invention may provide one or more improved physical, pharmacokinetic, biochemical or other beneficial properties. In other aspects these inventors also provide new formulations of 3,7-diamino-10H-phenothiazinium salts. In one aspect the present invention provides certain compounds, specifically, certain phenothiazindiaminium compounds, as described 1246454 of 249 hereby. The compound can be chosen from compounds of general formula (I): R9H R1 R R3NA R3NB RASOj RBSO^ (I) where: R1 and R9 are each independently selected from: -H, C1-4alkyl, C2-4alkenyl, and hologenated C1-4alkyl; R3NA and R3NB are each independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; R7NA and R7NB are each independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; and where: each of RA and RB is chosen independently of: C1-4alkyl, halogenated C1-4alkyl, and C6-waryl; either RA and RB are connected to form a RAB group, where RAB is selected from: C1-6 alkylene and C6-10 arylene; and pharmaceutically acceptable salts thereof. Another aspect of the invention relates to processes for synthesizing a compound as previously described. Another aspect of the invention relates to a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable carrier or diluent. 1246454 of 249 Another aspect of the invention relates to a method of preparing a pharmaceutical composition comprising admixing a compound as described herein and a pharmaceutically acceptable carrier or diluent. Another aspect of the invention relates to a pharmaceutical composition in solid dosage form, comprising a compound as described herein and further comprising at least one diluent suitable for dry compression, and optionally one or more other excipients. Another aspect of the invention relates to a process for the manufacture of a pharmaceutical composition by a dry compression method, wherein said composition in a solid dosage form comprises a compound as described herein, at least one suitable diluent for dry compression, and optionally one or more other excipients. Another aspect of the invention relates to a free-flowing cohesive powder, comprising a compound as described herein and at least one diluent suitable for dry compression, and optionally one or more other excipients, wherein said powder is capable of being compressed into a solid dosage form. Another aspect of the present invention relates to a method for reversing and / or inhibiting the aggregation of a protein (for example, a tau protein, a synuclein, etc.), for example, the aggregation of a protein associated with neurodegenerative disease. and / or clinical dementia, comprising contacting the protein with an effective amount of a compound or composition as described herein. This method can be carried out 1246454 of 249 performed in vitro, or in vivo. Another aspect of the present invention relates to a method of treating or prophylaxis of a pathological disorder in a subject comprising administering to said subject a prophylactically or therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition, preferably a pharmaceutical composition in solid dosage form, as further described herein. Another aspect of the present invention relates to a compound or composition as described herein for use in a method of treatment or prophylaxis (eg, of a pathological disorder) of a human or animal body by therapy. Another aspect of the present invention relates to the use of a compound or composition as described herein, in the manufacture of a medicament for use in the treatment or prophylaxis of a pathological disorder. In some embodiments, the pathological condition is a protein aggregation disease. In some embodiments, the pathological condition is a tauopathy, eg, a neurodegenerative tauopathy, eg, Alzheimer's disease or another disease described herein below. In some embodiments, the pathological condition is skin cancer, eg, melanoma. In some embodiments, the pathological condition is a 1246454 of 249 viral, bacterial, or protozoan-related pathological condition, eg, Hepatitis C, HIV, West Nile Virus (WNV), or malaria. Another aspect of the present invention relates to a method of inactivating a pathogen in a sample (for example a blood or plasma sample), comprising the steps of introducing a compound or composition as described herein, into the sample. , and then expose the sample to light. Another aspect of the present invention relates to a kit of components comprising (a) a compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and / or with a suitable packaging system; and (b) instructions for use, eg, written instructions on how to administer the compound or composition. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. Brief description of the figures Figure 1 shows the 1H NMR spectrum of an example of a compound of the invention (LMT.2MsOH) in deuterated methanol (CD3OD) at 600 MHz. Figure 2 shows the 13C NMR spectrum of LMT.2MsOH in CD3OD at a frequency of 100.56 MHz. Figure 3 shows the DEPT-135 spectrum of LMT.2MsOH in CD3OD at a frequency of 100.56 MHz. Figure 4 shows the HSQC spectrum of LMT.2MsOH in CD3OD at a frequency of 100.56 MHz. 1246454 of 249 Figure 5 shows an expanded section of the HSQC spectrum of LMT.2MsOH in CD3OD at a frequency of 100.56 MHz. Figure 6 shows the infrared spectrum (FT-IR) of LMT.2MsOH (KBr). Figure 7 shows the electron impact (EI) mass spectrum of LMT.2MsOH. Figure 8 shows the electrospray ionization (ESI) mass spectrum of LMT.2MsOH. Figure 9 shows the UV / Vis spectrum of LMT.2MsOH in deionized water. Figure 10 shows the HPLC signal for LMT.2MsOH. Figure 11 shows an X-ray powder diffractogram for LMT.2MsOH, measured with Cu Ka radiation. Figure 12 shows the FT-Raman spectrum for crystalline LMT.2MsOH. The strongest signals are found at 1615 cm-1, 1588 cm-11258 cm-1, at 1042 cm-1. Figure 13 shows the thermogravimetric profile for crystalline LMT.2MsOH. Constant weight was detected by TG and TG-FTIR until the start of decomposition at 240-270 °C. Figure 14 shows differential scanning calorimetry analysis for crystalline LMT.2MsOH. a m.p. acute at 271 °C (ΔΗ = 87 J / g) was immediately followed by decomposition. Figures 15a and 15b show the dynamic vapor adsorption (DVS) curve for crystalline LMT.2MsOH measured at 25 °C with 5% / h scan rate. Horizontal broken lines indicate one-equivalent water uptake steps. A constant weight was observed 1246454 of 249 sample (less than 0.5% weight change) in the relative humidity (r.h.) range between 0% and 70%. Above this r.h., water uptake increased rapidly, and the sample eventually became liquid. On drying, the water content decreased again to about 4 equivalents at 50% r.h. The DVS curve of the crystalline dihydrochloride salt (LMT.2HCl) is shown for comparison as a broken line, the DVS curve of the dihydrochloride salt (LMT.2HBr) as a dotted line. Figure 15c shows the dynamic vapor adsorption (DVS) curve for crystalline LMT.2MsOH as a function of time. Relative humidity (right axis) is also indicated. The horizontal broken lines indicate capture steps of a water equivalent. Figure 16 shows polarization microscopy photos of LMT.2MsOH (left) and recrystallized LMT.2MsOH (right). Crystals up to 100 µm in size were obtained by recrystallization from 2PrOH / water. The crystals have irregular shapes. Figures 17a-c show the X-ray crystal structures of LMTEsOH, LMT.EDSA. and LMT.2MsOH Figure 18 shows a comparison of plasma concentration in pigs from the MT group over time, after dosing with LMT.2HBr, LMT.2HCl and LMT.2MsOH. Figure 19 is a diagram of the apparatus that was used in the dissolution studies (see Formulation Example 12). Detailed description of the invention These inventors have identified a new class of phenothiazindiaminium compounds having physical or other properties 1246454 of 249 desirable and / or surprisingly better activity compared to previously discussed phenothiazindiaminium compounds and salts. In other aspects they have also provided new formulations of phenothiazindiaminium compounds, including (but not limited to) the above class. compounds In general terms, unless the context indicates otherwise, the compounds of the invention may be described as bis(sulfonate) salts (or bis(sulfonic acid) acid salts) of 3,7-diamino-10H-phenothiazine compounds. In other words, the compounds are salts of the compounds 3,7-diamino-10H-phenothiazine corresponding with organic sulfonic acids. More specifically, a compound of the invention is a bis(sulfonate) salt of a compound of the general formula: where R1, R9, R3NA, R3NB, R7NA and R7NB are as defined above. In some embodiments, the salt is a bis(alkylsulfonate) salt or a bis(arylsulfonate) salt. In some embodiments, the salt is selected from a bis(methanesulfonate) salt, a bis(ethanesulfonate) salt, a bis(p-toluenesulfonate) salt, a bis(benzenesulfonate) salt, an ethanedisulfonate salt, a propanesulfonate salt, or a naphthalenedisulfonate salt. In some embodiments, the salt is a bis(methanesulfonate) salt (which may also be called a bis(mesylate) salt). 1246454 of 249 In some embodiments, the salt is a bis(ethanesulfonate) salt (which may also be called a bis(esylate) salt). In some embodiments, the salt is a bis(p-toluenesulfonate) salt (which may also be called a bis(tosylate) salt). In some embodiments, the salt is a bis(benzenesulfonate) salt. In some embodiments, the salt is an ethanedisulfonate salt. In some embodiments, the salt is a propanedisulfonate salt. In some embodiments, the salt is a naphthalene disulfonate salt, preferably a naphthalene-1,5-disulfonate salt. In other words, the compounds of the invention can be considered as products obtained from the reaction of a 3,7-diamino-10H-phenothiazine compound, for example as described, with two organic sulfonic acid moieties (RASO3H and RBSO3H) . The two organic sulfonic acid moieties may optionally be present on the same molecule, for example where RA and RB join. In some embodiments, the compounds of the invention are selected from the compounds of general formula (I): where: R9 H R RASOj N +O3NAr7Nb / N yes RBSOg HR H(I) R1 and R9 are each independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; each of R3NA and R3NB is independently selected from: -H, 1246454 of 249 Ci-4alkyl, C2-4alkenyl, and halogenated Ci-4alkyl; R7NA and R7NB are each independently selected from: -H, Ci-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; and where: each of RA and RB is independently selected from: C1-4alkyl, halogenated C1-4alkyl, and C6-10aryl; RA and RB join to form a group RAB, where RAB is selected from: C1-6 alkylene and C6-10 arylene; and pharmaceutically acceptable salts, solvates, and hydrates thereof. The compounds of the invention are represented herein by a general formula showing the structure of the compound 3,7-diamino-10H-phenothiazine, where the 3,7-diamino groups are in the protonated form. The resulting doubly positively charged species is associated with two sulfonate counterion moieties (which may optionally be present on the same molecule, e.g. RA and RB): H R9 R1 , 3NA , 3NB R R' RASO3 RbSOÍ^ However, as one skilled in the art will understand, the same salt can be represented in other ways, such as: 1246454 of 249 RaSO3H rbso3h h I N\, / ly D 7NA ® I I I d ®t D3NB R \ •X'Xs / R r 7NB / NS N^p3NB Ο Ό Ox zO ' s' X Ra / οθrB ΟΘ ; R7NBR3NB.2 RSO3H (where Ra=Rb=R) etc. Additional definitions and preferences The term "C^ alkyl", as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from a hydrocarbon compound with 1 to 4 carbon atoms, which may be aliphatic or acyclic, or a combination of them. Similarly, the term "C2-4alkenyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a C2-4 alkene compound (for example, a hydrocarbon compound with at least one double bond and between 2 and 4 carbon atoms). carbon). The term "C1-6 alkylene", as used herein, refers to a bidentate moiety obtained by removing two hydrogen atoms, either from the same carbon atom, or from two different carbon atoms, from a compound. linear aliphatic hydrocarbon with between 1 and 6 carbon atoms. In some embodiments, the C1-4alkyl groups may be selected 1246454 of 249 from: linear Ci-4alkyl groups, such as -Me, -Et, -nPr, -iPr, and -nBu; C3-4 branched alkyl groups, such as -iPr, -iBu, -sBu, and -tBu; and cyclic C3-4alkyl groups, such as -cPr and -cBu. In some embodiments, the C2-4alkenyl groups may be selected from linear C1-4alkenyl groups, such as -CH=CH2 (vinyl) and -CH2-CH=CH2 (allyl). In some embodiments, the halogenated C1-4alkyl groups can be selected from: -CF3, -CH2CF3, and -CF2CF3. The term “C6-10 aryl”, as used herein, refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a C6-10 aromatic compound, where said compound has a C6-10 aromatic ring. or two or more rings (eg, fused), and with between 6 and 10 ring atoms, and wherein at least one of said rings is an aromatic ring. The term "C6-10 arylene", as used herein, refers to a bidentate moiety obtained by removing two hydrogen atoms from an aromatic compound with 6 to 10 carbon atoms. In some embodiments, the C6-10 aryl groups may be selected from C6-10 carboaryl groups such as phenyl, and naphthyl. In some embodiments, the C6-10 arylene groups can be selected from phenylene and naphthylene. Said C1-4 alkyl and C1-6 alkylene groups may be unsubstituted or may be optionally substituted, for example with one or more groups selected from halo (for example F, Cl, Br, or I), amino (for example -NH2 , -NHR, or -NR2, where each R is independently C1-4alkyl), hydroxy 1246454 of 249 (-OH), alkoxy (-O, where R is independently Ci-4alkyl), nitro (-NO2), etc. Said C6-10 aryl and C6-10 arylene groups may be unsubstituted or may be optionally substituted, for example with one or more groups selected from C1-4 alkyl, eg -Me, halogenated C1-4alkyl, eg -CF3, halo (for example F, Cl, Br, or I), amino (for example -NH2, -NHR, or -NR2, where each R is independently C1-4alkyl), hydroxy (-OH), alkoxy (-O , where R is independently C1-4alkyl), nitro (-NO2), etc. RA and RB groups RA and RB are each independently selected from: C1-4alkyl, halogenated C1-4alkyl, and C6-10aryl; either RA and RB are joined to form a group RAB, where RAB is selected from: C1-6 alkylene and C6-10 arylene; In some embodiments, each of RA and RB is independently selected from: C1-4alkyl, halogenated C1-4alkyl, and C6-10aryl. In some embodiments, RA and RB are each independently C1-4 alkyl. In some embodiments, each of RA and RB is independently selected from Me, Et, nPr, iPr, nBu, iBu, tBu. In some embodiments, RA and RB are each independently selected from Me and Et. In some embodiments, each of RA and RB is independently C6-10aryl. 1246454 of 249 In some embodiments, each of RA and RB is independently selected from benzene, 1-naphthalene, 2-naphthalene, and p-toluene. In some embodiments, each of RA and RB is independently selected from Me, Et, benzene, and p-toluene. In some embodiments, RA and RB are the same. In some embodiments, RA and RB are different. In some embodiments, RA and RB are the same and are independently Me. The compound can then be called a salt of R1 +r3NA N^_3NB HRdiaminophenothiazine bis(methanesulfonate) which has the general formula (Ia): Θ MeSO! Θ MeSO¡ (Ia) In some embodiments, RA and RB are joined to form a RAB group. In these embodiments, the compounds of the invention may alternatively be represented by the general formula Ib: R9 H R1 YO . Yo N. / k r 7NA^@I Jl ® r3NAD7NB / NSzN^r_13NBRHHR SO3rab SO3(Ib) where RAB is selected from C1-6 alkylene and C6-10 arylene. In some embodiments, RAB is a C1-6 alkylene group. In some embodiments, RAB is a C1-6 alkylene group selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2, and -CH2CH2CH2CH2CH2CH2-. 1246454 of 249 In some embodiments, RAB is a C1-6 alkylene group selected from methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2-). In some embodiments, RAB is ethylene. In some embodiments, RAB is a C6-10 arylene group. In some embodiments, RAB is a C6-10 arylene group selected from phenylene and naphthylene. In some embodiments, RAB is phenylene. In some embodiments, RAB is selected from 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene. In some embodiments, RAB is phenylene optionally substituted with one or more substituents, for example selected from C1-4 alkyl, C14 halogenated alkyl, and halo. In some embodiments, RAB is naphthylene. In some embodiments, RAB is selected from 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, and 1,8-naphthylene. In some embodiments, RAB is selected from: 1,5-naphthylene, for example ΓΎί and 1,8-naphthylene, for example In some embodiments, RAB is naphthylene optionally substituted with one or more substituents, for example selected from C1-4 alkyl, C125 1246454 of 249 halogenated 4alkyl, and halo. R1 and R9 groups In some embodiments, R1 and R9 are each independently -H, -Me, -Et, or -CF3. In some embodiments, R1 and R9 are each independently -H, -Me, or -Et. In some embodiments, R1 and R9 are the same. In some embodiments, R1 and R9 are different. In some embodiments, stand-alone -H. In some embodiments, stand-alone -Me. In some embodiments, stand-alone -Et. R3NA and R3NB groups each of R1 and R9 is in the form each of R1 and R9 is in the form each of R1 and R9 is in the form Each of R3NA and R3NB is independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl. In some embodiments, each of R3NA and R3NB is independently selected from: C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl. In some embodiments, each of R3NA and R3NB is independently -Me, -Et, -nPr, -nBu, -CH2-CH=CH2, or -CF3. In some embodiments, each of R3NA and R3NB is independently -Me, -nPr, -nBu, -CH2-CH=CH2, or -CF3. In some embodiments, each of R3NA and R3NB is independently -Me or -Et. 1246454 of 249 In some embodiments, R3NA and R3NB are the same. In some embodiments, R3NA and R3NB are different. In some embodiments, each of R3NA and R3NB is independently -Me. R7NA and R7NB groups R7NA and R7NB are each independently selected from: -H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl. In some embodiments, each of R7NA and R7NB is independently selected from: C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl. In some embodiments, each of R7NA and R7NB is independently -Me, -Et, -nPr, -nBu, -CH2-CH=CH2, or -CF3. In some embodiments, each of R7NA and R7NB is independently -Me, -nPr, -nBu, -CH2-CH=CH2, or -CF3. In some embodiments, each of R7NA and R7NB is independently -Me or -Et. In some embodiments, R7NA and R7NB are the same. In some embodiments, R7NA and R7NB are different. In some embodiments, each of R7NA and R7NB is independently -Me. R3NA, R3NB, R7NA and R7NB groups In some embodiments: each of R3NA and R3NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl; each of R7NA and R7NB is independently C1-4alkyl, C2-4alkenyl, or halogenated C1-4alkyl. 1246454 of 249 In some embodiments: each of R3NA and R3NB is independently -Me, -Et, -nPr, -nBu, -CH2-CH=CH2, or -CF3; each of R7NA and R7NB is independently -Me, -Et, -nPr, -nBu, -CH2-CH=CH2, or -CF3. In some embodiments: each of R3NA and R3NB is independently -Me or -Et; each of R7NA and R7NB is independently -Me or -Et. In some embodiments, R3NA and R3NB and R7NA and R7NB are all the same. In some embodiments, R3NA and R3NB and R7NA and R7NB are the same and are all -Me or all -Et. In some embodiments, R3NA and R3NB and R7NA and R7NB are the same and are all -Me. Salts and solvates Although the compounds described herein are salts themselves, they can also be provided in mixed salt form (eg, the compound of the invention in combination with another salt). Such mixed salts are encompassed by the term "and pharmaceutically acceptable salts thereof". Unless otherwise specified, any reference to a particular compound also includes salts thereof. The compounds of the invention can also be provided in the form of a solvate or hydrate. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (eg, compound, salt of compound) and solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate, for example, a 1246454 of 249 mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, any reference to a compound also includes the solvate and hydrate forms thereof. Naturally, solvates or salt hydrates of the compounds are also encompassed by the present invention. isotopic variation In some embodiments, one or more carbon atoms in the compound is 11C, 13C, or 14C. In some embodiments, one or more carbon atoms in the compound is 11C. In some embodiments, one or more carbon atoms in the compound is 13C. In some embodiments, one or more carbon atoms in the compound is 14C. In some embodiments, one or more nitrogen atoms of the compound is 15N. In some embodiments, one or more or all of the carbon atoms in one or more or all of the R3NA, R3NB, R7NA, R7NB, R1, R9, RA, and RB groups is 11C, 13C, or 14C. In some embodiments, one or more or all of the carbon atoms in one or more or all of the R3NA, R3NB, R7NA, and R7NB groups is 11C, 13C, or 14C. combinations All compatible combinations of the described embodiments are explicitly described herein as if each combination were specifically and individually mentioned. 1246454 of 249 In particular, in the compounds of the invention, the groups R3NA, R3NB, R7NA, R7NB, R1, R9, RA, and RB(and RAB) are defined as independent variables and those skilled in the art will recognize that any compatible combination of these can be used. groups and substituents in the compounds and methods of the present invention. All compatible combinations of these and other defined variables are therefore specifically encompassed by the present invention, and are described herein as if each combination were specifically and individually mentioned. Some preferred embodiments In some embodiments, the compound of the invention may be selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates, solvates, and hydrates thereof: 1 H 1 x N Me^®X X ® Me N S ^Nx Me ' Me H Θ MeSO¡ Θ MeSO¡ LMT.2MsOH (LMTM) 2 H 1 N,.Me^XL JL JL XL® / Me z N S NC Me ' Me HO EtSOg Θ EtSOg LMT.2EsOH 1246454 of 249 1246454 of 249 A particular compound of the invention is compound 1: H I N^ / -;. Me-XX-JC. X^ y N S< Me \> Me H H Os / OOs zO / s'X N,N,N',N'-tetramethyl-10 H-phenothiazin-3,7-diaminium O© bis(methanesulfonate). This compound may also be called: N,N,N',N'-tetramethyl-10 H-phenothiazin-3,7-diamine bis(hydromethanesulfonate) leucomethylthioninium bis(hydromethanesulfonate) leucomethylthioninium bis(mesylate) LMTM LMT.2MsOH Purity The compounds of the present invention may be conveniently described as being in a "stabilized reduced form." Compounds are oxidized (eg autoxidized) to the corresponding oxidized forms. Therefore, it is likely, if not inevitable, that compositions comprising the compounds of the present invention will contain, as an impurity, at least some of the corresponding oxidized compound. Therefore, another aspect of the present invention relates to compounds as described herein, in substantially purified form and / or in a form substantially free of contaminants (eg, the corresponding oxidized compound, other contaminants). In some embodiments, the substantially purified form is at least 50 wt% pure, eg, at least 60 wt% pure, for 1246454 of 249 example, at least 70% by weight pure, for example, at least 80% by weight pure, for example, at least 90% by weight pure, for example, at least 95% by weight pure, for example, at less than 97 wt% pure, eg at least 98 wt% pure, eg at least 99 wt% pure. In some embodiments, the contaminants represent no more than 50 wt%, eg no more than 40 wt%, eg no more than 30 wt%, eg no more than 20 wt%. for example, not more than 10% by weight, for example, not more than 5% by weight, for example, not more than 3% by weight, for example, not more than 2% by weight, for example, not more than 1% by weight. Product by Process In some embodiments, the compound is one that is made by, or can be made by, a method as described herein. Chemical Synthesis Methods for the chemical synthesis of the compounds of the present invention are described herein. These and / or other well-known methods may be modified and / or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention. The compounds of formula (I): R9H R1 R R3NA R3NB RASOj RBSO^ (I) 1246454 of 249 can be prepared from compounds of formula (II): where R1, R9, R3NA, R3NB, R7NA, and R7NB are as previously defined. Compounds of formula (II) can be prepared, for example, from compounds of formula (III): where RProt is an amine protecting group and R1, R9, R3NA, R3NB, R7NA, R7NB, RA and RB are as previously defined. By way of non-limiting example, RProt may be an acyl group, for example an acetyl (-C(=O)Me) or benzoyl (-C(=O)Ph) group. Compounds of formula (II) can be prepared for example by deprotection of compounds of formula (III), or by other known methods. On the contrary, the compounds of formula (II) can be produced by protection of the compounds of formula (III). Compounds of formulas (II) and (III) are known, and may be prepared from known and / or commercially available starting materials, for example from the corresponding phenothiazine compounds, using known methods. For example, intermediates of formula (II) and (III) were used in the methods for the synthesis of 3,7-diamino-10H-phenothiazine hydrochloride, hydrobromide and hydroiodide salts disclosed in WO2007 / 110627. 1246454 of 249 As disclosed therein, a suitable phenothiazine can be converted to the corresponding 3,7-dinitro-phenothiazine, for example using sodium nitrite with acetic acid and chloroform. The ring amino group can then be protected, for example as acetate, for example using anhydrous acetic acid and pyridine. The nitro groups can then be reduced to amino groups, for example using tin(II) chloride with ethanol. The amino groups can then be substituted, for example disubstituted, for example methyl disubstituted, for example using methyl iodide, sodium hydroxide, DMSO, and tetra-n-butyl ammonium bromide, to provide a 3,7-dialkylamino-10H N-acetyl-protected phenothiazine. Examples of such a method are illustrated in schemes 1a and 1b. The use of any one or more of the reagents described herein in the process is of course encompassed by the present invention: Scheme 1a H 1 N\X^ Γ ϊ Ύ J S''^'^ OyM Ac2O, pyridine n XX 1 02^^^-^5^ Mel, NaOH, DMSO, (nBu)4NBr H NaNO2 1 —3—” XX XX 02N'' ^ no2 e O^Me SnCl2, EtOH N i ' XX XX no2 H2N'^ O^Me N'-'v'^ Me^ JX, XL „,Me N S N 1 1 Me Me 35 1246454 35 249 Scheme 1b O2N DMSO, NaNO2AcOH (a) Pd / C, 2-MeTHF, H2no2 (a) HCO, H or (b) Zn, NH4Cl(aq) NO MeOH, THF or (b) H2CO, NaCNBH3AcOH The amino group of this N-acetyl intermediate can then be deprotected, ie the N-acetyl group can be removed, for example using aqueous acid. Compounds of formulas (II) and (III) can also be made using the methods set forth in WO2008 / 007074. This document discloses compounds of formula (III) and compounds of formula (II) wherein RProtes an acyl group, for example an acetyl group. In one approach, a suitable thioninium chloride (eg, methyl thioninium chloride, ethyl thioninium chloride, etc.) can first be reduced and acetylated to give the corresponding 1-(3,7-bis-dimethylamino-phenothiazin-10- il)ethanone, for example, by reaction with hydrazine (NH2NH2), methyl hydrazine (MeNHNH2), or sodium borohydride (NaBH4); and acetic anhydride ((H3CCO)2O); for example, in the presence of a suitable base, for example, pyridine (C5H5N) or Hünig's base (diisopropylethylamine, C8H19N), for example, in 1246454 of 249 a suitable solvent, for example, ethanol or acetonitrile. The reduced and acetylated compound (of formula (III)) can then be deprotected (by removal of the acetyl group), for example by reaction with a suitable acid, to give a compound of formula (II) or used directly. Advantageously, this reaction can produce a product with a high degree of purity. An example is shown in the following schematic. Scheme 2 TCM 1. MeNHNH 2. Ac2O, iPr2EtN In another approach, a suitable thioninium salt, eg, ethyl thioninium semi zinc chloride, can be simultaneously reduced and protected at the ring amino group, eg, by reaction with a phenylhydrazine reducing agent, ethanol. , acetic anhydride, and pyridine. An example is shown in the following diagram: Scheme 3 In one aspect, the present invention therefore provides a method of preparing a 3,7-diamino-10H-phenothiazine compound of formula (I): 1246454 of 249 H R R9 R1 r3NA r3NB rAsc>3 RBSO^ (I) from a compound of formula (II): ......r3NAN\d3NB R (II) where RA, Rb, R1, R9, R3NA, R3NB, R7NA, and R7NB are as previously defined. In some embodiments, the method comprises the step of: forming the salt (SF). In some embodiments, the formation of the (SF) salt comprises treating a compound of formula (II) with an appropriate sulfonic acid. In some embodiments, salt formation comprises treating a solution of a compound of formula (II) with an appropriate sulfonic acid, in an organic solvent. In another aspect, the present invention provides a method for preparing a 3,7-diamino-IOH-phenothiazine compound of formula (I): H R R9 R1 r3NAr3NB RASÓRBSOj (I) from a compound of formula (III): 1246454 of 249 where RA, RB, R1, R9, R3NA, R3NB, R7NA, and R7NB are as previously defined and where RProt is an amine protecting group. A wide variety of amine protecting groups are widely used and well known in organic synthesis. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006). In some embodiments, the amine protecting group is an acid cleavable protecting group. In some embodiments, the amine protecting group is an acyl group, such as an acetyl group. In some embodiments, the method comprises the steps of: deprotecting the ring amine (DP); and form the salt (SF). Ring amino deprotection (DP) comprises removal of the protecting group to convert the N-protected ring amino group (-NRProt-) to a free ring amino group (-NH-). Deprotection of a compound of formula (III) produces the corresponding compound of formula (II). Methods for the removal of amine protecting groups are known in the art. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006). In some embodiments, the step of deprotecting the ring amine (DP) and the step of forming the salt (SF) are carried out simultaneously. 1246454 of 249 (ie as a step). For example: r3NAN''~d3NB R H R9 R1 r3NAr3NB RASO® RBSO® In some embodiments, simultaneously deprotecting the ring amine (DP) and forming the salt (SF) comprises treating the compound of formula (III) with an appropriate sulfonic acid, to produce a bis(sulfonate) salt of formula (I ). In some embodiments, simultaneous amino ring deprotection and salt formation may comprise treating a solution of a compound of formula (III) in an organic solvent with the sulfonic acid and water. In some embodiments, the organic solvent is toluene. In the methods of the invention, the sulfonic acid can be chosen from alkylsulfonic acids and arylsulfonic acids. It may be a sulfonic acid of the formula RASO3H or RBSO3H, where RA and RB are as defined herein. In some embodiments, the sulfonic acid can be a disulfonic acid, ie a compound containing two sulfonic acid groups per molecule. These sulfonic acid groups can be connected by, for example, an alkylene or arylene group. In some embodiments the sulfonic acid can be chosen from: methanesulfonic acid (MsOH), ethanesulfonic acid (EsOH), benzenesulfonic acid (BSA), naphthalenesulfonic acid (NSA), p 1246454 of 249 toluenesulfonic acid (TsOH), ethanedisulfonic acid (EDSA), propanedisulfonic acid (PDSA), and naphthalene-1,5-disulfonic acid (NDSA). In some embodiments, the phenothiazine starting material (i.e. the compound of formula (III) in said organic solvent is first heated until completely dissolved and the resulting solution is filtered before addition of the reagents (i.e. the acid sulfonic acid and water). In some embodiments, the compound is heated in said organic solvent to a temperature between about 60 and 80°C, for example to a temperature of about 70°C. In some embodiments, the sulfonic acid is added in an amount of at least 2 molar equivalents, eg, about 2.2 molar equivalents, relative to the phenothiazine starting material. If a disulfonic acid is used, it will be understood that the molar amount of the acid will be at least 1 molar equivalent, for example about 1.1 molar equivalents, so as to achieve the same number of sulfonic acid groups per phenothiazine molecule of material. of departure. It may be desirable to add the sulfonic acid slowly to prevent an (exothermic) increase in temperature. Therefore, in some embodiments, the sulfonic acid is added gradually. In some embodiments, the sulfonic acid is added at a temperature of about 15-25°C. In some embodiments, after adding the sulfonic acid and water, the reaction is heated to a temperature of about 80-90°C. In some embodiments, the reaction is maintained at this 1246454 of 249 temperature until judged complete by eg chromatographic analysis. In some embodiments, after the reaction, the solution is treated with a counter solvent to precipitate the product. In some embodiments, the counter solvent is an alcohol, for example ethanol. It may be desirable to "seed" the reaction mixture with a small amount, eg about 1 mg per gram of starting material (compound of formula (II)), of the desired bis(sulfonate) product. Without being bound by theory, it is believed that the addition of the seed ensures early and efficient precipitation of the desired product, which reduces the opportunity for possible side reactions and by-product formation. The seed is also thought to be useful in controlling the particle size of the precipitated product. Therefore, in some embodiments, after the reaction, the resulting mixture is seeded with a small amount of the desired bis(sulfonate) salt. In some embodiments, the seed comprises particles of the desired bis(sulfonate) salt that have been ground. In some embodiments, the seed comprises particles of the desired bis(sulfonate) salt that have been ground to a size of less than about 100 pm. In some embodiments, the precipitated product is isolated by filtration. In some embodiments, after filtration, the product is washed with an organic solvent, eg, ethanol or acetonitrile. 1246454 of 249 Salt formation (SF) yields the bis(sulfonate) salt of formula (I) from the compound of formula (II): xR3NAN\d3NB R (II) SF R1 R9H (I)R3NAR3NB rasORBSOj As explained previously, the bis(sulfonate) salt can also be prepared directly from a corresponding amino-protected (eg N-acetyl) compound of formula (III). DP, SFxr3NaN\d3NB R (III) H R9 R1 R3NA r3NB(I) RASO® RBSO® In this case, the salt formation can be carried out at the same time as the deprotection, for example by using the appropriate sulfonic acid, eg methanesulfonic acid, for the deprotection step. An example is illustrated in the following scheme: Scheme 4 X Men Yo me me MsOH, H2O H I In another aspect, the present invention provides a method for preparing a compound of formula (I): 1246454 of 249 H R R9 R1 r3NA r3NB SATIN; RBSO^ (I) where RA, RB, R1, R9, R3NA, R3NB, R7NA, and R7NB are as previously defined. The method comprises: preparing a compound of formula (II) or (III) as defined herein, followed by forming the salt (SF) and / or deprotecting the ring amine (DP). The salt formation (SF) and amino ring deprotection (DP) steps are as previously described. In some embodiments, the preparation of said compound of formula (II) or (III) comprises a method as disclosed in WO2007 / 110627. In some embodiments, the preparation of said compound of formula (II) or (III) comprises a method as set forth in WO2008 / 007074. In some embodiments, the preparation of a compound of formula (II) comprises ring amino deprotection (DP) of a compound of formula (III), as previously stated. In some embodiments, the preparation of a compound of formula (III) comprises one or more steps selected from: nitrating (NO), 1246454 of 249 protect ring amino (AP), reduce nitro (NR), substitute amine (AS). In some embodiments, the preparation of a compound of formula (III) comprises the steps of reducing (RED), and protecting the ring amino (AP). The steps can be carried out in any logical order. In some embodiments, the steps are performed in the order listed (ie, any step in the list is performed at the same time as, or subsequent to, the preceding step in the list). In some embodiments, the nitration (NO) comprises: nitrate (NO), where a 10H-phenothiazine is converted to a 3,7-dinitro10H-phenothiazine, for example: R9 H R1 YO . I Nx / X - χχ X x O2N s NO2 In some embodiments, the nitration is carried out using a nitrite, eg, sodium nitrite, eg, sodium nitrite with acetic acid, and a solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, tetrahydrofuran, dimethoxyethane, acetone, dichloromethane or chloroform. In some embodiments, ring amino protection (AP) comprises: protect ring amino (AP), where the ring amino group (-NH) of a 3,7-dinitro-10H-phenothiazine is converted to a ring protected amino group (-NRprot), for example: 1246454 of 249 R9H R1 I I I no.,4 J Ϊ 1 Ί_ O2N'^^^^ In some embodiments, protection of the ring amino is achieved as acetate, eg, using anhydrous acetic, eg, using anhydrous acetic, and a base such as a basic amine, eg, triethylamine or pyridine. In some embodiments, the nitro reduction (NR) step comprises: nitro reduce (NR), where each of the nitro groups (-NO2) of a protected 3,7-dinitro-10H-phenothiazine is converted to an amino group (-NH2), for example: R9RProtR1R9RProtR1 I I I I I I N\zA^ r^^ / N^ / V r t 1Ί A ϊ IA O2N''''^''“'^S'''^^ H2N''''^'''--^Sx'^^ In some embodiments, the nitro reduction can be carried out using, for example, tin(II) chloride, eg, tin(II) chloride with ethanol. In some embodiments, the nitro reduction can be carried out using, for example, palladium on carbon (Pd / C) and hydrogen in, for example, 2-methyl-tetrahydrofuran. In some embodiments, the nitro reduction can be carried out using, for example, zinc and aqueous ammonium chloride in methanol and THF. In some embodiments, the amine substitution (AS) step comprises: substitute the amino group (AS), where each of the amino groups (46 1246454 of 249 NH2) of a protected 3,7-diamino-10H-phenothiazine is converted to a disubstituted amino group, for example: R9 RProtR1 I I I N\ / A XX XX-h2n AA s A^nHj In some embodiments, the amine substitution is carried out using an alkyl halide, eg, an alkyl iodide, eg, methyl iodide, eg, methyl iodide with sodium hydroxide, DMSO, toluene, and tetra-n-butyl ammonium bromide. In some embodiments, the amine substitution comprises treatment with formaldehyde (eg paraformaldehyde, formalin) under reducing conditions. For example, treatment with formalin and hydrogen gas, in the presence of a Pd / C catalyst; or treatment with paraformaldehyde in the presence of a reducing agent such as sodium cyanoborohydride and acetic acid. In some embodiments, the reduction step (RED) is: reduce (RED), wherein a 3,7-di(disubstituted amino)thioninium salt is reduced to give the corresponding 3,7-di(disubstituted amino)-10H-phenothiazine, for example by treatment with a reducing agent, such as such as hydrazine (NH2NH2), methyl hydrazine (MeNHNH2), or sodium borohydride and a base, such as pyridine, triethylamine, or Hünig's base (diisopropylethylamine). In some embodiments, the amino ring protection (AP) step is: protect the ring amino (AP), where a 3,7-di(disubstituted amino)-10H-phenothiazine is protected, for example by anhydride treatment 1246454 of 249 acetic, to give the corresponding protected 3,7-di(disubstituted amino)-10H-phenothiazine, eg the corresponding N-acetyl-3,7-di(disubstituted amino)10H-phenothiazine. In some embodiments, the steps are performed in the order in which they are listed (ie, any step in the list is performed at the same time as, or subsequent to, the preceding step in the list). In some embodiments, the reduction step (RED) and the amino ring protection step (AP) are performed simultaneously (ie, as one step). For example, in some embodiments, the combination of the reduction step (RED) with the amino ring protection step (AP) is: reduce (RED) and protect ring amino (AP), where a 3,7-di(disubstituted amino)-thioninium salt is reduced to the corresponding 3,7-di(disubstituted amino)-10H-phenothiazine, and converting the ring amino group (-NH-) of 3,7-di(disubstituted amino)-10H-phenothiazine to a ring-protected amino group (-Rprot) to give the corresponding 3,7-di(amino disubstituted)-10H-protected phenothiazine, for example: , 7NA R9 r7NB R1 r3NAr3NB where Y is a counterion. In some embodiments, Y represents Cl- In some embodiments, the 3,7-di(disubstituted amino)thioninium salt is methylthioninium chloride (MTC). 1246454 of 249 In some embodiments, the combination of the reduction step (RED) and the amino ring protection step (AP) is achieved using a hydrazine, such as phenylhydrazine, MeNHNH2, or NH2NH2.H2O, and acetic anhydride. In some embodiments, the step is carried out under a nitrogen atmosphere. In some embodiments the combination of the reduction step (RED) and the amino ring protection step (AP) is carried out using, for example, phenylhydrazine, ethanol, acetic anhydride, and pyridine. In some embodiments, the combination of the reduction step (RED) and the amino ring protection step (AP) is carried out using, for example, hydrazine hydrate, acetonitrile, acetic anhydride, and triethylamine, under a nitrogen atmosphere. In some embodiments, the protected 3,7-di(disubstituted amino)-10H-phenothiazine, for example N-acetyl-3,7-di(disubstituted amino)-10H-phenothiazine, is subjected to a purification step. In some embodiments, purification comprises the addition of an organic solvent, eg, toluene, and an acid, eg, acetic acid, to dissolve the compound, followed by a washing step. In some embodiments, washing comprises adding water and / or aqueous acetic acid to the compound solution; stirring and / or heating; and separation of the organic layer. In some embodiments, the wash is repeated, for example up to three times. In some embodiments, washing is followed by isolation. 1246454 of 249 of the purified product. In some embodiments, isolating the purified product comprises cooling, precipitating, and filtering the product. Crystal Forms In some embodiments, the compound of the invention is provided in crystalline form. In some embodiments, the crystalline form is "Form A" as described herein. In some embodiments, the crystalline form has the structure shown in Figure 17 and / or characterized by crystal data shown in an Appendix of Table 1 and / or atomic coordinates shown in an Appendix of Table 2 and / or the bond lengths and angles shown in an Addendum to Table 3 and / or the anisotropic displacement parameters shown in an Addendum to Table 4 and / or the hydrogen coordinates and displacement parameters isotropics that are shown in an Annex of Table 5. Reversal and / or Inhibition of Protein Aggregation One aspect of the invention is the use of a compound or composition as described herein, to regulate (eg, to reverse and / or inhibit) the aggregation of a protein, eg, the aggregation of a protein associated with a neurodegenerative disease and / or clinical dementia. The aggregation may be in vitro, or in vivo, and may be associated with a disease state as discussed below. Therefore, one aspect of the invention relates to a method of regulating (for example, reversing and / or inhibiting) the aggregation of a protein, e.g. For example, aggregating a protein that is associated with neurodegenerative disease and / or clinical dementia, comprising contacting the protein with an effective amount of a compound or composition as described herein. The method can be carried out in vitro, or in vivo. Similarly, one aspect of the invention relates to a method for regulating (eg, reversing and / or inhibiting) the aggregation of a protein in the brain of a mammal, which aggregation is associated with a disease state as described in herein, wherein the treatment comprises the step of administering to said mammal in need of said treatment, a prophylactically or therapeutically effective amount of a compound or composition as described herein, which is an inhibitor of said aggregation. Treatment Methods Another aspect of the present invention relates to a method of treatment comprising administering to a patient in need of treatment, a prophylactically or therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition. Use in Therapy Methods Another aspect of the present invention relates to a compound or composition as described herein, for use in a method of treating (eg, a pathological disorder) of a human or animal body by therapy. Use in the Manufacture of Medicines Another aspect of the present invention relates to the use of a 1246454 of 249 compound or composition as described herein, in the manufacture of a medicament for use in a treatment (eg, of a pathological disorder). In some embodiments, the medicament comprises a compound of the invention. In some embodiments, the medicament is a composition as described hereinafter. Pathological Conditions Treated - Protein Aggregation Diseases The compounds and compositions of the present invention are useful in the treatment or prophylaxis of protein aggregation diseases. Thus, in some embodiments, the pathological condition is a protein aggregation disease, and, for example, treatment is with an amount of a compound or composition as described herein that is sufficient to inhibit protein aggregation. of the protein associated with said pathological condition. In general, protein aggregation is that which originates from a conformational-induced polymerization interaction, that is, one in which a conformational change of the protein, or a fragment thereof, gives rise to binding and aggregation by copies of additional (precursor) protein molecules in a self-propagating manner. Once nucleation is initiated, an aggregation cascade can ensue involving conformationally induced polymerization of additional protein molecules, leading to the formation of toxic product fragments in aggregates that are substantially resistant to further proteolysis. Therefore the protein aggregates that form are thought to be a proximal cause of 1246454 of 249 pathological states that manifest as neurodegeneration, clinical dementia, and other pathological symptoms. The following Table lists different aggregating proteins associated with disease and the corresponding protein aggregation diseases. The use of the compounds and compositions of the invention with respect to these proteins or diseases is encompassed by the present invention. Protein aggregation diseases Protein Disease Domain and / or aggregation mutations Fibril subunit size (kDa) Reference Neurodegenerative disorders Prion protein Prion-associated diseases Inherited or sporadic forms 27 Prusiner (1998) (CJD, nvCJD, Fatal Familial Insomnia, Syndrome Gerstmann-Straussler-Scheinker, Kuru) PrP-27-30; many mutations. 27 Prusiner (1998) Fibrillogenic domains: 113-120, 178-191, 202-218. Gasset et al. (1992) Tau protein Alzheimer's disease, Down syndrome, FTDP-17, CBD, post-encephalitic parkinsonism, Pick's disease, parkinsonism with Guam dementia complex Inherited or sporadic forms 10-12 Wischik et al. (1988) Truncated Tau (tubulin-binding domain) 297-391. 10-12 Wischik et al. (1988) Mutations in tau in FTDP-17. Hutton et al. (1998) Many mutations in presenilin proteins. Czech et al. (2000) β-amyloid protein Alzheimer's disease, Down syndrome Inherited or sporadic forms 4 Glenner & Wong, (1984) β-amyloid protein; 142(3). 4 Glenner & Wong, (1984) ASF mutations in few families. Goate et al. (1991) Huntingtin Huntington's disease N-terminal protein with expanded glutamine repeats. 40 DiFiglia et al. (1997) Ataxins (1,2, 3, 7) Spinocerebellar ataxias (SCA1,2, 3, 7) Proteins with expanded glutamine repeats. Paulson et al. (1999) Atrophin Dentatorupallidolous Atrophy (DRPLA) Expanded Glutamine Repeat Proteins. Paulson et al. (1999) Androgen receptor Spinal and bulbar muscular atrophy Expanded glutamine repeat proteins. Paulson et al. (1999) Neuroserpina Familial encephalopathy with neuronal inclusion bodies (FENIB) Neuroserpina; S49P, S52R. 57 Davis et al. (1999) 1246454 of 249 Protein aggregation diseases Protein Disease Domain and / or aggregation mutations Fibril subunit size (kDa) Reference α-Synuclein Parkinson's disease with Lewy bodies, multiple system atrophy Inherited or sporadic forms 19 Spillantini et al. (1998) also PCT / GB2007 / 001105 A53T, A30P in few families with autosomal dominant PD. Polymeropoulos et al. (1997) TDP-43 FTLD-TDP Many mutations of TDP-43 10-43 Mackenzie et al. (2010) Amyotrophic lateral sclerosis Many TDP-43 mutations 10-43 Mackenzie et al. (2010) Cystatin C Hereditary Cerebral Angiopathy (Icelandic) Cystatin C minus 10 residues; L68Q. 12-13 Abrahamson et al. (1992) Superoxide dismutase 1 Amyotrophic lateral sclerosis Mutations of SOD1. 16 Shibata et al. (1996). Non-neurodegenerative disorders Hemoglobin Sickle cell anemia Hemoglobin beta (S) chain. Carrell & Gooptu (1998) Inclusion body hemolysis Many mutations. Serpins α1-antitrypsin deficiency (emphysema, cirrhosis) Mutations Lomas et al. (1992) Antithrombin deficiency (thromboembolic disease) Mutations Carrell & Gooptu (1998) C1-inhibitor deficiency (angioedema) Mutations Carrell & Gooptu (1998) Immunoglobulin light chain Plasma cell dyscrasias (primary systemic AL amyloidosis) Light chain or fragments. 0.5-25 Westermark et al. (1985) Serum Amyloid A Reactive Secondary Systemic AA Amyloidosis Fragment of 76 residues (critical residues 2-12). 4.5-7.5 Westermark et al. (1985) Chronic inflammatory disease Transthyretin Familial amyloid polyneutropathy (systemic; FAP I) Tetramer dissociated from conformational monomer variant. 10-14 Gustavsson et al. (1991) Many mutations (some not associated with amyloid; several different types of disease). Senile cardiac amyloidosis Normal transthyretin 10-14 Gustavsson et al. (1991) Gelsolin Familial Amyloidosis - Finnish type (FAP IV) D187Q leads to 173225 / 243 truncated (critical residues 182-192). 9.5 Maury & Baumann (1990) β2-Microglobulin Amyloidosis due to hemodialysis e2-Microglobulin 12-25 Gorevic et al. (1985) Prostatic amyloid Apolipoprotein AI Familial polyneuropathic amyloid (systemic; FAP III) N-terminal residues 83-93; G26R, W50R, L60R 9 Booth et al. (1997) Lysozyme Familial visceral amyloidosis Lysozyme or fragments (with or without I56T, D67H) 14 Pepys et al. (1993) Amylin (Islet Amyloid Polypeptide) Type II Diabetes (NIDDM) Fragments (critical core of 20-29); no mutations 3,9 Westermark (1990) Fibrinogen α chain Hereditary renal amyloidosis Fibrinogen fragments 7-10 Uemichi et al. (1992) 1246454 of 249 Protein aggregation diseases Protein Disease Aggregation domain and / or mutations Fibril subunit size (kDa) Reference Procalcitonin Medullary thyroid carcinoma Calcitonin fragments 3,4 Sletten et al. (1976) Atrial natriuretic factor Cardiac amyloidosis ANF, non-3,5 mutants Johansson et al. (1987) Insulin Localized injection amyloidosis Insulin Dische et al. (1988) Multiple protein myositis due to inclusion bodies β-amyloid, tau, ubiquitin, ApoE, and presenilin-1 Askenas et al. (2009) Other amyloid-forming proteins (in vitro) Other proteins Chiti et al. (1999) As described in WO 02 / 055720, WO2007 / 110630, and WO2007 / 110627, diaminophenothiazines have utility in the inhibition of said protein aggregation diseases. It will therefore be appreciated that, unless the context otherwise requires, the description of the embodiments with respect to tau protein or tau-like proteins (eg, MAP2; see below), should be taken as equivalently applicable to the other proteins discussed herein (eg, β-amyloid, synuclein, prion, etc.) or other proteins that can initiate or undergo similar pathological aggregation by virtue of a conformational change in a domain critical for aggregation propagation, or imparting proteolytic stability to the aggregate so formed (see, for example, the article by Wischik et al. in "Neurobiology of Alzheimer's Disease", 2nd Edition, 2000, Eds. Dawbarn, D. and Allen, S.J., The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford). All such proteins may be referred to herein as "aggregation disease proteins." Similarly, where mention is made herein to "tau-tau aggregation", or the like, this should also be taken to apply to other "aggregating protein aggregations", such as β aggregation. 1246454 of 249 amyloid, prion aggregation, synuclein aggregation, etc. The same applies to "proteolytic degradation of tau", etc. Preferred Aggregation Disease Proteins Preferred embodiments of the invention are based on the tau protein. The term "tau protein," as used herein, refers generally to any protein in the family of tau proteins. Tau proteins are characterized as one of a large number of protein families that co-purify with microtubules during repeated cycles of assembly and disassembly (see, eg, Shelanski et al., 1973, Proc. Natl. Acad. Sci. USA, Vol. 70, pages 765-768), and are known as microtubule-associated proteins (MAPs). Members of the tau family share the common features of having a characteristic N-terminal segment, approximately 50 amino acid sequences inserted into the N-terminal segment, which are developmentally regulated in the brain, a region of tandem repeats characteristic consisting of 3 or 4 tandem repeats of 31 to 32 amino acids, and a C-terminal tail. MAP2 is the predominant microtubule-associated protein in the somatodendritic compartment (see, for example, Matus, A., in “Microtubules” [Hyams and Lloyd, Eds.] pages 155-166, John Wiley and Sons, New York, USA). USA). MAP2 isoforms are almost identical to tau protein in the tandem repeat region, but differ substantially in both sequence and length of the N-terminal domain (see, eg, Kindler and Garner, 1994, Mol. Brain Res., Vol. 26, pages 218-224). However, aggregation in the tandem repeat region is not selective for the tau repeat domain. Therefore it will be appreciated that 1246454 of 249 any discussion herein regarding tau protein or tau-tau aggregation should also be interpreted in relation to tau-MAP2 aggregation, MAP2-MAP2 aggregation, etc. In some embodiments, the protein is tau protein. In some embodiments, the protein is a synuclein, eg, α- or β-synuclein. In some embodiments, the protein is TDP-43. TAR DNA Binding Protein 43 (TDP-43) is a 414 amino acid protein encoded by TARDBP on chromosome 1p36.2. The protein is highly conserved, widely expressed, and predominantly localized in the nucleus, but can be exchanged between the nucleus and the cytoplasm (Mackenzie et al. 2010). It is involved in the regulation of transcription and splicing and may have roles in other processes, such as: microRNA processing, apoptosis, cell division, messenger RNA stabilization, regulation of neuronal plasticity, and maintenance of dendritic integrity. Furthermore, since 2006 a substantial body of evidence has accumulated in support of the toxic gain-of-function hypothesis of TDP-43 in amyotrophic lateral sclerosis (ALS). TDP-43 is an inherently aggregation-prone protein, and the aggregates that form in vitro are ultrastructurally similar to the TDP-43 deposits seen in degenerating neurons in ALS patients (Johnson et al. 2009) . Johnson et al. (2008) showed that when TDP-43 is overexpressed in a yeast model, only the aggregated form is toxic. Several in vitro studies have also shown that the C-terminal fragments of TDP-43 are more likely than TDP-43 to 1246454 full length to form insoluble cytoplasmic aggregates that become ubiquitinated, and which are toxic to cells (Arai et al. 2010; Igaz et al. 2009; Nonaka et al. 2009; Zhang et al. 2009). Although Nonaka et al. (2009) suggested that these cytoplasmic aggregates bind to the endogenous full-length protein causing it to disappear from the nucleus, Zhang et al. (2009) found retention of normal nuclear expression, suggesting a purely toxic effect of the aggregates. Yang et al. (2010) have described the capture of full-length TDP-43 within aggregates of C- and N-terminal fragments of TDP-43 in cultured NSC34 motor neurons. Neurite appendages, damaged as a result of the presence of such truncated fragments, could be rescued by overexpression of the full-length protein. Although the role of neurite appendages in vivo has not been established, this model would support the suggestion made by Nonaka and colleagues for a role for TDP-43 aggregation in the pathogenesis of ALS. It has been repeatedly reported that expression of mutant TDP-43 in cell culture has resulted in increased generation of C-terminal fragments, with even greater cytoplasmic aggregation and toxic effects than wild-type protein (Kabashi et al. 2008; Sreedharan et al. 2008; Johnson et al 2009; Nonaka et al 2009; Arai et al 2010; Barmarda et al 2010; Kabashi et al 2010). In cases where the protein is tau protein, in some embodiments of the present invention, a method is provided for inhibiting the production of protein aggregates (for example in the form of paired helical filaments (FHAs), optionally in neurofibrillary tangles 1246454 of 249 (MNFs) in the mammalian brain, where treatment is as previously described. Preferred Indications - Protein Aggregation Diseases Notably, it is not only Alzheimer's disease (AD) in which tau protein (and aberrant function or processing thereof) may play a role. The pathogenesis of neurodegenerative disorders such as Pick's disease and progressive supranuclear palsy (PSP) appears to correlate with a pathological accumulation of truncated tau protein aggregates in the dentate gyrus and stellate pyramidal cells of the neocortex, respectively. Other dementias include frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP 17), frontotemporal lobar degeneration (FTLD) syndromes; disinhibition-dementia-parkinsonism-amyotrophic complex (DDPAC), pallidum-ponto-nigra degeneration (PPND), Guam-ALS syndrome, pallidonigra-louisiana degeneration (PNLD), cortico-basal degeneration (CBD), and others (see, for Wischik et al article in "Neurobiology of Alzheimer's Disease", 2nd Edition, 2000, Eds Dawbarn, D. and Allen, S.J., The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford; especially Table 5.1) . All of these diseases, which are characterized primarily or partially by abnormal tau aggregation, are referred to herein as "tauopathies." Therefore, in some embodiments, the pathological condition is a tauopathy. In some embodiments, the pathological condition is a neurodegenerative tauopathy. 1246454 of 249 In some embodiments, the pathological condition is chosen from Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), FTD with parkinsonism linked to chromosome 17 (FTDP 17), syndromes frontotemporal lobar degeneration (FTLD); disinhibition-dementia-parkinsonismamyotrophic complex (DDPAC), pallidum-ponto-nigra degeneration (PPND), Guam-ALS syndrome, pallidum-nigra-louisiana degeneration (PNLD), corticobasal degeneration (CBD), argyrophilic granule dementia (AgD) , dementia pugilistica (DP) or chronic traumatic encephalopathy (CTE), Down syndrome (DS), dementia with Lewy bodies (DLB), subacute sclerosing panencephalitis (SSPE), MCI, Niemann-Pick disease, type C (NPC) , Sanfilippo syndrome type B (or mucopolysaccharidosis III B (MPS III B)), or myotonic dystrophies (DM), DM1 or DM2, or chronic traumatic encephalopathy (CTE). In some embodiments, the pathological condition is a lysosomal storage disorder with tau pathology. NPC is caused by mutations in the NPC1 gene, which affects cholesterol metabolism (Love et al 1995) and Sanfilippo type B syndrome is caused by a mutation in the NAGLU gene, where there is lysosomal accumulation of heparin sulfate (Ohmi et al . 2009). In these lysosomal storage disorders, tau pathology is seen and its treatment can slow the progression of the disease. Other lysosomal storage disorders may also be characterized by accumulation of tau. The use of phenothiazindiaminium salts in the treatment of Parkinson's disease and MCI is described in more detail in PCT / GB2007 / 001105 and PCT / GB2008 / 002066. 1246454 of 249 In some embodiments, the pathological condition is Parkinson's disease, MCI, or Alzheimer's disease. In some embodiments, the pathological condition is Huntington's disease or other polyglutamine disorders such as medullary spinal muscular atrophy (or Kennedy's disease), and dentate rubro-pallidal luisian atrophy and various spinocerebellar ataxias. In some embodiments, the pathological condition is a FTLD syndrome (which may, for example, be a tauopathy or TDP-43 proteinopathy, see below). In some embodiments, the pathological condition is PSP or ALS. In some embodiments, the treatment (eg, treatment of a neurodegenerative tauopathy, eg, Alzheimer's disease) may optionally be in combination with one or more other agents, eg, one or more cholinesterase inhibitors (such such as Donepezil (also known as Aricept™), Rivastigmine (also known as Exelon™), Galantamine (also known as Reminyl™), NMDA receptor antagonists (such as Memantine (also known as Ebixa™, Namenda™), muscarinic receptor, and / or inhibitors of amyloid precursor protein processing leading to enhanced generation of beta-amyloid. TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS; ALS-TDP) and frontotemporal lobar degeneration (FTLD-TDP). The role of TDP-43 in neurodegeneration in ALS and other neurodegenerative disorders has been reviewed in several recent publications (Chen-Plotkin et al 2010; Gendron et al 2010; Geser et al 2010; Mackenzie et al. 1246454 of 249 col 2010). ALS is a neurodegenerative disease, characterized by progressive paralysis and loss of muscle mass, consistent with degeneration of upper and lower motor neurons in the primary motor cortex, brainstem, and spinal cord. It is sometimes referred to as motor neuron disease (MND) but there are different diseases from ALS that affect upper and lower motor neurons. A definitive diagnosis requires upper and lower motor neuron signs in the bulbar musculature, arms, and legs with clear evidence of clinical progression that cannot be explained by any other disease process (Wijesekera and Leigh 2009). Although the majority of cases are ALS-TDP, there are other cases where the pathological protein differs from TDP-43. Misfolded SOD1 is the pathological protein in ubiquitin-positive inclusions in ALS with SOD1 mutations (Seetharaman et al 2009) and in a very small subset (approximately 3-4%) of familial ALS due to mutations in FUS. sarcoma), the pathological ubiquitinated protein is FUS (Vance et al 2009; Blair et al 2010). FUS, like TDP-43, appears to be important in nuclear-cytoplasmic transport although the pathways in which nuclear import of FUS is impaired are unclear. A new molecular classification of ALS, adapted from Mackenzie et al (2010), reflects the different pathological mechanisms underlying the different subtypes (see Table below). New Molecular Classification of ALS (modified from Mackenzie et al 2010). In most cases, TDP-43 is the ubiquitinated protein 1246454 of 249 pathological found in ALS Ubiquitin-positive inclusions in ALS Ubiquitinated disease protein TDP-43 FUS SOD1 Clinicopathological subtype ALS-TDP ALS-FUS ALS-SOD1 Associated genotype TARDBP FUS SOD1 Frequency of ALS cases Common Rare Rare Amyotrophic lateral sclerosis has been recognized as a nosological entity for nearly a century and a half and is recognized in ICD-10 and classified as a subtype of MND in ICD 10 (G12.2). Reliable clinical diagnoses are available for ALS, differing very little from Charcot's original description, and neuropathological criteria, reflecting the underlying molecular pathology, have also been agreed upon. While ALS is pathologically classified into three subgroups, ALSTDP, ALS-SOD1, and ALS-FUS, the latter two conditions are rare. The largest study to date showed that all sporadic ALS cases have TDP-43 pathology (Mackenzie et al 2007). Only about 5% of ALS is familial (Byrne et al 2010) and mutations in SOD1, the most common mutation found in FALS, account for 12-23% of cases (Andersen et al 2006). SOD1 may also be involved in between 2 and 7% of SALS. Mutations in FUS appear to be less common, representing 1246454 of 249 only about 3-4% of FALS (Blair et al 2010). Therefore, a clinical case of SALS can be reliably predicted to have TDP-43-based pathology. Similarly this can be reliably predicted in FALS due to mutations in TDP-43, which account for about 4% of cases (Mackenzie et al 2010). ALS with mutations in: VCP, accounting for 1-2% of FALS (Johnson et al 2010), ANG (Seilhean et al 2009), and CHMP2B (Cox et al 2010) have also been reported with TDP-43 positive pathology3 . Although mutations of SOD1, FUS, and ATXN2 have not been found to be associated with positive aggregates of TDP-43, TDP-43 has nevertheless been reported to be involved in the pathological processes putatively derived from these mutations (Higashi et al 2010; Ling et al 2010; Elden et al 2010). It was therefore established that TDP-43 plays an important, and potentially central, role in the pathogenesis of the vast majority of SALS cases and may be involved in the pathogenesis of a significant proportion of FALS. ALS is now widely considered to be a TDP-43 proteinopathy (Neumann et al 2009) and numerous in vitro and in vivo studies provide support for the hypothesis that toxic gain of function due to TDP-43 aggregation is responsible for at least part of the neurotoxicity in the disease. FTLD syndromes are insidious-onset, inexorably progressive, neurodegenerative conditions with peak onset in midlife. There is often a positive family history of similar disorders in first-degree relatives. The behavior variant of FTD is characterized by a change 1246454 of 249 early prominent in social and interpersonal function, usually accompanied by repetitive behaviors and changes in eating pattern. In semantic dementia there are prominent word finding problems, despite speaking equally fluently, with degraded object knowledge and impaired single word comprehension on a cognitive assessment. Progressive nonfluent aphasia presents with a combination of motor speech problems and grammatical deficits. The core clinical diagnostic features for these three FTLD syndromes are shown in the Table below and the full criteria in Neary et al (1998). Clinical profile and core diagnostic features of FTLD syndromes Clinical Profile of FTLD Syndrome Core Diagnostic Features Frontotemporal Dementia Character change and disrupted social behavior are the dominant features initially and throughout the course of the disease. The instrumental functions of perception, spatial skills, praxis, and memory are intact or relatively preserved. 1. Insidious onset and gradual progression 2. Early decline in interpersonal social behavior 3. Early impairment in regulation of personal behavior 4. Early emotional abruption 5. Early vision loss Semantic dementia Semantic disorder (impaired understanding of meaning of words and / or object identity) is the dominant feature initially and throughout the course of the disease. Other aspects of cognition, including autobiographical memory, are intact or relatively well preserved. A) Insidious onset and gradual progression B) Language disorder characterized by 1. Progressive, fluent empty speech 2. Loss of meaning of words manifested by impaired mention and comprehension 3. Semantic paraphasias and / or Perceptual disorder characterized by 1246454 of 249 1. Prosopagnosia: impaired recognition of identity of familiar faces and / or 2. Association agnosia: impaired recognition of identity of objects C) coincidence in perception and reproduction of drawings preserved D) Single word repetition preserved E) Ability to read preserved aloud and write with regular orthographic dictation of words Nonfluent Progressive Aphasia Expressive language disorder is the dominant feature initially and throughout the course of the disease. Other aspects of cognition are intact or relatively well preserved. A) Insidious onset and gradual progression B) Spontaneous nonfluent speech with at least one of the following: agrammatism, paraphasia, or anomie The discovery that TDP-43-positive inclusions characterize ALS and FTLD-TDP (Neumann et al 2006) was quickly followed by the identification of missense mutations in the TARDBP gene in familial and sporadic cases of ALS (Gitcho et al 2008; Sreedharan et al., 2008). So far, 38 different TARDBP mutations have been reported in 79 genealogically unrelated families around the world (Mackenzie et al 2010). TARDBP mutations account for approximately 4% of all familial ALS cases and approximately 1.5% of sporadic cases. As of December 2010, mutations in thirteen genes have been identified that are associated with familial and sporadic ALS. Binding of ALS to five other chromosome loci has been demonstrated but no specific mutations have been identified so far. Methylthioninium (MT) in TDP-43 proteinopathies 1246454 of 249 MT has a targeted mode of action and can reduce TDP-43 protein aggregation in cells, which is a pathological feature of the vast majority of familial and sporadic ALS and is also characteristic of FTLD-P. Additionally, laboratory data show that methylthioninium inhibits TDP-43 aggregate formation in SH-SY5Y cells. After treatment with 0.05 μM MT, the number of TDP-43 aggregates was reduced by 50%. These findings were confirmed by immunoblot analysis (Yamashita et al 2009). The compounds and compositions of the invention may therefore be useful for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Methylthioninium (MT) in Huntington's disease and polyglutamine disorders MT can reduce polyglutamine protein aggregation in cells, which is a pathologic hallmark of Huntington's disease. Huntington's disease is caused by expansion of a translated CAG repeat located at the N-terminus of huntingtin. Wild-type chromosomes contain between 6 and 34 repeats whereas, in Huntington's disease, chromosomes contain between 36 and 121 repeats. The age of disease onset is inversely correlated with the length of the CAG portion encoding the polyglutamine repeats in the protein. Laboratory data show that methylthioninium inhibits aggregate formation of a huntingtin derivative containing a 102-residue polyglutamine region in zebrafish (van Bebber et al. 2010). MT, 1246454 of 249 when tested at 0, 10 and 100 μM, prevented the formation of such aggregates in zebrafish in a dose-dependent manner. The compounds and compositions of the invention may thus be useful for the treatment of Huntington's disease and other polyglutamine disorders such as medullary spinal muscular atrophy (or Kennedy's disease), and rubro-pallidal-louisianal dentate atrophy and different ataxias. Spinocerebellar (Orr & Zoghbi, 2007). Mitochondrial diseases and Lafora disease The most frequently affected organs in mitochondrial disorders, particularly respiratory chain diseases (RCDs), in addition to skeletal muscle, is the central nervous system (CNS). CNS manifestations of RCDs include stroke-like episodes, epilepsy, migraine, ataxia, spasticity, movement disorders, psychiatric disorders, cognitive impairment, or even dementia (mitochondrial dementia). So far mitochondrial dementia has been reported in MELAS, MERRF, LHON, CPEO, KSS, MNGIE, NARP, Leigh syndrome, and Alpers-Huttenlocher diseases (Finsterer, 2009). There are four complexes in the mitochondrial respiratory chain, which involves a series of electron transfers. Abnormal function of any of these complexes can result in mitochondrial diseases secondary to an abnormal electron transport chain and subsequent abnormal mitochondrial respiration. Complex III of the mitochondrial respiratory chain acts to transfer electrons to cytochrome c. The compounds and compositions of the invention can also be used to treat mitochondrial diseases that are associated with a 1246454 of 249 deficient and / or impaired function of complex III of the respiratory chain. The compounds have the ability to act as an efficient carrier and / or electron carrier, since the thioninium group has a low reduction-oxidation potential for conversion between the oxidized form and the reduced form. In the event of impaired function and / or deficient function of complex III leading to mitochondrial diseases, the compounds of the invention also have the ability to perform the electron transport and transfer role of complex III due to the ability of the group thioninium to move between the oxidized form and the reduced form, thus acting as an electron carrier rather than a suboptimally functioning complex III, transferring electrons to cytochrome c. The compounds and compositions of the invention also have the ability to generate an active group that has the ability to divert misfolded protein monomers / oligomers / amino acids from the accumulation and / or refolding pathways of the ADP-associated protein Hsp70, and instead redirect these misfolded protein monomers / oligomers to the pathway that leads directly to the Hsp70 ATP-dependent proteasome-ubiquitin system (UPS), a pathway that removes these misfolded protein monomers / oligomers / amino acids via the direct pathway (Jinwal et al. 2009). Lafora disease (LD) is an autosomal recessive fatal adolescent-onset epilepsy associated with a gradual accumulation of poorly branched and insoluble glycogen, called polyglucosan, in many tissues. In the brain, polyglucosan bodies, or Lafora bodies, form in neurons. Inhibition of Hsp70 ATPase by MT (Jinwal 1246454 of 249 et al. 2009) can up-regulate the removal of misfolded proteins. Lafora disease is mainly due to a defect in the lysosomal ubiquitin-proteasomal system (UPS) due to a mutation in the Laforin or Malina genes, both located on Chromosome 6, resulting in inclusions that can accelerate protein aggregation. misfolded tau. Secondary mitochondrial damage from impaired UPS can further result in suppressed mitochondrial activity and impaired electron transport chain leading to additional lipofuscin and initiating the seizures that are characteristic of Lafora disease. The MT group can disaggregate existing tau aggregates, reducing further tau accumulation and enhancing lysosomal efficiency by inhibiting Hsp70 ATPase. MT can lead to a reduction of tau tangles by enhancing the removal of tau monomers / oligomers by the proteasomal ubiquitin system, through the inhibitory action on Hsp70 ATPase. Therefore the compounds and compositions of the present invention may have utility in the treatment of Lafora disease. Disease Conditions Treated - Other Disease Conditions In some embodiments, the pathological condition is skin cancer. In some embodiments, the pathological condition is melanoma. In some embodiments, the pathological condition is a viral, bacterial, or protozoan-related pathological condition. In some embodiments, the pathological (protozoan-related) condition is malaria. The treatment can be in combination with one 1246454 of 249 or more antimicrobial agents, eg, chloroquine and / or atovaquone. In some embodiments, the pathological (viral) condition is caused by Hepatitis C, HIV, or West Nile Virus (WNV). Other uses Another aspect of the present invention relates to the use of a compound as described herein, in a method of inactivating a pathogen in a sample (for example a blood or plasma sample), comprising the steps of introducing the compound inside the sample, and expose the sample to light. For example, in some embodiments, the method comprises the steps of introducing the compound into the sample, and then exposing the sample to light. Use as ligands Compounds described herein that have the ability to inhibit tau protein aggregation will also have the ability to act as ligands or labels for tau protein (or aggregated tau protein). Therefore, in some embodiments, the compound of the invention is a tau protein (or aggregated tau protein) ligand. Such compounds (ligands) may incorporate, be conjugated to, be chelated with, or otherwise associated with, other chemical moieties, such as stable and unstable detectable isotopes, radioisotopes, positron-emitting atoms, magnetic resonance markers, dyes, markers fluorescent, antigenic groups, therapeutic groups, or any other group that may aid in a prognostic, diagnostic, or therapeutic application. 1246454 of 249 For example, in some embodiments, the compound is as defined herein, but with the additional limitation that the compound incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (eg, 1, 2, 3, 4, etc.) detectable labels, eg, isotopes, radioisotopes, positron emitting atoms, magnetic resonance labels, dyes, fluorescent labels, antigenic groups, or therapeutic groups. In some embodiments, the compound is a ligand as well as a label, eg, a label for tau protein (or aggregated tau protein), and incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (eg, 1, 2, 3, 4, etc.) detectable marks. For example, in some embodiments, the compound is as defined above, but with the additional limitation that the compound incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (for example, example, 1, 2, 3, 4, etc.) detectable marks. Labeled compounds (for example, when bound to tau protein or tau protein aggregates) may be visualized or detected by any suitable means, and the skilled person will appreciate that any suitable detection means as known in the art may be used. art. For example, the compound (ligand-label) can be suitably detected by incorporation of a positron emitting atom (eg 11C) (eg as a carbon atom of one or more alkyl group substituents, eg , methyl group substituents) and detect the compound using positron emission tomography (PET) as known 1246454 of 249 in art. Said 11 C-labeled compounds can be prepared by adapting the methods described herein in known ways, for example, in analogy to the methods described in WO 02 / 075318 (see Figures 11a, 11b, 12 therein) and WO 2005 / 030676 . Therefore, another aspect of the present invention relates to a method for labeling tau protein (or aggregated tau protein) comprising the step of: (i) contacting the tau protein (or aggregated tau protein) with a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (eg, 1,2, 3, 4, etc.) detectable labels. The compound can be provided as a composition as described herein. Another aspect of the present invention relates to a method for detecting tau protein (or aggregated tau protein) comprising the steps of: (i) contacting the tau protein (or aggregated tau protein) with a compound that incorporates, is conjugated a, is chelated with, or is otherwise associated with, one or more (eg, 1, 2, 3, 4, etc.) detectable labels, and (ii) detecting the presence and / or amount of said bound compound to tau protein (or aggregated tau protein). The compound can be provided as a composition as described herein. Another aspect of the present invention relates to a method for the diagnosis or prognosis of a tau proteinopathy in a subject believed to be suffering from the disease, comprising the steps of: (i) introducing into the subject a compound with of labeling tau protein or aggregated tau protein, particularly tau protein (for example, a compound that 1246454 of 249 incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (eg, 1, 2, 3, 4, etc.) detectable labels); (ii) determining the presence and / or amount of said compound bound to tau protein or aggregated tau protein in the brain of the subject; and (iii) correlating the results of the determination made (ii) with the disease state of the subject. The compound can be provided as a composition as described herein. Another aspect of the present invention relates to a compound with the ability to label tau protein or aggregated tau protein (eg, a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more ( eg, 1, 2, 3, 4, etc.) detectable labels), for use in a method of diagnosing or prognosing a tau proteinopathy. The compound can be provided as a composition as described herein. Another aspect of the present invention relates to the use of a compound of the invention with the ability to label tau protein or aggregated tau protein, particularly tau protein (for example, a compound that incorporates, is conjugated to, is chelated with, or is otherwise associated with, one or more (eg, 1, 2, 3, 4, etc.) detectable labels), in a method for the manufacture of a diagnostic or prognostic reagent for use in the diagnosis or prognosis of a tau proteinopathy. The compound can be provided as a composition as described herein. Those skilled in the art will appreciate that instead of administering ligands / labels directly, they can be administered in a precursor form, for conversion to the active form (eg, binder form, label form) by an activating agent present therein, either 1246454 of 249 administered to the same subject. The ligands described herein can be used as part of a method for diagnosis or prognosis. It can be used to select a patient for treatment, or to assess the efficacy of a treatment or therapeutic (eg, an inhibitor of tau protein aggregation) administered to the subject. Treatment The term "treatment", as used herein in the context of treating a condition, generally refers to the treatment and therapy, of a human or an animal (for example, in veterinary applications), in which some effect is achieved. desired therapeutic effect, eg, inhibition of the progress of the condition, and includes a reduction in the rate of progress, an interruption in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (ie prophylaxis, prevention) is also included. The term "therapeutically effective amount," as used herein, relates to the amount of a compound of the invention, or a material, composition, or dosage form comprising said compound, that is effective in producing part of the therapeutic effect. commensurate with a reasonable benefit / risk ratio, when administered according to a desired treatment regimen. Similarly, the term "prophylactically effective amount," as used herein, relates to the amount of a compound of the invention, or a material, composition, or dosage form comprising said compound, which is effective for produce part of the prophylactic effect 1246454 of 249 desired, commensurate with a reasonable benefit / risk ratio, when administered according to a desired treatment regimen. "Prophylaxis" in the context of the present specification is not to be understood as circumscribing complete success ie complete protection or complete prevention. Rather, prophylaxis in the present context refers to a measure that is administered prior to the detection of a symptomatic condition with the goal of preserving health by helping to delay, mitigate, or prevent that particular condition. The term "treatment" includes combination of treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. Examples of treatments and therapies include, by way of illustrative example, chemotherapy (the administration of active agents, including, for example, drugs, antibodies (for example, as in immunotherapy), prodrugs (for example, as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; and gene therapy. For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (eg, 1, 2, 3, 4) agents or therapies. The particular combination may be at the discretion of the physician who may select the dosages using his or her common general knowledge and dosage regimens known to an experienced physician. The agents (i.e., a compound as described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in dosage schedules. 1246454 of 249 variants individually and through different routes. For example, when administered sequentially, agents may be administered at closely spaced intervals (eg, over a period of 5 to 10 minutes) or at longer intervals (eg, 1, 2, 3, 4, or more hours apart). separation, or even longer periods of separation when required), the precise dosage regimen being proportional to the properties of the therapeutic agent(s). The agents (i.e., a compound as described herein, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together. in the form of a set of components, optionally with instructions for their use. Routes of administration The compound of the invention, or pharmaceutical composition comprising it, can be administered to a subject / patient by any convenient route of administration, systemically / peripherally or topically (ie, at the site of action). Routes of administration include, by way of illustrative example, oral (eg, by ingestion); oral; sublingual; transdermal (including, for example, by patch, band-aid, etc.); transmucosal (including, for example, by a patch, band-aid, etc.); intranasal (eg, by nasal spray); ocular (for example, by drops); pulmonary (eg by inhalation or insufflation therapy using, eg, an aerosol, eg, through the mouth or nose); rectal (eg, by suppository or enema); vaginal (eg, by diaphragm); parenterally, for example, by injection, including subcutaneous, 1246454 of 249 intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal (including, for example, intracatheter injection into the brain); by implantation of a reservoir or reservoir, for example, subcutaneously or intramuscularly. Preferred compositions are oral compositions, formulated as described in more detail hereinafter. The subject / patient The subject / patient may be an animal, mammal, placental mammal, rodent (eg, guinea pig, hamster, rat, mouse), murine (eg, mouse), lagomorph ( (for example, a rabbit), avian (for example, a bird), canine (for example, a dog), feline (for example, a cat), equine (for example, a horse), porcine (for example, a pig ), ovine (for example, a sheep), bovine (for example, a cow), a primate, ape (for example, a monkey or ape), a monkey (for example, marmoset, baboon), a monotreme (for example, platypus) , an ape (eg gorilla, chimpanzee, orangutan, gibbon), or a human. Furthermore, the subject / patient may be in any of its forms of development, for example, a fetus. In some embodiments, the subject / patient is a human. Compositions / Formulations Where it is possible for the compound of the invention to be used (eg administered) alone, it is often preferred to present it as a composition or formulation. Another aspect of the invention therefore provides a composition that 1246454 of 249 comprises a compound as described herein, and a pharmaceutically acceptable carrier or diluent. In some embodiments, the composition is a pharmaceutical composition (eg, formulation, preparation, medicament) comprising a compound as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is a pharmaceutical composition comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those of skill in the art, including, a by way of illustrative example, carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (eg, wetting agents), masking agents, coloring agents, flavoring agents, and sweetening agents pharmaceutically acceptable. In some embodiments, the composition further comprises other active agents, eg, other therapeutic or prophylactic agents. Vehicles, diluents, excipients, etc. suitable can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and Handbook of Pharmaceutical Excipients, 2nd Edition, 1994. Another aspect of the present invention relates to methods for making a pharmaceutical composition comprising mixing at least one 1246454 of 249 [11C]-radiolabeled compound, as defined herein, together with one or more other pharmaceutically acceptable ingredients well known to those of skill in the art, eg, carriers, diluents, excipients, etc. If formulated as discrete units (eg, tablets, etc.), each unit contains a predetermined amount (dosage) of the compound. The term "pharmaceutically acceptable," as used herein, relates to compounds, ingredients, materials, compositions, dosage forms, etc., that are, within the scope of medical judgment, suitable for use in contact with tissues. of the subject in question (for example, human) without excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio. Each vehicle, diluent, excipient, etc. it must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. The formulations can be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing the compound into association with a carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing the compound into association with carriers (eg, liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary. The formulation can be prepared to provide fast or slow release; immediate, delayed, measured, or sustained; or a combination thereof. Formulations suitable for parenteral administration (for 1246454 of 249 example, by injection), includes aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g. , in a liposome or other microparticulate). Such liquids may contain other additional pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickening agents, and solutes that render the formulation isotonic with the blood (or other relevant body fluid) of the recipient. . Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic vehicles suitable for use in such formulations include sodium chloride injection, Ringer's solution, or Lactated Ringer's solution. Generally, the concentration of the compound in the liquid is between about 1 ng / ml and about 10 µg / ml, for example between about 10 ng / ml and about 1 µg / ml. The formulations may be presented in sealed single-dose or multi-dose containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections. , immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. Examples of some preferred formulations One aspect of the present invention relates to a dosage unit (for example, a pharmaceutical tablet or capsule) comprising between 20 and 300 mg of a compound as described herein (for 1246454 of 249 example, obtained by, or obtainable by, a method as described herein; having a purity as described herein; etc.), and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the dosage unit is a tablet. In some embodiments, the dosage unit is a capsule. In some embodiments, said capsules are gelatin capsules. In some embodiments, said capsules are capsules of HPMC (hydroxypropylmethylcellulose). In some embodiments, the amount is between 30 and 200 mg. In some embodiments, the amount is about 30 mg. In some embodiments, the amount is about 60 mg. In some embodiments, the amount is about 100 mg. In some embodiments, the amount is about 150 mg. In some embodiments, the amount is about 200 mg. Throughout this specification dosage amounts, for example as indicated above, may refer to the amount of the compound itself or may refer to the amount of 1246454 of 249 free base equivalent (ie the amount of LMT group) contained in the dosage unit. Both of these alternatives are expressly described herein. In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is or comprises one or both of a glyceride (eg, Gelucire 44 / 14®; lauroyl macrogol-32 glycerides PhEur, USP) and colloidal silicon dioxide (eg, example, 2% Aerosil 200®; Colloidal Silicon Dioxide PhEur, USP). Novel Formulations - solid dosage forms The processes generally used for tablet formulation and film coating generally require the use of heat accompanied by low humidity during the drying process. LMTM and the other leuco-methylthionium salts are potentially prone to oxidation to the methylthioninium (MT) group and degradation to, for example, L Azure B (LAB) (see Scheme, below): 1246454 of 249 For a material such as LMTM, which is prone to oxidation (as explained above), conventional formulation processes may thus lead to degradation and thus potentially instability in product performance. The principle behind the formulations of the present invention is therefore the provision of a method for the manufacture of compressed pharmaceutical formulations and capsules containing leuco-methylthionium salts for example bis(methanesulfonate) (LMTM) as active substance, by technology of direct tablet compression or by another technique to make single tablets, and by encapsulation, wherein the active substance exists in substantially a stable form. The most commonly used method for the preparation of solid dosage forms is wet granulation (also called wet granulation). 1246454 of 249 with humidity). This involves the addition of a granulating fluid to a powder. The granulating fluid can be water or some other solvent that is sufficiently volatile that it can be subsequently removed by drying. The granulating fluid can also include a binder. Once the solvent has been removed, the resulting mass is ground. Wet granulation is often preferred over direct compression because in wet granulation it is easier to overcome any problems associated with the physical characteristics of different ingredients in the formulation. Wet granulation provides material having the required flow and cohesive properties necessary to obtain an acceptable solid dosage form. Uniformity of solid dosage form content is generally improved by wet granulation because all granules generally contain the same amount of drug. Segregation of the drug from the excipients is also prevented. In direct compression, the individual constituents of the composition to be compressed are mixed without prior granulation and then directly compressed. While this appears to be an elegant and simple process, it can be difficult to obtain commercially usable tablets that are potent enough and also disintegrate easily enough after administration. Furthermore, many active substances cannot be processed by direct compression as they cannot be compressed without a granulation step. At present, surprisingly, the compounds of the present invention have been found to be stable in a form of 1246454 of 249 dry compressed stable solid dosage such as a tablet, during manufacture and storage, and that the amount of degradation products such as L Azure B (LAB) and methylthioninium (MT) formed can be controlled in the specifications ( for example, LAB less than 2% and MT less than 12%). This is in contrast to the behavior of eg LMTM when processed by conventional wet granulation processes. Without wishing to be bound by theory, in conventional wet granulation processes LMTM, for example, can be very unstable and a substantial amount of LAB and MT can be formed. Accordingly, one aspect of the present invention provides a pharmaceutical composition comprising a compound of the invention, in solid dosage form. The composition preferably further comprises at least one diluent suitable for dry compression. The pharmaceutical composition is characterized in that the compound exists in a substantially stable form. Another aspect of the invention provides a free-flowing cohesive powder, comprising a compound of the invention and at least one diluent suitable for dry compression, and optionally one or more other excipients, wherein said powder has the ability to be compressed. to a solid dosage form. These compositions and formulations are initially described herein with respect to the bis(sulfonate) salts of the present invention, in particular LMTM. However, the advantages of the present formulation methods are equally applicable to other members of the family of salts. 1246454 of 249 leuco-methylthionium. For example, the formulations described herein are also applicable to 3,7-diamino-10H-phenothiazinium salts described in WO2007 / 110627 (WisTa Laboratories Ltd), which are briefly described above. These include leuco-methylthionium bis(hydrobromide) (LMT.2HBr, LMTB) and leuco-methylthionium bis(hydrochloride) (LMT.2HCl, LMTC). Therefore, in a broader aspect, the present invention provides a pharmaceutical composition comprising a compound of the following formula I: HX1 HX2(I) where: R1, R9, R3NA, R3NB, R7NA, and R7NB are as previously defined; and wherein HX1 and HX2 are each independently a protic acid; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; in a solid dosage form as described herein. For completeness, it is noted that, as will be understood by one skilled in the art, the above formula could equally well be written as: R9H R1 , 3NA , 3NB X2® (I)* 1246454 of 249 where X1 and X2 are the corresponding counter ions. Preferably X1 and X2 are independently sulphonate (such as alkylsulphonate or arylsulphonate, eg RASO3 or RBSO3 as defined above) or halide (Cl , Br , I ). In other words, HX1 and HX2 are independently preferably sulfonic acids (RASO3H, RBSO3H) or hydrohalides (HCl, HBr, HI). As used hereinafter, the term "active ingredient" refers to the relevant leuco(methylthioninium) salt. In other words it refers to a compound of formula (I), such as a compound of the invention, for example LMTM. Another aspect of the invention provides a process for the manufacture of said pharmaceutical compositions, by means of a dry compression method. The process preferably comprises dry compression of an intimate powder mixture of the active compound with at least one diluent suitable for dry compression, and optionally one or more other excipients. In some embodiments, the process comprises direct compression. In some embodiments, the process comprises simple direct compression. In some embodiments, the process comprises dry granulation. In some embodiments, the process comprises wet granulation of excipients, followed by adding the active ingredient extragranularly. 1246454 of 249 Said dosage forms according to the invention advantageously exhibit long-term chemical and physical stability of the active ingredient (compound of the invention - eg LMTM). Pharmaceutical compositions according to the invention also have fast dissolution rates, even after long-term storage. A substantially stable form of the active ingredient means, in the present context, a form that does not react to form impurities such as oxidative impurities or other degradation products to any extent during the formulation process, or during storage of the formulated product. Thus, in the present context, it can refer to a material that contains, for example, less than 20% wt-wt, less than 15% wt-wt, or less than 10% wt-wt of impurities. oxidative or other degradation products. In other words, the material contains at least 80% weight by weight, at least 85% weight by weight, or at least 90% weight by weight of the pure active ingredient, in its original (unreacted) form. In some embodiments, the active ingredient-containing material may contain, for example, less than 20% weight by weight, less than 15% weight by weight, less than 12% weight by weight, or less than 10 % weight by weight of MT. In some embodiments, the material may contain, for example, less than 5 wt%, less than 3 wt%, or less than 2 wt% LAB. A stable tablet is, in the context of the present invention, a tablet that remains substantially stable after storage. 1246454 of 249 prolonged under controlled conditions of temperature and humidity. Stability tests can be performed with the solid dosage forms directly exposed to the chosen environmental conditions, or with the solid dosage forms contained in the packaging system. Active ingredient content The amount of the active ingredient in the uncoated composition is generally more than about 10% weight by weight, but can be more than 20%, or more than 30% weight by weight. The amount of the active ingredient is generally less than about 70% weight by weight, and usually less than 60% or less than 50% weight by weight in a tablet formulation. Generally, the amount of the active ingredient in the uncoated tablet core composition is therefore between about 10% weight by weight (or 20% or 30%) and about 70% weight by weight (or 60% or 50%). %). When a coating is applied to the composition, as described below, the total weight of the composition is increased and therefore the percentage of the active ingredient in the total composition is somewhat reduced. thinners The active ingredient may not be inherently compressible and therefore may require the addition of suitable diluents to aid compression. The pharmaceutical compositions of the invention therefore commonly comprise at least 15% weight by weight, more commonly at least 20%, at least 30%, at least 40% or at least 50% weight by weight. 1246454 of 249 of diluent(s). Diluents that can be used include one or more of microcrystalline cellulose, lactose, mannitol, calcium salts such as dibasic calcium phosphate, calcium sulfate, and calcium carbonate, and sugars such as lactose, sucrose, dextrose, and maltodextrin. Preferred diluents are microcrystalline cellulose, lactose, and mannitol. Spray dried forms of lactose and mannitol are particularly suitable forms of these compounds for direct compression or dry granulation techniques. It has been unexpectedly found that when an active ingredient as described herein, for example a compound of the present invention, such as LMTM, is formulated with dry compression diluents such as one or more of microcrystalline cellulose, spray dried lactose , anhydrous lactose, and mannitol, the resulting solid dosage forms are stable in the sense that the active ingredient remains chemically stable, even after extended storage. The invention therefore provides a method for preparing low, medium or high dose tablets, for example low, medium or high dose tablets of LMTM, which are stable and have good dissolution profiles, acceptable degrees of hardness and resistance to chipping. as well as a short disintegration time. Dissolution of compositions of the invention These inventors have also surprisingly found that the single solid dosage forms described herein provide a very rapid rate of dissolution. 1246454 of 249 As explained hereinabove, and without wishing to be bound by theory, it is believed that the active methylthioninium (MT) group may be preferentially absorbed from the stomach and / or upper GI tract. A rapidly disintegrating and rapidly dissolving formulation of leuco(methylthioninium) salts could therefore be advantageous, as this would deliver the maximum possible amount of drug to the intended point of absorption. The rapid dissolution rate of the solid dosage forms described herein means that they have the ability to rapidly dissolve in the stomach and / or upper GI tract and thus present the active ingredient there efficiently, for rapid absorption. In some embodiments, the formulations of the invention, when evaluated using a standard pharmacopoeial method, provide at least 80% dissolution in 30 minutes, preferably at least 80% dissolution in 15 minutes, more preferably at least 80%. dissolution in 10 minutes. In some embodiments, the formulations of the invention, when evaluated using a standard pharmacopoeial method, provide at least 90% dissolution in 30 minutes, preferably at least 90% dissolution in 15 minutes, more preferably at least 90%. dissolution in 10 minutes. In some embodiments, the formulations of the invention, when evaluated using a standard pharmacopoeia method, provide at least 95% dissolution within 30 minutes, preferably at least 95% dissolution within 15 minutes, more preferably at least 95% dissolution. dissolution in 10 minutes. 1246454 of 249 Dissolution rates can be measured by standard pharmaceutical methods as described in the United States Pharmacopeia (USP) General Chapter <711>. The current USP is USP 34 (2011). For example, dissolution rates for formulations of the invention can be measured using apparatus according to USP Dissolution Apparatus 2 (Paddle). In some embodiments, the above dissolution rates are evaluated in 0.1M hydrochloric acid at a working concentration of approximately 5 µg / ml LMT, with stirring at a paddle speed of 50 rpm. In some embodiments, dissolution rates are evaluated by spectrophotometric analysis. In some embodiments, the analysis comprises UV / vis spectrophotometry (λmax lmt = 255nm). As a consequence of its surprisingly high dissolution rate, the formulation methods described herein can provide the active compound with a high degree of bioavailability. The high dissolution rate is maintained after prolonged storage, even if storage is under “stressed” conditions (ie increased temperature and humidity). The high dissolution rate, and thus good bioavailability, of compositions formulated according to the processes of the present invention is also highly tolerant to variations in the formulation itself. Other ingredients The pharmaceutical composition will generally also include a lubricant. Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behaptate, polyethylene glycol, ethylene oxide polymers (for example, those 1246454 of 249 under the trademark Carbowax of Union Carbide, Inc., Danbury, CT), sodium lauryl sulfate, magnesium lauryl stearate, mixtures of magnesium stearate with sodium lauryl sulfate, and hydrogenated vegetable oil. Preferred lubricants include calcium stearate, magnesium stearate, and sodium stearyl fumarate. Most preferred as a lubricant is magnesium stearate. Lubricants generally comprise between about 0.5 and about 5.0% of the total (uncoated) tablet weight. The amount of lubricant employed is generally between about 1.0 and about 2.0%, preferably between 0.5 and 2.0% weight by weight. In addition to the diluent(s) and lubricant(s), other conventional excipients may also be present in the pharmaceutical compositions of the invention. Such additional excipients include disintegrants, binders, flavoring, coloring and gliding agents. Some excipients can serve multiple functions, for example as a binder and tablet disintegrant. A tablet disintegrant may be present in an amount necessary to achieve rapid dissolution. Disintegrants are excipients that oppose the physical bonding forces in a tablet or capsule when the dosage form is placed in an aqueous environment. Examples of disintegrants include cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), and pregelatinized starch. Generally the amount of disintegrant can be between 0 and about 25% weight by weight, more commonly between about 1% and about 15% of 1246454 249 weight by weight, and usually less than 10% or less than 5% weight by weight, of the composition. Binders are excipients that contribute to the adhesion of particles in a solid formulation. Examples of binders include cellulose derivatives (carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, microcrystalline cellulose) and sugars such as lactose, sucrose, dextrose, glucose, maltodextrin, and mannitol, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, pregelatinized starch, alginic acids, and salts thereof such as sodium alginate, magnesium aluminum silicate, polyethylene glycol, carrageenan and the like. Generally, the amount of binder can vary widely, for example between 0% and 95% weight by weight of the composition. As indicated above, excipients can serve multiple functions. For example, the tablet diluent can also serve as a binder. Glidants are substances added to a powder to improve its flowability. Examples of glidants include magnesium stearate, colloidal silicon dioxide (such as grades sold as Aerosil), starch, and talc. Glidants may be present in the pharmaceutical composition at a level of between 0 and about 5% weight by weight. Again, however, it should be noted that excipients can serve multiple functions. The lubricant, for example magnesium stearate, can also function as a glidant. Examples of colorants that can be incorporated into the pharmaceutical compositions of the invention include titanium dioxide and / or food-grade colorants such as those known as 1246454 of 249 FD&C dyes and natural coloring agents. A coloring agent may not be used in the powder mixture that is compressed according to the aspects of the invention described above, but may form part of a coating applied to the composition, as described below, in which case the coloring agent it may be present in the film coating in an amount up to about 2.0% weight by weight. The tablet is desirably coated with a conventional film coating which imparts toughness, ease of swallowing, and an elegant appearance to the final product. Many polymeric film coating materials are known in the art. A preferred film coating material is hydroxypropylmethylcellulose (HPMC) or partially hydrolyzed polyvinyl alcohol (PVA). HPMC and PVA are commercially available, for example from Colorcon, in coating formulations containing excipients serving as coating aids, under the Opadry trademark. Opadry formulations may also contain talc, polydextrose, triacetin, polyethylene glycol, polysorbate 80, titanium dioxide, and one or more colorants or lakes. Other suitable film-forming polymers can also be used, including hydroxypropylcellulose, vinyl copolymers such as polyvinylpyrrolidone and polyvinyl acetate, and acrylate-methacrylate copolymers. The use of a film coating is beneficial for ease of handling and because a blue colored uncoated core can stain the inside of the mouth while swallowing. The coating also slightly improves the stability of the dosage form. Tablet coating can be done conveniently 1246454 of 249 using a bed for conventional coating. In preferred embodiments of the process, the bed for coating is preheated using a hot air inlet until the outlet temperature reaches between 35° and 55°C, more preferably between 40 and 50°C. This may generally require the application of a hot air inlet with an inlet temperature of between 45 and 75°C, preferably between 50 and 65°C, for between 10 and 15 minutes. Tablet cores containing the active ingredient (eg LMTM) are then added to the coating bed and the aqueous film coating is applied. The spray rate is controlled such that the bed temperature is maintained at 38-48°C, more preferably 42-44°C, until the desired weight gain (coat weight) is achieved. Dry Compression Methods "Dry compression," as used herein, refers to compression techniques that do not involve the use of heat or moisture. Dry compression may comprise direct compression of the active ingredient with suitable diluents or may comprise dry granulation (for example a pre-compression / double compression method or roller compaction). Direct compression may comprise simple direct compression of the active ingredient with diluents suitable for direct compression. Alternatively, it may comprise granulation, eg wet granulation, of the excipients to produce a dry granular mixture of excipients which can then be directly compressed with the dry active ingredient (and optionally other dry excipients). This may be referred to as "extra-granular incorporation" of the active ingredient. 1246454 of 249 As a consequence, in some embodiments the solid dosage forms of the invention may be produced in a manufacturing process comprising simple direct compression. In this embodiment, the tablet ingredients, i.e. the active ingredient (eg LMTM), diluent(s), and optional other excipients, are mixed together in solid particulate form to create an intimate mixture, for example in a blender. free fall, and then compressed using a tablet machine. In other embodiments, the composition is prepared by a dry granulation process. Dry granulation refers to the granulation process without the use of granulating fluids. In order to dry granulate a material, at least one of its constituents, the active ingredient or a diluent, must have cohesive properties. Dry granulation can be done by a process known as precompression. In pre-compression, the material to be granulated is first made into a well-compressed or compressed mass, generally using a tablet press with a large flat-faced instrument (an example of a linear press is illustrated in US 4,880,373). A fairly dense compact can be formed by giving enough time for the air to escape from the material to be compacted. The compacted tablets are then milled through a screen of desired mesh manually or automatically, such as by means of a grinding mill. The formation of granules by precompression is also known as precompression. When tablets are made from the granulated compressed material, the process is referred to as the double compression method. 1246454 of 249 Dry granulation can also be done using a roller compactor. In a roller compactor, material particles are consolidated and denser as the material passes between two high-pressure rollers. The denser material from a roller compactor is then reduced to a uniform granule size by grinding. The uniform granules can then be mixed with other substances, such as a lubricant, to tablet the material (such as by means of a rotary tabletting machine). In addition to pharmaceutical use, roller compaction is used in other industries, such as the food industry, animal feed industry, and fertilizer industry. Dry granulation is now generally understood to mean roller compaction or pre-compression, and is well known to those of skill in the art (see, for example, Pharmaceutical dosage forms: Tablets (Lieberman, Lachman, and Schwartz (Eds) ; Marcel Dekker, Inc, 2nd Edition, 1989) and Remington's Pharmaceutical Sciences (A. R. Gennaro (Ed); Mack Publishing Co, Easton, PA, 18th Edition, 1990). In other embodiments of the invention, tablets are prepared by wet granulating excipients and incorporating the active ingredient (eg LM™) extra-granularly. Such a process generally involves wet granulation diluents such as lactose and / or microcrystalline cellulose with water, optionally with the addition of a binder such as polyvinylpyrrolidone. The wet mass is dried, then passed through a mesh, to form granules. The active ingredient and any remaining excipients, such as a lubricant, are then mixed with the dry granules and compressed to form tablets. 1246454 of 249 Use of acids in the compositions of the invention Compositions containing leuco(methylthioninium) compounds, including compounds of the invention such as LM™ can, in some embodiments, be stabilized by adding an appropriate amount of certain acids to the raw material prior to formulation. These acids can be used to prevent the formation of additional MT, either during formulation or during the life of the product, thereby providing a stable pharmaceutical composition for the purpose of obtaining regulatory approval with associated cost savings in the delivery system. packing. According to the present invention, therefore, a pharmaceutical composition comprising an active ingredient as described herein and a pharmaceutically acceptable carrier is also provided, characterized in that said formulation additionally comprises an acid in an amount sufficient to prevent the formation of MT. Without wishing to be bound by theory, it is believed that acids having a pK1 greater than 1.5 are preferred. In some embodiments, the acid is present in an amount of between 5% and 25% weight by weight. Preferably the composition is prepared by a dry compression method as previously described. Preferred acids for purposes of the invention are maleic acid (pK1 1.9), phosphoric acid (pK1 2.12), ascorbic acid (pK1 4.17), sorbic acid (pK1 4.76), aspartic acid, and sialic acid. The stabilizing effect of the added acid can be enhanced by the selection of an appropriate carrier. The carrier is preferably mannitol, a cellulosic material, or a starch, or 100 1246454 100 of 249 mixtures thereof. The carrier is generally present in an amount of at least 40% weight by weight of the formulation. particle size It has also been found that a significant reduction in MT formation can be achieved by selecting an appropriate particle size range for the dry powder mix, generally where more than 10% of the particles are larger than 10 microns in size. . Therefore, according to one aspect of the invention, a pharmaceutical composition is provided comprising an active ingredient as described herein and a pharmaceutically acceptable carrier, further characterized in that said composition comprises particles of which more than 10% have a size greater than 10 microns. Vehicles It has been found that a significant reduction in MT formation can be achieved by choosing an appropriate carrier, particularly one having a particle shape that resists the ingress of water. Elcema TM, for example, which has long, lamellar particles that are smooth and flat in shape with a non-porous surface, appears to reduce MT formation by limiting water access. Ethylcellulose, mannitol and starch 1500 TM and microcrystalline cellulose are also particularly suitable for this purpose. Therefore, according to another aspect of the invention, a pharmaceutical composition is provided that comprises a leuco(methylthioninium) compound, for example a compound of the invention such as LMTM, and a pharmaceutically acceptable vehicle, characterized in that said 101 1246454 101 of 249 carrier is Elcema™, ethylcellulose, mannitol, or Starch 1500™. encapsulation The stabilized dry powder mixtures according to the invention can be formulated, for example, by compression into tablets or filled into capsules (with or without prior conversion to granulated powder as described in Formulation Examples 1 to 4). to give pharmaceutical compositions having an excellent shelf life. The capsules according to the invention are generally gelatin or preferably HPMC. Preferred excipients include lactose, starch, a cellulose, milk sugar, and high molecular weight polyethylene glycols. Conclusions Pharmaceutical compositions and formulations prepared according to the methods described above are more stable, immediately after completion of manufacture, than formulations produced using conventional aqueous granulation. Furthermore they can demonstrate improved stability during storage. For example, a pharmaceutical formulation prepared in this way, with a content of between 10 and 50% by weight of LMTM, preferably between 15% and 40% by weight of LMTM, makes it possible that in standard stability tests, for example in tests accelerated long-term stability tests, at a temperature of 25 °C and a relative humidity of 60±5%, the content of L Azure B does not increase by more than 2%, in relation to the area of ​​the peak of LMTM, in a period of 24 months. During processing and storage leuco(methylthioninium) compounds, such as LMTM can also be oxidized to produce 102 1246454 102 of 249 a small amount of MT (see Scheme, above). The presence of relatively small concentrations (eg less than 12%) of MT in the leuco-formulations of the present invention, while undesirable, is not considered to be of adverse clinical significance per se since even if the body is presents with MT in its charged or oxidized form of LMTM and the various other leuco salts, it can then reduce to the uncharged (reduced) form of MT before absorption. In addition to the small amount of MT formed during processing such as mixing or tableting, the leuco-methylthioninium salts of the present invention can react with oxygen absorbed in the excipients and be present in the tablet to give more MT particularly in presence of moisture. An advantage of the formulations of this invention is to minimize the amount of MT formed in the tablets, eg to less than 12% over 2 years when stored at 25°C at 60% relative humidity. This refers to the cumulative amount of MT formed during tablet processing and storage: generally, the formulation methods of the invention result in less than 5% MT formation during processing; a minimum of about 5-7% MT is then formed during storage of the finished package. This provides a shelf life of at least 24 months. This is demonstrated in the Formulation Examples, below. Dosage Those skilled in the art will appreciate that appropriate dosages of the compound, and compositions comprising the compound, 103 1246454 103 of 249 may vary from patient to patient. Determination of the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or detrimental side effect. The dosage level selected will depend on a variety of factors including, by way of illustrative example, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs , compounds, and / or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and previous medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action that achieve the desired effects without causing substantial harmful or detrimental side effects. Administration may be in one dose, continuously, or intermittently (eg, in divided doses at appropriate intervals) during the course of treatment. Methods for determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject. that is being treated. Single or multiple administrations can be made with the dose level and pattern selected by the physician, veterinarian, or clinician. In general, a suitable dose of the compound is in the range between about 100 ng and about 25 mg (more generally between 104 1246454 104 of 249 about 1 µg and about 10 mg) per kilogram of subject body weight per day. In some embodiments, the compound is administered to a human patient according to the following dosage regimen: about 100 mg, 3 times per day. In some embodiments, the compound is administered to a human patient according to the following dosage regimen: about 150 mg, 2 times per day. In some embodiments, the compound is administered to a human patient according to the following dosage regimen: about 200 mg, 2 times per day. examples The following examples are provided only to illustrate the present invention and are not intended to limit its scope. Example 1 - Synthesis and characterization Laboratory synthesis of 10-acetyl-N,N,N',N'-tetramethylphenothiazin-3,7-diamine step i; NaNO2, DMSO, CH3COOH, step ii; (H3CCO)O2, Et3N, DMF, step iii; Pd / C, 2-MeTHF, H2step iv; H2CO, H2or step iii; Zn, (aq) NH4Cl, MeOH, THF step iv; H2CO, NaCNBH3, CH3COOH 105 1246454 105 of 249 Synthesis of 3,7-dinitro-10H-phenothiazine (2) To a 1-liter 3-necked flask fitted with a thermometer, dropping funnel, and condenser, phenothiazine (MW 199.28 g / mol, 25.00 g, 125.5 mmol) and dimethyl sulfoxide (250 mL) were added to the mixture. it was stirred for 2 minutes or until the phenothiazine had dissolved. The condenser was then connected to a Dreschel vessel half filled with water. Sodium nitrite (MW 69.00 g / mol, 51.94 g, 752.7 mmol) was then added to the flask and acetic acid (150 mL) was added to the filling funnel. Acetic acid was then added to the balloon by dripping over a 20 minute period. The pale yellow suspension turned red and a solid precipitated out of solution. On completion of the acetic acid addition the mixture was stirred for 2 hours at room temperature (36-20°C) before increasing the temperature to 95°C and stirring for 17 hours. After this time the mixture was cooled to 50 °C and methanol (100 mL) was added and the mixture was cooled to 22 °C. The cooled mixture was then filtered and the pad washed with methanol (3 x 25 mL). The washed pad was left on the filter under vacuum for 30 minutes before being dried for 15 hours at 50°C to give the product as a brown solid (MW 289.27 g / mol, 29.45 g, 81%). Grades 1. The addition of acetic acid produced NOx gases, which were converted to nitric acid by bubbling the gas in a Dreschel vessel half filled with water. 2. The addition of acetic acid was exothermic and the mixture rose from 22°C to 36°C. 3. Methanol was added to facilitate dissolution of any acetate. 106 1246454 106 of 249 sodium and as an antisolvent to maximize the product obtained. 4. The synthesis was also successful using dimethylformamide (DMF), acetonitrile (MeCN), tetrahydrofuran (THF), acetone, or dimethoxyethane (DME) as the reaction solvent. NMR: The product (5mg) dissolved in DMSO-d6 (1.5ml) and may require heating to completely dissolve the solid. δH(400 MHz; DMSO-d6): 6.72 (2H, d, J 8.8, ArH), 7.77 (2H, d, J 2.8, ArH), 7.87 (2H, dd, J2.8, 8.8, ArH) Synthesis of 3,7-dinitro-10-acetylphenothiazine (3) To a 500 mL 3-necked flask fitted with a thermometer and condenser was added 3,7-dinitro-10H-phenothiazine (MW 289.27 g / mol, 29.00 g, 100 mmol), dimethylformamide (58 mL), anhydride acetic (MW 102.09 g / mol, 102.09 g, 1000 mmol) and triethylamine (MW 101.19 g / mol, 40.88 g, 401 mmol). The mixture was heated to 105°C and stirred at this temperature for 3 hours. The mixture was cooled to room temperature (21°C) before being cooled to 5°C and then stirred for 1 hour. The product was isolated by filtration and washed with methanol (3 x 30 mL) to give a light yellow crystalline solid, which was dried at 50 °C for 15 hours (MW 331.31 g / mol, 26.94 g, 81%). Grades 1. Product crystals formed during the reaction, after ~1 hour at 105°C. 2. After cooling the mass of the product precipitated at ~70 °C. 3. The product was orange before being washed with methanol. NMR: The product (10mg) was dissolved in DMSO-d6 (1.5ml). δΗ(400 MHz; DMSO-d6): 2.25 (3H, s, CH3), 7.92 (2H, d, J 8.8, ArH), 8.28 (2H, 107 1246454 107 of 249 dd, J 8.8, 2, ArH), 8.47 (2H, d, J 2, ArH) Synthesis of 10-Acetyl-N,N,N'N'-tetramethylphenothiazin-3,7-diamine (5) To a 100 mL three-neck flask fitted with a thermometer and condenser was added 3,7-dinitro-10-acetylphenothiazine (MW 331.31 g / mol, 5 g, 15.09 mmol), palladium on carbon (10%, dry, 0.5 g) and 2-methyltetrahydrofuran (25 mL). The vessel was evacuated and purged with hydrogen 5 times before heating the mixture to 56°C. After 17 hours the reduction was considered complete (see TLC conditions) to give compound 4, and formalin (MW 30.03 g / mol, 14.7 g, 181.1 mmol) was added. The vessel was re-evacuated and purged 5 times with hydrogen. After 71 hours of formalin addition (total time 88 hours) at 56 °C the tetra-methylation was considered complete by TLC. The mixture was filtered at 50°C, the gray catalyst was washed with 2-methyltetrahydrofuran (3 x 5 mL), and the filtrate and washings were combined. To this solution, methanol (5 mL) was added to homogenize the mixture. Cooling to 5 °C resulted in the precipitation of a colorless solid from solution. Another two volumes of methanol (10 ml) were added and the suspension was stirred for 50 minutes at 5 °C. The crude product was isolated by filtration to give a colorless solid, which was washed with methanol (3 x 5 ml) and dried at 50 °C for 16 hours (MW 327.45 g / mol, 2.26 g, 46% ). Water (50 ml) was added to the filtrate from the isolation process, which gave more solid. The suspension was stirred at 5 °C for 2 hours before being collected by filtration, washed with methanol (3 x 5 ml) and dried at 50 °C for 13 hours. (MW 327.45 g / mol, 0.83 g, 17%). The total yield of product was (3.09 g, 63%). Grades 1. Normal phase TLC conditions, eluant 75% ethyl acetate, 25 108 1246454 108 of 249% petroleum ether (40-60 °C), and UV lamp at 254nm. 2. The retention factor of the dinitro starting material is 0.68 as a yellow spot, the retention factor of the hydrogenation product is 0.25 as a blue spot, and the retention factor of the methylation product is 0.67 as a light blue stain. 3. The method for TLC analysis of the hydrogenation step was direct spotting where for analysis of the methylation product water was added to a reaction aliquot which was extracted with ethyl acetate and then analyzed. 4. After 17 hours TLC analysis showed two spots, where the larger spot was the reduction product and the smaller unknown spot. 5. After 88 hours TLC analysis showed mainly the tetra-methylated product as the major spot. 6. Typically the reduction and methylation were complete within 72 hours. 7. 1H NMR spectroscopy of the two samples gave identical spectra, and traces of 2-methyltetrahydrofuran were detected along with an unknown signal at 5 ppm. NMR: The product (10 mg) was dissolved in CDCl3 (1.5 ml). δκ(400 MHz; CDCh): 2.09 (3H, s, CH3), 2.86 (12H, s, NCH3), 6.54 (2H, d, J8, ArH), 6.64 (2H , s, Ar H), 7.19 (2H, s broad, Ar H) Alternative synthesis of 10-Acetyl-N,N,N'N'-tetramethylphenothiazin-3,7-diamine (5) To a 50 mL flask was added 3,7-dinitro-10-acetylphenothiazine (MW 331.31 g / mol, 1 g, 3.02 mmol), zinc dust (MW 65.39 g / mol, 1.38 g, 21.13mmol), 109 1246454 109 of 249 methanol (6 ml) and tetrahydrofuran (2 ml). The mixture was heated to 50°C and then a hot (45-50°C) aqueous ammonium chloride solution (MW 53.49 g / mol, 2.26 g, 42.26 mmol dissolved in 6 mL of water) slowly to maintain a gentle reflux. The mixture was then heated to 70°C and stirred at this temperature for two hours and then cooled to room temperature (23°C). The cooled mixture was filtered to remove zinc salts and the filtrate containing compound 4 was treated with paraformaldehyde (MW 30.03 g / mol, 1.09 g, 36.22 mmol), sodium cyanoborohydride (MW 62 0.84 g / mol, 1.14 g, 18.11 mmol) and acetic acid (2 mL). The mixture was heated to 50°C and stirred at this temperature for 3 hours. After cooling to room temperature (23 °C), water (2 x 10 ml) was added and the colorless suspension was stirred for 16 hours. The solid was then collected by filtration and washed with methanol (3 x 2 mL) to give the title compound (MW 327.45 g / mol, 0.91 g, 92%) as an off white solid. Grades 1. The reduction reaction using zinc and aqueous ammonium chloride was fast and clean, taking only 2 hours to complete and no other spots were recorded on TLC analysis. 2. Reductive methylation using sodium cyanoborohydride, paraformaldehyde, and acetic acid was fast and clean, taking only 3 hours to complete. NMR: The product (10 mg) was dissolved in CDCl3 (1.5 ml). δΗ(400 MHz; CDCl3): 2.17 (3H, s, CH3), 2.94 (12H, s, NCH3), 6.61 (2H, d, J8, ArH), 6.71 (2H , s, ArH), 7.26 (2H, broad s, ArH) 110 1246454 110 of 249 Synthesis 1: Synthesis of N,N,N',N'-tetramethyl-10Hphenothiazin-3,7-diaminium bis(methanesulfonate) (LMT.2MsOH) Yo. ii. MeSO! I I Yo. MSA, H2O, toluene, 85 °C ii. EtOH 10-Acetyl-N,N,N'N'-tetramethyl-10 H-phenothiazin-3,7-diamine (AcMT) (150 g) was added to a 3-neck flask. Toluene (1.8 L) was added and the mixture was heated at reflux for 30 min. The solution was allowed to cool to 70°C before being passed through a 5μ in-line filter into a coated flask fitted with distillation apparatus.1 Toluene (150 mL) was added to the flask. This was used to rinse the transfer line and filter. About 1.4 L was distilled. of toluene under reduced pressure. 2 The temperature was brought to 18 °C before adding water (42 mL). 3 Methanesulfonic acid (MSA) (65.5 mL, 99%, 2.2 equiv.) was then added throughout a period of 5 min. 4 A second portion of water (18 ml) was added. The mixture was heated at 85 °C for 3 h until the reaction was judged complete by TLC analysis. The biphasic solution was allowed to cool to 50 °C before adding absolute EtOH (150 mL) over 20 min. The mixture was seeded using 150 mg of N,N,N',N'-tetramethyl-10H- bis(methanesulfonate). phenothiazin-3,7-diaminium.6-8A second portion of EtOH (600 mL) was added over 90 min.9 and the reaction was allowed to cool to 20 °C over 1 h.10 It was stirred at this temperature for 1 h. before collecting the solid by filtration. The pad was washed with 3 x 300 mL MeCN,11 suction dried for 5 min. and placed under vacuum overnight 111 1246454 111 of 249 to give the product as a yellow crystalline solid (85-90% yield). vmax (KBr) / cm-1; 3430 (NH), 3014 (=CH), 2649 (C-H), 1614 (C=C), 1487 (C-C), 1318 (S=O), 1199 (SO2-O), 1059 (S=O), 823 (ArC=-H) δκ(600 MHz; CD3OD); 2.71 (6H, s, SCH3), 3.21 (12H, s, NCH3), 6.75 (2H, d, J 8.8 Hz, ArH), 7.22 (4H, d J 2.9 Hz, ArH), 7.24 (4H, dd J 2.9, 8.8 Hz, ArH), δc(100 MHz; CD3OD); 38.2 (SCH3), 45.9 (NCH3), 115.0 (CH), 118.2 (CH), 118.7 (QC), 119.9 (QH), 137.1 (CH), 142 .8 (Q C) MP: 271 °C m / z (EI+): Calculated 285.129970; Observed 285.131292 (100%, [M-2MSA]+). m / z (ES-): Calculated 95; Observed 95 (100%, [M-LMT]-). Elemental analysis % (C18H27N3O6S3): Calculated C (45.26), N (8.80), S (20.14), H (5.70); Observed C (45.19), N (8.76), S (19.84), H (5.53) Notes 1. Heating to reflux ensures complete dissolution of AcMT for transfer through a 5 pm filter. Toluene is a good solvent and a target of 70oC is a compromise between ensuring the material stays in solution and minimizing potential damage to plastic transfer hoses and filters. 2. 500 ml remaining toluene ensures that the reaction volume meets the minimum stirring depth of the reactor. 3. The volume of water is controlled to ensure that the product crystallizes as a free flowing precipitate. The addition of crystallization germs to the reaction reduces the impact of small variations in the volume of water. 112 1246454 112 of 249 4. 2.2 equivalents of MSA are used for hydrolysis to occur and salt formation while leaving a sufficient amount of excess acid (0.2 equivalents) to ensure product stability in solution. The addition of MSA causes a slight exotherm, hence the 5 minute additional time. 5. EtOH is used as a counter solvent to precipitate the product. A portion is added before the addition of germs to ensure that the germs do not dissolve. Extended additional time ensures controlled crystallization of the product (see notes 7 and 8). 6. It is possible to carry out the reaction without the use of a seed, however its incorporation ensures early precipitation of LMT.2MsOH which in turn prevents the formation of by-products (such as the alcohol ester EMS a potential genotoxic by-product - not detected in the synthetic process) and encapsulation of EtOH. 7. The addition of crystallization germs is also used as a means to control the particle size of the product. When using seed material that has been ground in a mortar and pestle to less than 100 pm, a significant reduction in the average particle size of the product is observed. When germs that have not been ground to less than 100 μ were used, such effects are not observed. Therefore, without wishing to be bound by theory, it appears that the ability of germs to control particle size is not a function of the particle size of the germ, it is tied to the proportion of internal or "new" faces of the germ. glass that has exposed the crushing of germs. 113 1246454 113 of 249 8. Finally, when the crystallization material was relatively large and not crushed, a considerable amount of product (skin) may adhere to the side of the reactor vessel during the EtOH addition. This can be reduced by introducing a heating / cooling cycle into the process after the addition of EtOH. However, an unexpected bonus of using the uncrushed seeds was that the level of adhering material present after EtOH addition was reduced by approximately 90%. Therefore it was no longer necessary to perform the heating / cooling cycle. It seems that this is linked to the small size of the germs rather than new faces since when the reaction is performed using non-crushed germs of less than 100 μ, the same reduction in skin adherence was observed. 9. The rate of EtOH addition has an effect on the particle size and inclusion of EtOH. Rapid addition (less than 1 hour) reduces the particle size even though the EtOH inclusion increases. A slow addition (2 hours) has the opposite effect so a balance must be achieved. 10. Cooldown rate has a similar but reduced effect. Rapid cooling (less than 1 hour) leads to a reduction in particle size with a concomitant increase in EtOH levels. A slow cooldown has the opposite effect. 11. EtOH is equally effective as MeCN in removing related substances, however its use is accompanied by a slight increase in the level of retained EtOH. 114 1246454 114 of 249 Characterization of / V, / V, / V\ / V-tetramethyl-1QH-phenothiazine-3,7-diaminium bis(methanesulfonate) (LMT.2MsOH) Elemental Analysis (Microanalysis) The analysis has good correlation between the theoretical values ​​and the analysis values ​​for carbon, nitrogen, hydrogen and sulfur. Elemental Analysis Results: Molecular Formula C18H27N3O6S3 Element % Theoretical % Found C 45.26 45.19 H 5.70 5.53 N 8.80 8.76 S 20.14 19.84 1H Nuclear Magnetic Resonance Spectroscopy (NMR) The 1H NMR spectrum was obtained in CD3OD deuterated methanol, on a Varian 600 MHz instrument and is shown in Figure 1. The assignment of the 1H NMR spectrum is below: θ O 16 O G H3C-S-0 H3C-S-0 or or Assignment Chemical Shift (ppm) Protons Group 15 / 16 2.71 6H, s 2 x SCH3 11 / 12 / 13 / 14 3.21 12H, s 2 x N(CH3)2 1 / 9 6.75 2H, d, 8.8 Hz 2 x C-H (Aromatic) 4 / 6 7.22 2H, d, 2.9 Hz 2 x C-H (Aromatic) 2 / 8 7.24 2H, dd, 8.8 and 2.9 Hz 2 x C-H (Aromatic) 115 1246454 115 of 249 13C Nuclear Magnetic Resonance Spectroscopy (NMR) The 13C NMR spectrum was obtained on a Varian 400 MHz NMR instrument at a frequency of 100.56 MHz in CD3OD deuterated methanol and is shown in Figure 2. The initial assignment of the 13C-NMR spectrum was based on correlation with plots of known chemical shifts, (Lit. Reference: Structure Determination of Organic Compounds: Tables of Spectral Data, Pretsch E., et al., Springer, London, p 122 ). Other assignments used experiments with DEPT-135, HSQC, and HMBC to unambiguously confirm the assignments. DEPT-135 (Polarization Transfer Distortion Free Enhancement), HSQC (Heteronuclear Single Quantum Coherence) and HMBC (Heteronuclear Multiple Bond Correlation) spectra were obtained on a Varian 400 MHz NMR instrument at . frequency of 100.56 MHz (see Figures 3-5). Assignment Chemical Shift (PPM) NMR Region DEPT-135 15 / 16 38.2 Alkyl CH3 11 / 12 / 13 / 14 45.9 Alkyl CH3 1 / 9 115.0 Aromatic C CH 4 / 6 118.2 Aromatic C CH 4a / 5a 118.7 Aromatic C C 2 / 8 119.9 Aromatic C C 3 / 7 137.1 Aromatic C CH 9a / 10a 142.8 Aromatic C C Infrared Spectroscopy (IR) A sample was vigorously mixed and ground in a mortar and pestle. 116 1246454 116 of 249 with 200 mg of anhydrous KBr. This mix was then pressed into a disk, using a mold at a pressure of 1500 psi. The IR spectrum was then obtained on a Nicolet Avatar 320 FT-IR spectrometer. The spectrum is shown in Figure 6. Infrared Spectrum Assignment:__________________________________ Peak Wavenumber (cm-1) Peak Type Assignment ~3430 wide N-H Voltage 3014 medium =C-H Voltage 2649 Medium C-H Voltage 1614 Medium C=C Voltage 1487 strong C-C Voltage 1318 strong S=O Voltage 1199 strong SO2-O Voltage 1059 strong S=O strain 823 strong C-H strain aromatic Mass Spectrometry (MS) Mass spectrometric analysis was performed using a Waters, LCT Premier XE mass spectrometer. A flow rate of 1 ml / hour was adopted. The source used for the analysis of the active component was electron impact ionization in the positive mode. The source used for methanesulfonate counterion analysis was electrospray ionization in the positive mode. Using electron impact ionization a peak was observed 117 1246454 117 from 249 main to 285 (see Figure 7). This corresponds to the molecular ion C16H19N3S. A comparison of the exact measured mass and the theoretical value is provided below: Theoretical Peak m / z Abundance (%) Assignment 285.129970 285.131292 100 C16H19N3S The precise measured mass is in good agreement with the calculated mass for C16H19N3S. Using electrospray ionization a major peak was observed at 95 (see Figure 8). This corresponds to the molecular ion of the CH3O3S counterion: Peak m / z Abundance (%) Assignment 95 100 CH3O3S Ultraviolet-Visible Spectroscopy (UV-Vis) 5 mg of sample was dissolved in deionized water, and made up to 100 ml in a volumetric flask. Analysis was performed using quartz cuvettes on a Perkin Elmer Lambda 25 UV / Vis spectrometer. The UV-Vis spectrum is shown Α ε =---C x l 118 1246454 118 of 249 where A = Log Absorbency (10 / 1) 3.5860; C = Concentration Mol / L; l = optical path 1 cm High Performance Liquid Chromatography (HPLC) 100 mg of sample was subjected to HPLC analysis. Analysis was performed on an Agilent 1200 series with a VWD or PDA detector for identification, according to the method summarized in the table below. HPLC method: Parameters Conditions Column Zorbax SB-CN, 50 x 4.6 mm, 3.5 μm, Column temperature 283 K Mobile phase A: 0.1% volume by volume formic acid in water B: 100% acetonitrile Flow rate 1 ml / min Injection volume 5 pl Detention time 22 min. UV wavelength at 255nm Bandwidth at 4nm. Reference wavelength set to off. PDA scan between 190 nm and 800 nm (Identity only) Autosampler temperature 278 K Protected from light. Mobile phase gradient Time (min) Mobile phase A (%) Mobile phase B (%) 0.0 100 0 10.0 90 10 17.0 50 50 18.0 50 50 18.1 100 0 22.0 100 0 The HPLC trace is shown in Figure 10. The organic purity was found to be 99.45% w / w._______________________ HPLC analysis (% purity) including retention times LMT MT+ Leuco Azure B 6.39 min. 14.38 min. 5.77 min. 99.45 0.55 <0.05 119 1246454 119 of 249 crystalline form In the method described above, LMT.2MsOH is produced in crystalline form. The crystalline form of LMT.2MsOH is illustrated by the X-ray powder diffraction pattern shown in Figure 11. XRPD exhibits sharp signals, indicative of a high degree of crystalline order. Variations in relative peak intensity can be observed, which can be attributed to orientation effects in combination with differences in particle size. Only slight variations in relative peak intensity (less than 50%) are observed as a function of sample thickness (0.1 mm vs. 1.0 mm). The crystalline form is further characterized by FTRaman analysis, thermogravimetry (TG), differential scanning calorimetry (DSC), dynamic vapor adsorption (DVS), and microscopy (Figures 12-16). This form may be conveniently referred to as "Form A". Crystals for single crystal X-ray analysis were obtained from ethanol, methanesulfonic acid and water. See Figure 17c. Instrument details X-ray powder diffraction: Bruker 08 Advance, Cu Ka radiation (λ= 1.54180 A), 40 kV / 40 mA, LynxEye detector, step size 0.02° in 2θ, 37 s per step, between 2 .5° and 50° 2Θ sweep range. Samples were prepared in 0.1 or 1.0 mm deep silicon single crystal sample holders without any special treatment other than applying slight pressure to obtain a flat surface. All samples were rotated during measurement. Differential Scanning Calorimetry: Perkin Elmer DSC 7. Gold Crucibles 120 1246454 120 of 249 closed under N2, heating rate 20°C / min, sweep between -50°C and 280°C. Dynamic Value Adsorption: Projekt Messtechnik SPS 11-100n Water Vapor Adsorption Analyzer. The samples were placed in aluminum crucibles above a microbalance and equilibrated at 25 °C and 50% R.H. before starting a predefined humidity program at 25 °C (50-0-95-50% R.H., sweep at Δ R.H. = 5% h-1 and with equilibration periods at “isohumidity” at extreme values). FT-Raman spectroscopy: Bruker RFS100. Excitation with Nd:YAG 1064 nm, laser power 50 mW, Ge-detector, 128 scans, range between 50 and 3500 cm1, 2 cm-1 resolution. Aluminum support for samples. Polarized light microscopy: Leitz Orthoplan microscope with Leica OFC280 CCO camera. TG: TA TGA Q5000 instruments. Open aluminum crucible, N2 atmosphere, heating rate 10 °C min-1, range 25 to 300 °C. TG-FTlR: Netzsch Thermo-Microbalance TG 209 with Bruker Vector 22 FT-IR Spectrometer. Aluminum crucible with microhole, N2 atmosphere, heating rate of 10 °C min-1, range between 25 and 250 °C. Without wishing to be bound by theory, it is suggested that this form represents the only stable polymorphic form of LMT.2MsOH. Polymorphism studies have shown that Form A is reproduced in almost all crystallization systems (studies were performed using degassed solvents, under an inert atmosphere). Amorphous LMT.2MsOH can be prepared by evaporation of an aqueous solution of LMT.2MsOH, however the amorphous material recrystallizes to Form A 121 1246454 121 of 249 with additional drying. Industrial scale synthesis of AcMT and LMT.2MsOH LMTM i; N2H4.H20, Et3N, MeCN, N2, 65 °C, 1 h, ¡i; Ac2O, N2, 95 °C, 2 h, iii; MSA, H2O, Toluene, N2, 85 °C, iv; EtOH. Large-scale synthesis of 10-acetyl-N,N,N'N'-tetramethyl-10H-phenothiazin-3,7diamine (AcMT) Acetonitrile (MeCN) (300 I) was added to reactor 1 (R1) and cooled to -5-0 °C. Methylthioninium chloride trihydrate (MTC,3H2O) (150 kg) was added and the temperature was increased to 15-25 °C. Triethylamine (EtsN) (100 L) was added followed by a rinse with MeCN (20 L). Hydrazine Hydrate (N2H4.H2O) (12 I) was added over 30 min. The reaction temperature was increased to 60-70°C for 1h and then held at this temperature for 1h before cooling to 40-50°C. Acetic anhydride (AC2O) (240 L) was added over 1 h followed by a rinse with MeCN (20 L). The temperature was increased to 90-100 °C for 2 h. The temperature was reduced to 55-65 °C and water (340 I) was added during 2 maintaining the temperature. The temperature was then lowered to -5-5 °C for 2 h. and kept for 6 h. The solid was collected by filtration. The pad was completely dried before adding water (400 L) to R1. The temperature in R1 was allowed to rise to 15-25°C before the water was used in portions to wash the filter pad. The product was dried under a stream of nitrogen for 6 h. before unloading (Yield: 90110 kg). Large-scale purification of 10-acetyl-N,N,N'N'-tetramethyl-10H-phenothiazin-3,7122 1246454 122 of 249 diamine (AcMT) Water (300 L) was added to R1, followed by 10-acetyl-N,N,N'N'-tetramethyl10 H-phenothiazin-3,7-diamine (AcMT) (100 kg). Toluene (400 L) and 80% aqueous acetic acid (40 L) were added, followed by a water rinse (50 L). The temperature was increased to 75-85 °C for 1 h. Stirring was stopped and the layers were allowed to stand for 30 min. The lower aqueous phase was removed and then water (300 L) and 80% aqueous acetic acid (40 L) were added followed by a water rinse (50 L). The mixture was stirred at 75-85 °C for 1 h and then the stirring was stopped and the layers were allowed to stand for 30 min. The lower aqueous phase was removed and then water (300 L) and 80% aqueous acetic acid (40 L) were added followed by a water rinse (50 L). The mixture was stirred at 75-85 °C for 1 h before stirring was stopped. The layers were allowed to stand for 30 min and then the lower layer was removed and water (390 L) was added and the mixture stirred for 1 h. Stirring was stopped and the layers were allowed to stand for 30 min. The lower aqueous phase was removed and the temperature was lowered to -5-5°C. The temperature was increased to 80oC and then when it reached 60oC the temperature was lowered to -10-0°C for 2 h. The mixture was stirred for 4 h and then transferred to the filter. The pad was completely dried before toluene (150 L) was added to R1. Toluene was stirred in R1 for 30 min. and then used in portions to wash the filter pad. The product was dried on the filter under a stream of nitrogen for 48 h to <1% loss on drying and then discharged (Yield: 75-90 kg). Large-scale synthesis of N,N,N',N'-tetramethyl-10Hphenothiazin-3,7-diaminium bis(methanesulfonate) (LMT.2MsOH) 123 1246454 123 of 249 AcMT (18-22 kg) was added to R1. Toluene (volume (l) = 16 x weight of AcMT) was added and the mixture was heated at 90-100 °C for 30 min. The solution was allowed to cool to 60-80 °C before being passed through a 5 μ in-line filter to Reactor 2 (R2). Toluene (50 L) was added to Reactor 1 (still ~70 °C) and stirred for 30 min. This was used to rinse the transfer line and filter. This process was repeated again. The process of removing excess toluene from R2 by distillation under reduced pressure was then started. Allowing the capacity of R2, two more portions of AcMT (18-22 kg each) were transferred from R1 to R2 following the method described. Distillation was complete when the volume in R2 was reduced to ~340 L. The temperature was increased to 95-105°C for 15-30 min. before cooling to 15-25 °C. Water (20 L) was added to R2. Methanesulfonic acid (MSA) (33 L, 99%, 2.2 equiv) was then added while maintaining the temperature at 15-30 °C. A second portion of water (10 L) was added and the mixture was stirred at this temperature for 2 h. The mixture was heated at 80-90 °C for 3-4 h. The biphasic solution was allowed to cool to 48-58 °C and then absolute EtOH (75 L) was added over 15-30 min. Stirring was stopped and the mixture was seeded using 150 g of chopped N,N,N',N'-tetramethyl-10H-phenothiazin-3,7diaminium bis(methanesulfonate) (<100 μ). A second portion of EtOH (300 µl) was added over 80-110 min. The temperature was brought to 10 °C and when the temperature reached 25 °C the temperature was brought back to 20 °C. It was stirred at 15-25 °C for 2 h. before collecting the solid by filtration. The pad was completely dried. MeCN (300 µl) was added to R2 and stirred for 15 min and then used in portions to wash the filter pad. Another 300 µl of MeCN was added to R2 and the washing process was repeated. The product is 124 1246454 124 of 249 were dried on the filter to <0.2% loss on drying and then discharged (80-90% yield). Synthesis 2: Synthesis and analysis of N,N,N',N'-tetramethyl-10Hphenothiazin-3,7-diaminium bis(ethanesulfonate) (LMT.2EsOH) step i; H2O, MeOH, EsOH, IPA, Acetone Synthetic method for LMT.2EsOH The synthesis of LMT.2EsOH was carried out by acid hydrolysis of 10-acetyl / V, / V,A / ’,A / ’-tetramethyl-10 / 7-phenothiazin-3,7-d¡am¡na. The acid used was ethanesulfonic acid and the solvent combination was aqueous methanol. Experimental details In a 100 mL flask, 10-acetyl- / V, / V,A / ', / V-tetramethyl-10 / 7-phenothiazin3,7-diamine (5 g, 15.27 mmol, MW 327, 45 g / mol), (70%, aq) ethanesulfonic acid (7.21 g, 45.81 mmol, MW 110.13 g / mol), and methanol (25 mL). The mixture was heated to 75°C and stirred at this temperature for 4 hours, and then the mixture was quenched with ice water. No solid formed and the methanol was removed in vacuo to give a viscous green oil. Isopropanol (25 mL) was added to this oil and the mixture was heated to reflux to homogenize the solution. Cold acetone was added until a precipitate formed. The suspension was cooled with ice water for 1 hour before filtering to give the crude product as a yellow solid, which turned green on exposure to air. The crude was washed with acetone (3x5 mL) and air dried for 3 days to give the crude product (3.35 g, 43%, MW 505.68 g / mol) as a solid. 125 1246454 125 of 249 light green. vmax (KBr) / cm-1; 3448 (NH), 3263 (=CH), 3030 (=CH), 2987 (CH), 2938 (CH), 2582 (SO3H), 2452 (SO3H), 1487 (C-C), 1211 (O=S=O) , 1188 (O=S=O), 1145 (O=S=O), 1026. oh(400 MHz; D2O): 1.07 (6H, t, J7.6, CH3), 2.72 (4H, q, J7.6, SCH2), 3.02 (12H, s, NCH3 ), 6.54 (2H, d, J9.2, ArH), 7.02 (4H, broad s, Ar / 7); 5c(100MHz; D2O): 142.3(QC), 136.6(QC), 119.9(CH), 118.4(QC), 118.2(CH), 115.2(CH), 46.2 (NCH3), 45.3 (SCH2), 8.3 (CH3). MP: 208-210 °C (IPA / Acetone) m / z (EI+): Calculated mass 285.129970; Observed 285.129761 (100%, [M2EsOH]+). m / z (ES-): Calculated mass 109; Observed 109 (100%, [M-LMT]'). Crystallography A 1 g sample of LMT.2EsOH was dissolved in acetic acid (-0.1 g) and ethyl acetate was placed on top and allowed to diffuse slowly over 3 days in the dark. Crystals grew, were collected and analyzed by X-ray diffraction and the product was confirmed as the / s(ethanesulfonate). See Figure 17a. Synthesis 3: Synthesis and analysis of Ν,Ν,Ν',Ν'-tetramethyl10H-phenothiazin-3,7-diaminium bis(p-toluenesulfonate) (LMT.2TsOH) step i; H2O, Na2CO3, THF, Et2O, p-TsOH Synthetic method for LMT.2TsOH 126 1246454 126 of 249 The synthesis of LMT.2TsOH was carried out by neutralizing N,N,N',N'tetramethyl-10H-phenothiazin-3,7-diaminium dichloride with sodium carbonate and extracting the neutral species with the organic solvent. The extract was treated with p-toluenesulfonic acid and the mixture was concentrated to dryness. Experimental details Sodium carbonate (0.59 g, 5.58 mmol, MW 105.99 g / mol) and water (10 mL) were added to a 50 mL vessel, the mixture was stirred until the solid dissolved. In a 100 mL separatory funnel N,N,N',N'tetramethyl-10H-phenothiazin-3,7-diaminium dichloride (1 g, 2.79 mmol, MW 358.33 g / mol) was added, tetrahydrofuran (35 ml) and diethyl ether (5 ml) and then aqueous sodium carbonate solution. The neutral species was extracted with the organic solvent and separated from the aqueous layer. Ptoluenesulfonic acid monohydrate (1.06 g, 5.58 mmol, MW 190.20 g / mol) previously dissolved in tetrahydrofuran (5 mL) was added to the organic extract and the mixture was concentrated to dryness to give the product (MW 629.8216 g / mol) as a green brittle amorphous foam. vmax (KBr) / cm-1; 3440 (NH), 3270 (=CH), 3032 (=CH), 2628 (SO3H), 1484 (C-C), 1194 (O=S=O), 1122 (O=S=O), 1032. δH(400MHz; D2O); 2.24 (6H, s, CH3), 3.09 (12H, s, NCH3), 6.62 (2H, d, J 8.4, ArH), 7.10 (4H, s, ArH), 7 0.13 (4H, d, J 8.4, Ts-H), 7.61 (4H, d, J 8.4, Ts-H) δο(100 MHz; D2O); 19.9 (CH3), 45.9 (NCH3), 115.0 (CH), 118.2 (CH), 118.6 (QC), 119.9 (CH), 125.5 (CH) , 128.5 (CH), 137.0 (QC), 140.5 (QC), 141.9 (QC), 142.8 (QC). Mp: 108 °C (THF / Et2O) m / z (EI+): Calculated mass 285.129970; Observed 285.129398 (100%, [M127 1246454 127 of 249 2TsOH]+). m / z (ES-): Calculated mass 171.0116; Observed 171.0121 (100%, [M-LMT]'). Synthesis 4: Synthesis and analysis of N,N,N',N'-tetramethyl-10H phenothiazin-3,7-diaminium ethanedisulfonate (LMT.EDSA) The synthesis of LMT.EDSA was carried out by acid hydrolysis of 10-acetylA / ,A / ,A / ’,A / ’-tetramethyl-10 / 7-phenothiazin-3,7-diam¡na. The acid used was 1,2-ethanedisulfonic acid and the solvent combination was aqueous ethanol. Experimental details 10-Acetyl-A / ,A / ,A / ',A / '-tetramethyl-10 / 7-phenothiazin-3,7-diamine (1 g, 3.05 mmol, MW 327.45 g / mol), 1,2-ethanedisulfonic acid monohydrate (0.95 g, 4.58 mmol, MW 208.21 g / mol), water (1 mL), and ethanol (5 mL). The mixture was heated to 85°C and stirred at this temperature for 2.5 hours and then a yellow-green solid precipitated out of solution. The suspension was cooled with ice water for 30 min and then filtered to give the crude product as a yellow-green solid. The crude material was washed with ethanol (3x3 mL) and air dried for 15 min and then oven dried for 3.5 hours at 70 °C to give the crude product (1.33 g, 91%, MW 475 0.61 g / mol) as a yellow solid. Purification of LMT.EDSA In a 50 mL conical flask crude LMT.EDSA (1 g, 2.10 mmol, MW 475.61 g / mol) and water (10 mL) were added. The suspension was heated to 95 °C and stirred at this temperature until the solid dissolved. The solution was then allowed to cool 128 1246454 128 from 249 to 25°C and then a light green crystalline solid was formed. The suspension was then cooled with ice water for 30 min and then filtered. The collected solid was washed with methanol (3 x 3 mL) and air dried for 18 hours to give the purified product (0.88 g, 88%, MW 475.61 g / mol) as a light green crystalline solid. Vmax (KBr) / cm-1; 3408 (NH), 3280 (=CH), 3221 (C-H), 3036 (=CH), 2574 (SO3H), 2480 (SO3H), 1484 (C-C), 1226 (O=S=O) δH(400 MHz; D2O); 2.98 (12H, s, NCH3), 3.06 (4H, s, SCH2), 6.45 (2H, d, J 6, Ar H), 6.95 (4H, d J 4, Ar H) δc(100 MHz; D2O); 46.2 (NCH3), 46.4 (SCH2), 115.1 (CH), 118.1 (CH), 118.4 (QC), 119.8 (CH), 136.5 (QC), 142 .1 (QC) MP: decomposes at 268 °C (H2O) m / z (EI+): Calculated 285.129970; Observed 285.130948 (100%, [M-EDSA]+). m / z (ES-): Calculated 188.9528; Observed 188.9535 (100%, [M-LMT]-). Crystallography A 40 mg sample of LMT.EDSA was dissolved in hot deuterated water (~1 ml) and allowed to slowly cool in the dark. The crystals that developed were collected, analyzed by X-ray diffraction, and the product was confirmed as the LMT adduct monohydrate at 1:1 EDSA. See Figure 17b. Synthesis 5: Synthesis and analysis of N,N,N',N'-tetramethyl10H-phenothiazin-3,7-diaminium naphthalenedisulfonate (LMT.NDSA) 129 1246454 129 of 249 Synthetic method for LMT.NDSA The synthesis of LMT.NDSA was carried out by acid hydrolysis of 10-acetyl / V, / V, / V', / V'-tetramethyl-10 / 7-phenothiazin-3,7-diam¡ne. The acid used was 1,5-naphthalenedisulfonic acid and the solvent combination was aqueous ethanol. Experimental details To a 25 mL flask was added 10-acetyl- / V, / V,A / ', / V-tetramethyl-10 / 7-phenothiazin3,7-diamine (1 g, 3.05 mmol, MW 327, 45 g / mol), 1,5-naphthalenedisulfonic acid tetrahydrate (1.65 g, 4.58 mmol, MW 360.36 g / mol), water (1 mL), and ethanol (5 mL). The mixture was heated to 85 °C and stirred at this temperature for 30 minutes, still resulting in insoluble mixture. Water (4 mL) was added to the hot mixture and the reaction was heated to 95 °C and stirred at this temperature for 8 hours. The suspension was cooled with ice water for 10 minutes before filtering to give the crude product as a pale green solid. The crude was washed with ethanol (3x5 mL) and air dried for 3 days to give the crude product (1.75 g, 100%, MW 573.71 g / mol) as a light blue-green solid. vmax (KBr) / cm-1; 3382 (NH), 3302 (=CH), 3040 (=CH), 2525 (SO3H), 1478 (C-C), 1238 (O=S=O), 1219 (O=S=O), 1179, 1158, 1030 . 6h(400MHz; D2O); 3.06 (12H, s, NCH3), 6.70 (2H, brd, ArH), 7.14 (4H, brd, ArH), 7.43 (2H, t, J 8.0, 7.6, Naph-H), 7.94 (2H, d, J7.2, Naph-H), 8.87 (2H, d, J 78.4, Naph-H), 9.10 (1H, s, NH) 6c(100MHz; D2O); 46.0 (NCH3), 115.3 (CH), 117.5 (QC), 118.7 (CH), 120.4 130 1246454 130 of 249 (CH), 124.6 (CH), 124.7 (CH), 129.6 (CH), 129.9 (QC), 138.3 (QC), 141.7 (QC), 143 .8 (QC). PM; decomposes at 256°C (MeCN) m / z (EI+): Calculated mass 285.129970; Observed 285.130367 (100%, [MNDSA]+). m / z (ES-): Calculated mass 286.9684; Observed 286.9697 (100%, [M-LMT]-). Example 2 - Solubility studies i) Solubility of dibromide, dichloride and bis(methanesulfonate) salts of N,N,N',N'tetramethyl-10H-phenothiazin-3,7-diaminium (LMT.2HBr, LMT.2HCI and LMT.2MsOH ) Two aqueous solutions (pH 2.00 and 3.01 at 21.4 °C) by carefully adding HCl (5 M) to deionized water. In each experiment, a 5 ml aliquot of one of the mentioned solutions was heated to 37oC. A portion of the appropriate salt (LMT.2MsOH, LMT.2HCl or LMT.2HBr) was added and the mixture was stirred for a few moments until complete dissolution of the solid. This step was repeated until no further dissolution occurred. The results are shown in the Table: Salt pH (21.4 oC) g / 5 ml* (37 oC) LMT.2HBr 3.01 4.726-5.236 LMT.2HBr 2.00 4.822-5.096 LMT.2HCl 3.01 4.978-6.029 LMT.2HCl 2.00 4.404-4.961 LMT.2MsOH 2.00 8.825-9.943 *The lower limit of the range corresponds to the total weight at which the 131 1246454 131 of 249 complete dissolution. The upper limit is the total weight added until saturation is reached. As can be seen, LMT.2MsOH has good solubility in water. independence of the pH of the salt LMT.2MsOH In the experiments listed three pH-regulated stock solutions (pH 2, pH 3, and pH 7) as follows: aqueous solution regulated at pH 2 Initially a solution of potassium chloride (KCl) (0.2 M) (0.745 g in 50 mL of deionized water) was prepared. From this solution 50 mL was added and diluted with approximately 80 mL of deionized water. Hydrochloric acid (HCl) solution (0.2 M) was then used to adjust the pH to 2, and then further diluted with deionized water to 200 mL. A final pH of 2.00 was recorded at 21.6°C. aqueous solution regulated at pH 3 Initially a solution of potassium hydrogen phthalate (0.1 M) (2.042 g in 100 mL of deionized water) was prepared. From this solution 100 mL was added and diluted with approximately 50 mL of deionized water. 0.2M HCl solution was then used to adjust the pH to 3, and then further diluted with deionized water to 200 mL. A final pH of 2.99 was recorded at 21.7°C. pH 7 aqueous solution regulated to Initially a solution of (0.1 M) monobasic potassium phosphate (KH2PO4) (1.370 g in 100 mL deionized water) was prepared. From this solution 100 mL was added and diluted with approximately 80 mL of deionized water. Then a 0.5 M sodium hydroxide (NaOH) solution was used. 132 1246454 132 of 249 to adjust the pH to 7, and then further diluted with deionized water to 200 mL. A final pH of 7.07 at 22°C was recorded. Method A 5 mL aliquot of a pH regulated aqueous solution was added to a vial containing a Micro-Flea stirrer. This vial was placed in a 25°C water bath. LMT.2MsOH was added to the solution in 1-1.5 g portions. After each addition, stir for 10 min to maximize dissolution. The homogeneity of the mixture was determined visually. If any solid was still present after agitation, as determined visually, the saturation point was considered to have been reached. Results The viscosity of the resulting mixtures prevented the adequate isolation of the excess solid, therefore it was not possible to determine the exact values ​​of solubility. Therefore, each of the results will be reported in a range in which the total mass of LMT.2MsOH added before the saturation point is the lower limit and the total mass of LMT.2MsOH added, after the saturation point, provides the lower limit. the upper limit. The results of each of the three experiments are shown below: pH Solubility (g / mL) 2.00 1.600 - 1.773 2.99 1.981 - 2.092 7.07 2.033 - 2.114 As can be seen, the solubility decreased slightly as the pH decreased, however LMT.2MsOH performed well in each of the 133 1246454 133 of 249 the three aqueous systems. In conclusion LMT.2MsOH has better aqueous solubility than MTC (not shown) and improved solubility compared to the corresponding chloride and bromide salts. This suggests increased utility relative to the treatment and uses described herein. Example 3 - inhibition of aggregation and toxicity Methods: Solid phase assay for tau aggregation The tau-tau aggregation assay uses purified recombinant tau fragments in a solid phase immunoassay. The methods are described in detail for example in WO 96 / 30766. Briefly, the assay measures the binding of truncated tau (amino acids 297-391) in solution to solid phase bound truncated tau (residues 297-390). The binding of the former is detected with the mAb 423 antibody, which specifically recognizes peptides containing a C-terminal Glu-391 residue. The Tau complex formed in vitro is similar to the aggregate complex that forms in Alzheimer's disease as a consequence of the stability of the pathological Tau-Tau binding interaction through the 94 / 95 amino acid repeat domain (residues 297-390). ), which are found in the proteolytically stable core of the paired helical filament. The B50 value (expressed as mean ± SE) is determined as the concentration of compound at which tau-tau binding decreases by 50%. Methods: Cell-Based Tau Aggregation Assay The assay is based on mouse 3T6 cells that have been engineered to express human full-length tau protein (htau40) under the control of an inducible promoter (pOPRSVI), t to express low levels of tau 134 1246454 134 of 249 truncated (295-390, dGA) under the control of a constitutive promoter (pcDNA3.1). Expression of large amounts of htau40 is induced by the addition of IPTG (10-50μΜ), which in turn leads to the production of additional truncated tau by a process in which aggregation and processing of full-length tau occurs in the presence of of dGA tau that acts as a template. The addition of tau-tau aggregation inhibitors to the assay blocks this process. The methods are described in more detail in WO 02 / 055720. Results are expressed as the concentration at which there is 50% inhibition of generation of the 12 kD fragment. It is referred to as the EC50 value. Cells (4A and clones thereof) were grown to approximately 80% confluency in a 10-cm dish, before splitting into two 24-well plates and grown for 24 hours. The test article is added at different concentrations and after 24 hours IPTG is added. After overnight incubation, the medium is removed, the wells are washed with PBS, and the cells are harvested by the addition of Laemmli's buffer. Samples were stored at -20°C for subsequent gel electrophoresis, Western blotting, and antibody labeling. Samples were separated by SDS PAGE, blotted onto PVDF membrane and tau labeled with a 7 / 51 antibody detected by ECL on a Kodak Imaging Station. The compound was generally tested at four concentrations in triplicate over a range of concentrations by running all samples on one gel. The ratio of band intensities from dGA to htau40, normalized to control samples in which there had been no drug, was plotted against drug concentration and graphically determined the 135 1246454 135 of 249 EC50 value of the concentration at which the ratio drops to 0.5. The method is summarized in Table 1 immediately below. MTC (TRx0014.047) was run as a control in all experiments and the EC50 value was normalized to MTC having an EC50 = 0.59μΜ. Time Action Day 1 Detach cells to 24-well plates Day 2 Add drugs at different concentrations Day 3 In the evening, add IPTG Day 4 Morning, collect in Laemmli buffer, store at -20oC before further processing Day of processing Run samples in SDS-PAGE gels, transfer to PVDF membrane, label with 7 / 51 anti-tau antibody. Bands were quantified using Kodak 1D software and data transferred to Systat statistics package for plotting. Table 1: Summary of the test procedure to measure EC50 Methods: cell toxicity assay Cells (mouse 3T6 fibroblasts) were grown to approximately 80% confluency in a 10-cm dish, before spreading into 96-well plates, 10% of the 10-cm dish per 96-well plate, 50μl per well. An 8-well column was left empty (to be a reagent blank in the assay). Cells were allowed to grow overnight before drug was added to four wells at the initial concentration (usually 200μΜ for MTC or LMT.2HBr) and to subsequent wells using a 1:2 dilution series using the final four wells of cells as 136 1246454 136 of 249 control without drug. This allows two drugs to be tested per 96-well plate. The cells were left in the presence of the drug for 48 hours, after which the medium was removed and the cells were washed with PBS. Cell number was determined using a Cytotox 96-well kit (Promega) which is based on the lactate dehydrogenase (LDH) assay. The assay quantitatively measures LDH, a stable cytosolic enzyme released upon cell lysis. Released LDH is measured with an enzyme assay that results in the conversion of a tetrazolium salt to a red formazan product. The amount of color formed is proportional to the number of cells lysed. Briefly, cells are lysed with 50μl / well of 1x lysis buffer for 45-60 minutes, followed by 50μl / well of LDH assay reagent for 30 minutes and the reaction stopped with 50μl / well of lysis buffer. detention. The absorbance was read at 490nm. Relative absorbance to untreated wells (untreated cells = 1.0) was plotted against drug concentration. The LD50 was graphically determined from the concentration at which the Absorbance decreases by 50%. MTC (TRx0014.047) was run as a control in all experiments when LMT.2HBr was tested and the LD50 value was corrected to MTC with an LD50 = 65μΜ. Results: Different bis(sulfonate) salts according to the invention were tested and compared with N,N,N',N'tetramethyl-10H-phenothiazine-3,7-diaminium bis(halide) di(chloride) salts ( LMTC, LMT.2HCl) and N,N,N',N'-tetramethyl-10H-phenothiazine-3,7-diaminium di(bromide) LMT.2HBr and with 137 1246454 137 of 249 methylthioninium (MTC). In vitro data for the different forms of methylthioninium salts are summarized in Table 2 immediately below: Compound LD50 (μΜ) EC50 (μΜ) THx B50 (μΜ) MTC 65 ± 5 0.59 ± 0.04 110 195.6 ± 16.1 (n=10) LMT.2HBr 61 ± 4 (n=20) 0.66 ± 0.15 (n=8) 92,472.4 ± 27.6 (n=3) LMT.2MsOH 34 ± 4 (n=8) 0.19 ± 0.04 (n=8) 179,238.2 ± 74.2 (n=3) LMT.2HCl 64 ± 8 (n=10) 0.63 ± 0.10 (n=7) 102 360.8 ± 38.2 (n=3) LMT.2TsOH 87 ± 10 (n=8) 0.62 ± 0.34 (n=2) 140 296.0 ± 37.9 (n=3) LMT.NDSA 77 ± 15 (n=8) 0.71 ± 0.34 (n =4) 108 333.7 ± 63.2 (n=2) LMT.EDSA 78 ± 6 (n=8) 0.68 ± 0.32 (n=4) 115 399.9 ± 17.6 (n= 2) LMT.2EsOH 52 ± 3 (n=8) 0.52 ± 0.13 (n=3) 100 297.0 ± 75.1 (n=3) MSA* - NE (20) - >500 EDSA* - NE (20) - >500 Table 2: Summary of in vitro data. THx, therapeutic index THx = LD50 / EC50 ) Values ​​expressed as mean ± SE. NE = not effective (at maximum dose 138 1246454 138 of 249 tested) *MSA = methanesulfonic acid; EDSA = ethanesulfonic acid Comments EC50 values ​​(mean ± SE) for LMT.2MsOH and LMT.2HCl are 0.19 ± 0.04 μΜ and 0.63 ± 0.10 μΜ, respectively, with corresponding therapeutic indices of 179 and 102. The relative potency of compounds in the cell-based model of tau-tau aggregation is LMT.2MsOH > MTC, LMT.2HBr, LMT.2HCl. The therapeutic index is 63% higher for LMT.2MsOH compared to MTC. The order of potency in the cell-based assay is MTC, LMT.2MsOH > LMT.2HCl > LMT.2HBr. The B50 values ​​for LMT.2MsOH and LMT.2HCl are 238.2 ± 74.2 µM and 360.8 ± 38.2 µM, respectively. The order of relative potency in the cell free assay is LMT.2MsOH > MTC, LMT.2HCl, LMT.2HBr. Example 4 - toxicology, impurities and effect of the hematopoietic system LMT.2HBr, LMT.2HCl, LMT.2MsOH, or MTC were administered daily for 14 days to female Wistar rats; doses were 95 mg MT / kg / day between Days 1 and 10 and 60 mg MT / kg / day between Days 11 and 14. Clinical signs of raised body posture, subdued behavior and general weakness were seen in all groups treated. Treatment-related samples occurred in the LMT.2HBr and MTC treated groups. Changes in red blood cell parameters were seen in the blood and bone marrow of all treated groups that was indicative of an anemia 139 1246454 139 of 249 regenerative. These included: decreased numbers of red blood cells, low hemoglobin concentration and increased numbers of reticulocytes in the blood, and increased numbers of red blood cell precursors in the bone marrow. This was corroborated histologically by increased levels of erythropoiesis in the spleen. A decrease in the numbers of neutrophilic granulocytes was observed in the bone marrow of all treated animals although the magnitude of this effect was considerably greater in the LMT.2HBr-treated group than other groups. This difference was also noted in the severity of neutropenia observed in prepared blood smears where there was a marked decrease in mature neutrophils in animals treated with LMT.2HBr, a modest decrease with MTC, and no decrease in the LMT.2HCl or LMT groups. .2MsOH. The results of this study suggest that, in rats at least, LMT.2HBr has a greater propensity to cause neutrophil depletion than LMT.2HCl, LMT.2MsOH, or MTC. Decreased numbers of mature granulocytes and neutrophils were also observed in bone marrow at the high dose (45 mg MT / kg / day) in a 6-month study of LMP2HBr in the rat. The decreased neutrophils or neutropenia observed after LMT.2HBr, although it is reversible, would make patients more susceptible to bacterial infections since its main role is the destruction of bacteria. Therefore LMT.2MsOH shows improved properties compared to LMT.2HBr in rats in terms of tolerability (dose-related deaths) and a neutrophil response. Table: Neutrophil response in rats after 14 days of oral administration of different forms of LMT salts. Total neutrophils are recorded 140 1246454 140 of 249 as a percentage of total white blood cells (approximately 100 white blood cells (range 100-107) were examined from each slide); frequency in the presence of immature neutrophils was recorded by group of animals; dose-related deaths were recorded as numbers of animals per group of 8 rats. ___________________________________ Compound Neutrophils Early Neutrophils Dose Related Deaths Vehicle Control 15.50% 0 / 8 0 / 8 LMT.2HBr 3.00% * 8 / 8 2 / 8 LMT.2HCl 19.90% 2 / 8 0 / 8 LMT.2MsOH 18 .30% 1 / 8 0 / 8 * P < 0.001 compared to control Although LMT.2HCl and LMT.2MsOH are comparable in the above analysis, there is a distinction in the impurities found in the two salt forms. For LMT.2HCl, the presence of methyl chloride was detected during the synthesis and was trapped in the product such that it was difficult to remove entirely. In contrast, impurities such as ethyl and methyl methanesulfonate (EMS, MMS) can be controlled at much lower levels in the LMT.2MsOH synthesis process. Hematopoietic system studies were performed in rats, monkeys, and minipigs. The lowest doses at which methemoglobinemia was observed were 15 mg MT / kg / day in rats (MTC and LMT.2HBr) or 30 mg MT / kg / day 141 1246454 141 of 249 (LMT.2MsOH), 5.3 mg MT / kg / day in primates (MTC), and 10 mg MT / kg / day (LMT.2MsOH and LMT.2HBr) in minipigs. After the first 28 hours of dosing in the 9-month LMT.2MsOH study in minipigs, there are no indications of methemoglobinemia at 3 mg MT / kg / day. However, as expected, as dose levels of MTC, LMT.2HBr, or LMT.2MsOH are increased, signs of oxidative stress to RBCs emerge in a dose-dependent manner, evidenced by increasing levels of methemoglobin. and finally, at doses that were not tolerated, formation of Heinz bodies (aggregates of denatured hemoglobin, precipitated in red blood cells). Example 5 - Pharmacokinetics Figure 18 shows a comparison of the plasma concentration in pigs of the MT group over time after dosing of LMT.2HBr, LMT.2HCl and LMT.2MsOH at two oral doses (2 and 15 mg / kg). As can be seen the Cmax (at Tmax of 1 hour) for LMT.2MsOH was more than 2-fold higher than that of LMT.2HCl or LMT.2HBr. Therefore LMT.2MsOH may provide a more effective exposure to MT than LMT.2HCl or LMT.2HBr. Example 6 - Gastric Irritation Studies Study (28 days in rats with MTC or LMT.2HBr): Incidence and severity of selected microscopic findings in the stomach of terminal animals Incidence and severity of selected findings in the sternum, femur, liver and spleen: terminal death Male Female 1M 2M 3m 4m 5M 6M 7m 1F 2F 3f 4f 5F 6f 7f MTC LMT.2HBr MTC LMT.2HBr Tissue and finding Level (mg / kg / day) 0 5 30 90 5 30 90 0 5 30 90 5 30 90 No. examined: 5 0 0 5 0 0 5 5 0 0 5 0 0 5 142 1246454 142 of 249 Gastritis of the stomach (non-glandular) 1 1 2 1 1 3 1 1 1 Infiltration of inflammatory cells 1 1 Key: “-“ = finding not present, 1 = minimal, 2 = mild, 3 = moderate, 4 = moderately severe, 5 = severe From the above, the following can be predicted with 10 per group Incidence and severity of selected findings in the sternum, femur, liver and spleen: terminal death Male Female 1M 2M 3m 4m 5M 6m 7m 1F 2F 3f 4f 5F 6F 7f MTC LMT.2HBr MTC LMT.2HBr Tissue and finding Level (mg / kg / day) 0 5 30 90 5 30 90 0 5 30 90 5 30 90 No. examined: 10 0 0 10 0 0 10 10 0 0 10 0 0 10 Stomach gastritis (non-glandular) 1 2 2 2 2 3 2 2 2 total 2 4 2 4 Study (28-day LMT.2MsOH Rat Study): Incidence and Severity of Selected Microscopic Findings in the Sternum, Liver, Spleen, and Stomach of Terminal Animals_____________________________________ Incidence and severity of selected findings in the sternum, liver and spleen: terminal death Males Females 1M 2M 3M 4M 1F 2F 3F4F Tissue and finding Level (mg / kg / day) 0 5 30 90 0 5 3090 No. examined: 10 0 0 10 10 0 010 Grade * Stomach gastritis (non-glandular) 1 2 2 2 3 1 Total 2 3 Inflammatory cell infiltration 1 4 4 2 1 * Key: “-“ = finding not present, 1 = minimal, 2 = mild, 3 = moderate, 4 = moderately severe, 5 = severe 143 1246454 143 of 249 These results show that LMT.2MsOH causes less gastric irritation than LMT.2HBr. Example 7 - Formulations Formulation Example 1: Preparation of LM™ Tablets Using Direct Compression Tablets having the following compositions were prepared by a direct compression method: Tablet Strength (MLT mg / tablet) 50 75 100 125 150 Ingredient (mg / tablet) LMTM 84.43 126.65 168.86 211.08 253.29 Spray-dried mannitol 344.57 302.35 290.14 392 .92 425.71 Microcrystalline cellulose (Avicel PH102 or PH112) 50.00 75.00 95.00 125.00 150.00 Crospovidone (cross-linked polyvinylpyrrolidone) 15.00 15.00 15.00 15.00 15.00 Stearate magnesium 6.00 6.00 6.00 6.00 6.00 Tablet core total weight 500.00 525.00 575.00 750.00 850.00 The LMTM, spray-dried mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate were mixed in a free fall mixer, and then compressed using a tablet machine. The tablet cores were then film coated with a 144 1246454 144 of 249 Opadry* Blue Aqueous Suspension (*trademark of Colorcon for a range of film coating materials). Formulation Example 2: Preparation of LM™ Tablets Using Dry Granulation (Roller Compaction) Tablets having the following compositions were prepared by a dry granulation method: Tablet Strength (MLT mg / tablet) 50 75 100 125 150 Ingredient (mg / tablet) LMTM 84.43 126.65 168.86 211.08 253.29 Spray-dried mannitol 344.57 302.35 290.14 392 .92 425.71 Microcrystalline cellulose (Avicel PH102 or PH112) 50.00 75.00 95.00 125.00 150.00 Crospovidone (cross-linked polyvinylpyrrolidone) 15.00 15.00 15.00 15.00 15.00 Stearate magnesium 6.00 6.00 6.00 6.00 6.00 Tablet core total weight 500.00 525.00 575.00 750.00 850.00 The LM™, spray-dried mannitol, microcrystalline cellulose, crospovidone, and magnesium stearate were mixed in a free fall mixer. The mixture was then dry granulated using a roller compactor and then milled with an oscillating granulator using a suitable screen. In this case, half of the magnesium stearate was used before compaction. 145 1246454 145 of 249 with rollers and half of the magnesium stearate was then added to the granulation and mixed prior to compression in a conventional tabletting machine. The tablet cores were then film coated with an aqueous suspension of Opadry* blue (*trademark of Colorcon for a range of film coating materials). Formulation example 3: Preparation of LMTM tablets by dry granulation (pre-compression) Tablets having the following compositions were prepared by another dry granulation method. Tablet Strength (MLT mg / tablet) 50 75 100 125 150 Ingredient (mg / tablet) LMTM 84.43 126.65 168.86 211.08 253.29 Spray-dried mannitol 344.57 302.35 290.14 392 .92 425.71 Microcrystalline cellulose (Avicel PH102 or PH112) 50.00 75.00 95.00 125.00 150.00 Crospovidone (cross-linked polyvinylpyrrolidone) 15.00 15.00 15.00 15.00 15.00 Stearate magnesium 6.00 6.00 6.00 6.00 6.00 Tablet core total weight 500.00 525.00 575.00 750.00 850.00 The LMTM and the excipients were mixed in a blender. 146 1246454 146 of 249 free-fall mixer, and then compressed to produce tablets (flat, flat-sided tablets) using a tabletting machine. The tablets were then milled using an oscillating granulator set up with a 20 mesh screen. In this example, half of the magnesium stearate was used prior to precompression and then half of the magnesium stearate was added to the granulation and blended prior to compression in a conventional tabletting machine. The tablet cores were then film coated with an aqueous suspension of Opadry* blue (*trademark of Colorcon for a range of film coating materials). Formulation example 4: Preparation of LMTM tablets by wet granulation of excipients and incorporation of LMTM extra-granularly Tablets having the following compositions were prepared by a wet granulation method: Tablet Strength (MTL mg / tablet) 50 75 100 125 150 Ingredient (mg / tablet) LMTM 84.43 126.65 168.86 211.08 253.29 Mannitol 334.57 292.35 280.14 380.92 413 .71 Microcrystalline cellulose (Avicel PH102) 50.00 75.00 95.00 125.00 150.00 Crospovidone (cross-linked polyvinylpyrrolidone) 15.00 15.00 15.00 15.00 15.00 Polyvinylpyrrolidone 10.00 10.00 10.00 12.00 12.00 Magnesium Stearate 6.00 6.00 6.00 6.00 6.00 Tablet Core Total Weight 500.00 525.00 575.00 750.00 850.00 Mannitol, crospovidone (one third of the total) and microcrystalline cellulose were mixed in a free fall mixer. The mixed material is then 147 1246454 147 of 249 granulated using a solution of PVP in water. The wet mass was dried in a fluid bed dryer and then ground using an oscillating granulator configured with a suitable screen. The milled material was then blended with the remainder of the crospovidone and magnesium stearate, and the LMTM, prior to compression in a conventional tabletting machine. The tablet cores were then film coated with an aqueous suspension of Opadry* blue (*trademark of Colorcon for a range of film coating materials). Formulation Example 5: Preparation of LM™ Capsules Capsules having the following compositions were prepared. Capsule Strength (LMT mg / capsule) 50 75 100 125 150 200 Ingredient mg / capsule LMTM 84.43 126.65 168.86 211.08 253.29 337.72 Spray-drying mannitol 191.07 148.85 116, 64 79.42 42.21 37.78 Crospovidone (cross-linked polyvinylpyrrolidone) 3.00 3.00 3.00 3.00 3.00 3.00 Magnesium stearate 1.50 1.50 1.50 1.50 1, 50 1.50 Total weight of capsule filling 280.00 280.00 290.00 295.00 300.00 380.00 The LM™ and excipients were mixed in a free fall mixer. The resulting drug mixtures were used to fill capsules (50, 75, 100, 125 and 150mg formulations in size 1 capsules and the 200mg formulation in size 0 capsules) using a capsule filling machine. Gelatin capsules and HPMC capsules were prepared. Formulation Example 6: Stability Test Results of 75mg LMTM Film-Coated Tablets 148 1246454 148 of 249 Assay Time point (months) Storage location 25°C / 60%RH 40°C / 75%RH Assayed as % LMT free base 0 102.2 102.2 1 101.5 94.8 3 100.0 94.2 6 96.4 not realized 9 95.6 not realized 12 96.0 not realized Formulation example 7: Results of stability tests of tablets of 100mg film-coated LMTM________________________________ Assay Time point (months) Storage location 25°C / 60%RH 40°C / 75%RH Assayed as % LMT free base 0 101.0 101.0 1 96.7 93.7 3 95.9 92 .8 6 96.0 94.2 9 97.1 not realized 12 96.8 not realized Formulation example 8: Results of stability tests of tablets of 75mg film-coated LMTM Assay Time point (months) Storage location 25°C / 60%RH 40°C / 75%RH % of MT 0 2.16 2.06 149 1246454 149 of 249 trained 1 2.05 3.79 3 2.19 4.51 6 2.83 5.71 9 3.53 not done 12 3.28 not done Formulation example 9: Results of stability tests of tablets of 100mg film-coated LMTM Assay Time point (months) Storage location 25°C / 60%RH 40°C / 75%RH % MT formed 0 2.07 2.07 1 1.78 3.27 3 1 .81 4.92 6 2.51 5.07 9 2.72 12 2.88 Formulation Example 10: LMTB 100mg film-coated tablets______________________________________________________________ Material mg / tablet (as LMT) mg / tablet (as LMTM) % (core only) Tablet core LMTB (lot number 0802100070) 100.00 163.03 32.61 Dried Mannitol 329.00 265.97 53.19 150 1246454 150 of 249 by spray (Pearlitol 200 SD) Microcrystalline cellulose 50.00 50.00 10.00 Crospovidone 15.00 15.00 3.00 Magnesium stearate 6.00 6.00 1.20 Tablet core Total 500.00 500.00 100.00 Film coating Polyvinyl Alcohol (partially hydrolyzed) 8.80 8.80 Talc 4.00 4.00 Titanium dioxide 3.10 3.10 Macrogol PEG 3350 2.47 2.47 Lecithin (soy) 0.70 0.70 Iron Oxide Yellow 0.47 0.47 Lake Aluminum Indigo Carmine 0.45 0.45 Total Film Coated Tablet 520.00 520.00 Manufacturer Piramal, Morpeth, UK Tablet Core Lot Number A02581 Date manufacturing October 15, 2009 Tablets having the above formulation were prepared by a direct compression method as previously described and then film-coated (see formulation example 1). Formulation example 11: LMTM 75mg tablets coated with 151 1246454 151 of 249 movie Material mg / tablet (theoretical) mg / tablet (actual) % (core only) LMTM Tablet Core (lot numbers 800225510 & 80224450) 75.00 126.80 24.15 Spray-dried Mannitol (Pearlitol 200 SD) 354, 00 302.20 57.56 Microcrystalline cellulose 75.00 75.00 14.29 Crospovidone 15.00 15.00 2.86 Magnesium stearate 6.00 6.00 1.14 Total tablet core 525.00 525.00 100.00 Film coating Polyvinyl Alcohol (partially hydrolyzed) 13.86 13.86 Talc 6.30 6.30 152 1246454 152 of 249 Titanium dioxide 4.89 4.89 Macrogol PEG 3350 3.89 3.89 Lecithin (soy) 1.10 1.10 Yellow iron oxide 0.75 0.75 Indigo Carmine Aluminum Lake 0.71 0.71 Coated tablet with total film 556.5 556.5 Manufacturer Piramal, Morpeth, UK Tablet Core Lot Number A04827 Manufacture Date 5 Aug 2010 Tablets having the above formulation were prepared by a direct compression method as previously described and then film coated (see Formulation Example 1), Formulation Example 12 - dissolution studies Film-coated LMTB tablets (3 x 100mg) and LMTM tablets (4 x 75mg), prepared as in Examples, were shaken. 153 1246454 153 of 249 Formulation 10 and 11, (see Figure 19) at a paddle speed of 50 rpm and the rate of dissolution was evaluated, using a pharmacopoeia standard method (USP 34) and the conditions specified below. Instrumental Conditions Parameter Condition Medium 0.1M HCl (degassed with He purge) Medium Volume 1000 mL, 6 wells Dissolved Oxygen less than 3.00 ppm Bath Temperature 37°C ± 0.5°C Teflon Coated Paddles Paddle Speed ​​50 rpm Volume mobilized 10 mL - no media replacement HDPE filter 10 pm Time points 10, 15, 30 and 45 minutes Vessels 6 (light shielded) λmax LMT 255 nm Sample concentration of approximately 5 pg / mL (as free base) of working (pg / mL) LMT Sample concentration approximately 5 pg / mL (as free base) of standard (pg / mL) LMT (Q = 75% at 45 minutes. For S1, 6 of 6 tablets not less than 80% dissolution at 45 minutes). The results are shown in the following tables. LMTM (4 x 75mg; Lot No: A04827) Dissolution (% dissolved): 154 1246454 154 of 249 Vessel T=10 min T=15 min T=30 min T=45 min 1 94 95 97 99 2 90 91 94 95 3 94 94 97 97 4 95 94 97 97 5 92 92 94 94 6 93 92 96 97 Average 93 93 96 97 LMTB (3 x 100mq; Lot No: A02581) Dissolution (% dissolved):_____________ Vessel T=10 min T=15 min T=30 min T=45 min 1 91 95 96 96 2 96 100 99 99 3 95 98 98 99 4 93 95 96 96 5 96 98 99 100 6 98 102 102 102 Average 95 98 98 99 Tablets that had been stored for varying periods of time, under normal (25°C / 60% RH) or "stress" (40°C / 75% RH) conditions, were also tested using the same method. The results are shown in the tables below. LMTM (4 x 75mq; Lot No: A04827) - stored at 25°C / 60% RH Dissolution (% dissolved): 155 1246454 155 of 249 Storage time Container T=10 min T=15 min T=30 min T=45 min 1 month 1 97 97 97 99 2 96 98 101 101 3 98 99 102 102 4 95 97 98 100 5 97 98 101 101 6 98 98 100 101 Average 97 98 100 101 3 months 1 91 93 95 97 2 92 95 96 96 3 93 94 95 97 4 92 93 96 96 5 93 94 95 96 6 90 91 94 95 Average 92 93 95 96 6 months 1 89 29 819 91 90 93 94 3 98 97 98 98 4 97 97 99 99 5 94 94 96 96 6 88 90 93 93 Average 93 93 95 95 9 months 1 92 93 92 94 2 90 94 95 97 156 1246454 156 of 249 3 86 91 90 93 4 85 91 96 94 5 90 85 94 94 6 92 96 94 96 Average 89 92 93 94 LMTM (4 x 75mg; Lot No: A04827) - stored at 40°C / 75% RH Dissolution (% dissolved):_ _________________________________________ Storage Time Container T=10 min T=15 min T=30 min T=45 min 1 month 1 94 95 97 98 2 94 96 96 97 3 94 96 94 96 4 94 95 95 95 5 100 102 103 101 6 93 94 96 97 Average 95 96 97 97 3 months 1 92 93 95 96 2 93 94 95 97 3 89 91 92 92 4 89 89 89 91 5 93 95 96 97 6 93 95 98 97 Average 91 93 94 95 6 months 1 69 29 84 93 94 97 91 157 1246454 157 of 249 3 64 85 92 94 4 74 89 92 94 5 91 95 95 96 6 73 90 93 94 Average 77 89 94 94 LMTB (3 x 100mg; Lot No: A02581) - stored at 25°C / 60% RH Dissolution (% dissolved): _______________________________________ Storage Time Container T=10 min T=15 min T=30 min T=45 min 3 weeks 1 96 98 98 98 2 94 97 97 98 3 94 97 97 97 4 98 100 101 101 5 92 94 95 95 6 92 95 97 97 Average 94 97 98 98 3 months 1 89 92 92 92 2 89 92 93 92 3 93 96 96 96 4 95 98 99 98 5 95 96 96 96 6 96 99 98 97 Average 93 96 96 95 6 months 1 96 97 29 95 101 100 101 3 95 97 96 97 4 95 95 95 96 5 96 98 99 99 6 95 94 94 96 Average 95 97 97 98 9 months 1 87 91 93 91 2 88 92 94 92 3 92 9 9 1 3 94 5 91 93 93 92 6 94 95 95 93 Average 90 93 93 92 12 1 92 97 98 97 158 1246454 158 of 249 months 2 91 92 92 92 3 95 96 95 96 4 94 95 95 95 5 89 89 89 89 6 97 98 98 98 Average 93 94 95 94 LMTB (3 x 100mg; Lot No: A02581) - stored at 40°C / 75% RH Dissolution (% dissolved): Storage Time Container T=10 min T=15 min T=30 min T=45 min 3 weeks 1 94 98 99 98 2 96 100 100 101 3 94 97 96 97 4 94 98 98 98 5 95 97 98 98 6 95 97 98 97 Average 95 98 98 98 3 months 1 92 93 94 93 2 93 97 97 97 3 90 92 92 92 4 84 89 94 94 5 84 97 97 97 6 93 94 93 94 Average 95 99 89 695 months 1 8 72 96 96 2 48 82 95 96 3 91 93 94 94 4 94 98 98 99 5 13 71 93 93 6 74 87 92 93 Average 55 84 95 95 Annex - Crystallographic data Crystallographic data for LMT.EDSA (Figure 17a): Table 1. Crystal data and structure refinement for LMT.EDSA. Identification code 6408CM136 Empirical formula C18 H27 N3 O7 S3 Formula weight 493.62 159 1246454 159 of 249 Temperature 100(2) K Wavelength 0.71073 A Monoclinic Crystal System Space Group C2 / c Unit Cell Dimensions a = 18.2832(3) A α = 90°. b = 11.8667(3) A β = 114.1990(10)°. c = 10.9539(2) At γ = 90°. Volume 2167.74(8) A3 Z 4 Density (calculated) 1.519 Mg / m3 Absorption coefficient 0.389 mm-1 F(000) 1048 Crystal size 0.28 x 0.21 x 0.18 mm3 Theta range for collection of data 2.11 to 27.51°. Index ranges -23<=h<=23, -15<=k<=15, -14<=l<=14 Collected reflections 25214 Independent reflections 2487 [R(int) = 0.0486] 160 1246454 160 of 249 Extension a = 25.00° 99.9 % Semi-empirical absorption correction of equivalents Transmission max and min. 0.9333 and 0.8989 Full matrix least squares refinement method for F2 Data / constrained / parameters 2487 / 0 / 144 Goodness of fit for F2 1.080 Final R indices [I>2sigma(I)] R1 = 0.0315, wR2 = 0.0906 R Indices (all data) R1 = 0.0336, wR2 = 0.0925 Largest peak and orifice difference 0.333 and -0.654 e.A-3 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2x 103) for LMT.EDSA. U(eq) is defined as one third of the trace of the Uijorthogonalized tensor._____________________________________ x y z U(eq) S(1) 10000 2270(1) 12500 19(1) S(2) 3802(1) 204(1) 9934(1) 11(1) N(1) 10000 -370(1) 12500 18(1) N(2) 7750(1) 1619(1) 7782(1) 12(1) O(1) 3943(1) -435(1) 11137(1) 18(1) 161 1246454 161 of 249 O(2) 3830(1) 1425(1) 10131(1) 17(1) O(3) 3063(1) -144(1) 8793(1) 15(1) C(1) 9411(1) 1332 (1) 11218(1) 13(1) C(2) 9493(1) 154(1) 11332(1) 14(1) C(3) 9040(1) -512(1) 10228(1) 16( 1) C(4) 8481(1) -30(1) 9061(1) 16(1) C(5) 8383(1) 1126(1) 8996(1) 13(1) C(6) 8852(1 ) 1814(1) 10051(1) 13(1) C(8) 7127(1) 2225(1) 8087(1) 16(1) C(9) 8070(1) 2352(1) 7003(1) 17 (1) C(10) 4593(1) -141(1) 9448(1) 13(1) O(1S) 5000 2293(1) 2500 24(1) Table 3. Bond lengths [A] and angles [°] for LMT.EDSA. S(1)-C(1) 1.7696(13) S(1)-C(1)#1 1.7696(13) S(2)-O(1) 1.4488(10) S(2 )-O(2) 1.4629(10) S(2)-O(3) 1.4747(10) S(2)-C(10) 1.7802(13) N(1)-C(2 ) 1.3826(15) N(1)-C(2)#1 1.3826(15) N(1)-H(1) 0.8800 N(2)-C(5) 1.4785(16 ) N(2)-C(9) 1.4959(17) N(2)-C(8) 1.4970(17) 162 1246454 162 of 249 N(2)-H(2) 0.9300 C(1)-C(6) 1.3913(17) C(1)-C(2) 1.4049(18) C(2)-C(3 ) 1.3972(19) C(3)-C(4) 1.3908(19) C(3)-H(3) 0.9500 C(4)-C(5) 1.3804(19) C (4)-H(4) 0.9500 C(5)-C(6) 1.3881(18) C(6)-H(6) 0.9500 C(8)-H(8A) 0.9800 C(8)-H(8B) 0.9800 C(8)-H(8C) 0.9800 C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 C( 9)-H(9C) 0.9800 C(10)-C(10)#2 1.522(2) C(10)-H(10A) 0.9900 C(10)-H(10B) 0.9900 O (1S)-H(1O1) 0.7486 O(1S)-H(2O1) 0.9717 C(1)-S(1)-C(1)#1 102.05(9) O(1)- S(2)-O(2) 113.66(6) O(1)-S(2)-O(3) 112.60(6) O(2)-S(2)-O(3) 111 .52(6) 163 1246454 163 of 249 O(1)-S(2)-C(10) 106.77(6) O(2)-S(2)-C(10) 106.71(6) O(3)-S(2)- C(10) 104.89(6) C(2)-N(1)-C(2)#1 126.50(17) C(2)-N(1)-H(1) 116.7 C (2)#1-N(1)-H(1) 116.7 C(5)-N(2)-C(9) 113.51(10) C(5)-N(2)-C( 8) 112.13(10) C(9)-N(2)-C(8) 111.06(11) C(5)-N(2)-H(2) 106.5 C(9)- N(2)-H(2) 106.5 C(8)-N(2)-H(2) 106.5 C(6)-C(1)-C(2) 120.17(12) C (6)-C(1)-S(1) 116.69(10) C(2)-C(1)-S(1) 123.14(10) N(1)-C(2)-C (3) 118.76(13) N(1)-C(2)-C(1) 122.44(13) C(3)-C(2)-C(1) 118.79(12) C (4)-C(3)-C(2) 120.95(13) C(4)-C(3)-H(3) 119.5 C(2)-C(3)-H(3) 119.5 C(5)-C(4)-C(3) 119.15(13) C(5)-C(4)-H(4) 120.4 C(3)-C(4)- H(4) 120.4 C(4)-C(5)-C(6) 121.24(12) 164 1246454 164 of 249 C(4)-C(5)-N(2) 118.50(12) C(6)-C(5)-N(2) 120.25(12) C(5)-C(6)- C(1) 119.54(12) C(5)-C(6)-H(6) 120.2 C(1)-C(6)-H(6) 120.2 N(2)-C (8)-H(8A) 109.5 N(2)-C(8)-H(8B) 109.5 H(8A)-C(8)-H(8B) 109.5 N(2)- C(8)-H(8C) 109.5 H(8A)-C(8)-H(8C) 109.5 H(8B)-C(8)-H(8C) 109.5 N(2) -C(9)-H(9A) 109.5 N(2)-C(9)-H(9B) 109.5 H(9A)-C(9)-H(9B) 109.5 N(2 )-C(9)-H(9C) 109.5 H(9A)-C(9)-H(9C) 109.5 H(9B)-C(9)-H(9C) 109.5 C( 10)#2-C(10)-S(2) 111.21(12) C(10)#2-C(10)-H(10A) 109.4 S(2)-C(10)-H (10A) 109.4 C(10)#2-C(10)-H(10B) 109.4 S(2)-C(10)-H(10B) 109.4 H(10A)-C(10 )-H(10B) 108.0 H(1O1)-O(1S)-H(2O1) 100.8 Symmetry transformations used to generate equivalent atoms: 165 1246454 165 of 249 #1 -x+2,y,-z+5 / 2 #2 -x+1,-y,-z+2 Table 4. Anisotropic displacement parameters (A2x 103) for LMT.EDSA. The anisotropic displacement factor exponent takes the form: -2p2[ h2a*2U11 + ... + 2 h k a* b* U12] U11 U22 U33 U23 U13 U12 S(1) 20(1) 10(1) 14(1) 0 -6(1) 0 S(2) 10(1) 12(1) 9(1) 0(1) 2 (1) 0(1) N(1) 22(1) 9(1) 14(1) 0 -3(1) 0 N(2) 12(1) 13(1) 9(1) 0(1) 2(1) -1(1) OR(1) 16(1) 22(1) 13(1) 5(1) 5(1) 0(1) OR(2) 17(1) 13(1) 17 (1) -2(1) 4(1) 0(1) O(3) 11(1) 16(1) 13(1) -1(1) 0(1) -1(1) C(1) 12(1) 13(1) 11(1) -1(1) 2(1) -2(1) C(2) 12(1) 13(1) 13(1) 0(1) 2(1) 0(1) C(3) 19(1) 11(1) 14(1) -2(1) 3(1) -1(1) C(4) 16(1) 15(1) 12(1) -2(1) 2(1) -1(1) C(5) 12(1) 15(1) 10(1) 1(1) 2(1) 0(1) C(6) 13(1) 12(1) 12(1) 0(1) 4(1) 0(1) C(8) 13(1) 18(1) 15(1) 1(1) 5(1) 1(1) C( 9) 18(1) 22(1) 12(1) 2(1) 6(1) -2(1) C(10) 11(1) 17(1) 10(1) -2(1) 3( 1) -1(1) OR(1S) 25(1) 14(1) 18(1) 0 -7(1) 0 Table 5. Hydrogen coordinates ( x 104) and isotropic shift parameters (A2x 10 3) for LMT.EDSA. 166 1246454 166 of 249 x y z U(eq) H(1) 10000 -1111 12500 22 H(2) 7492 1019 7227 15 H(3) 9114 -1305 10275 19 H(4) 8171 -489 8319 19 H(6) 8791 2610 9978 15 H( 8A) 6937 1734 8616 23H(8B) 6675 2426 7248 23H(8C) 7359 2911 8596 23H(9A) 8321 3023 7531 26H(9B) 7629 2582 6164 26H(9C) 80203 6H 8169 4571 -955 9239 16H(10B) 4521 284 8628 16H(1O1) 5146 2050 3190 29H(2O1) 4556 1790 2015 29 Crystallographic data pLMT.2EsOH (Figure 17b) Table 1. Crystal data and structure refinement for LMT.2EsOH. Identification code 6408cm173c 0m Empirical formula C20H31N3O6S3 Formula weight 505.66 Temperature 100(2) K Wavelength 0.71073 A Monoclinic crystal system 167 1246454 167 of 249 Space group C2 / c Unit cell dimensions a = 40.8384(12) A α = 90°. b = 25.2658(7) A β = 115.4540(10)°. c = 20.3833(6) At γ = 90°. Volume 18990.2(9) A3 Z 32 Density (calculated) 1.415 Mg / m3 Absorption coefficient 0.354 mm-1 F(000) 8576 Crystal size 0.32 x 0.24 x 0.18 mm3 Theta range for collection of data 0.98 to 25.00°. Index ranges -48<=h<=48, -29<=k<=30, -24<=l<=23 Collected reflections 108984 Independent reflections 16707 [R(int) = 0.0912] Extension to theta = 25 .00° 99.9 % Semi-empirical absorption correction from equivalents Transmission max and min. 0.9391 and 0.8952 168 1246454 168 of 249 Refinement Method Full Matrix Least Squares for F2 Data / Constraints / Parameters 16707 / 25 / 1205 Goodness of Fit for F2 1.085 Final R Indices [I>2sigma(I)] R1 = 0.0628, wR2 = 0.1638 R Indices (all data) R1 = 0.0986, wR2 = 0.1918 Largest peak and orifice difference 2.683 and -0.811 e.A-3 Table 2. Atomic coordinates ( x 104) and equivalent isotropic shift parameters (A2x 103) for LMT.2EsOH. U(eq) is defined as one third of the trace of the Uijorthogonalized tensor.____________________________________ x y z U(eq) S(1A) 256(1) 3950(1) 1866(1) 69(1) N(1A) -401(1) 3176(1) 1220(2) 29(1) N(2A) 980(1) 2230(1) 2700(2) 25(1) N(3A) -743(1) 5348(1) 744(2) 25(1) C(1A) -207(1) 4102(2) 1408(3) 33(1) C(2A) -297(1) 4633(2) 1295(3) 32(1) C(3A) -652(1) 4786(2) 916(2) 24(1) C(4A) -926(1) 4413(2) 664(2) 27(1) 169 1246454 169 of 249 C(5A) -836(1) 3880(2) 784(3) 28(1) C(6A) -479(1) 3714(2) 1142(2) 25(1) C(7A) -60(1 ) 2948(2) 1584(2) 25(1) C(8A) -27(1) 2402(2) 1631(2) 24(1) C(9A) 308(1) 2154(2) 1988(2) 25(1) C(10A) 614(1) 2468(2) 2318(2) 24(1) C(11A) 588(1) 3011(2) 2281(3) 29(1) C(12A) 254( 1) 3255(2) 1917(3) 32(1) C(13A) 1017(1) 1896(2) 3334(3) 36(1) C(14A) 1092(1) 1933(2) 2196(3) 41(1) C(15A) -662(2) 5526(2) 130(3) 50(2) C(16A) -570(1) 5712(2) 1375(3) 33(1) S(1B) 2816(1) 1091(1) 1548(1) 26(1) N(1B) 2213(1) 258(1) 1144(2) 21(1) N(2B) 3639(1) -517(1) 2667 (2) 27(1) N(3B) 1743(1) 2378(1) 956(2) 22(1) C(1B) 2355(1) 1198(2) 1329(2) 19(1) C(2B ) 2237(1) 1719(2) 1291(2) 22(1) C(3B) 1873(1) 1825(2) 1032(2) 21(1) C(4B) 1620(1) 1417(2) 832 (2) 22(1) C(5B) 1738(1) 896(2) 890(2) 21(1) C(6B) 2104(1) 778(2) 1128(2) 21(1) C(7B ) 2566(1) 73(2) 1537(2) 22(1) C(8B) 2628(1) -468(2) 1684(2) 23(1) C(9B) 2974(1) -666(2 ) 2055(2) 24(1) 170 1246454 170 of 249 C(10B) 3263(1) -320(2) 2304(2) 24(1) C(11B) 3213(1) 220(2) 2178(2) 23(1) C(12B) 2866(1) 417 (2) 1788(2) 22(1) C(13B) 3693(2) -973(2) 3183(3) 38(1) C(14B) 3785(1) -651(2) 2126(2) 29 (1) C(15B) 1835(1) 2684(2) 426(3) 34(1) C(16B) 1872(1) 2660(2) 1668(3) 35(1) S(1C) 5390(1 ) 3672(1) 1826(1) 25(1) N(1C) 4792(1) 2826(1) 1436(2) 25(1) N(2C) 6224(1) 2099(1) 3029(2) 20 (1) N(3C) 4310(1) 4945(1) 1101(2) 26(1) C(1C) 4925(1) 3774(2) 1581(2) 20(1) C(2C) 4803(1 ) 4289(2) 1510(2) 21(1) C(3C) 4436(1) 4388(2) 1235(2) 21(1) C(4C) 4184(1) 3984(2) 1037(2) 25 (1) C(5C) 4307(1) 3464(2) 1126(2) 23(1) C(6C) 4676(1) 3350(2) 1388(2) 21(1) C(7C) 5145(1 ) 2651(2) 1833(2) 22(1) C(8C) 5213(1) 2113(2) 1990(2) 22(1) C(9C) 5559(1) 1925(2) 2384(2) 21 (1) C(10C) 5847(1) 2278(2) 2639(2) 20(1) C(11C) 5788(1) 2813(2) 2493(2) 21(1) C(12C) 5443(1 ) 3002(2) 2087(2) 20(1) C(13C) 6374(1) 1945(2) 2499(2) 26(1) C(14C) 6284(1) 1670(2) 3576(2) 24 (1) 171 1246454 171 of 249 C(15C) 4375(2) 5182(2) 496(3) 47(1) C(16C) 4468(2) 5280(2) 1771(3) 47(2) S(1D) 7907(1) 1349( 1) 2060(1) 32(1) N(1D) 7269(1) 547(1) 1633(2) 29(1) N(2D) 8670(1) -331(2) 2894(2) 28(1 ) N(3D) 6848(1) 2694(1) 1136(2) 27(1) C(1D) 7440(1) 1484(2) 1723(2) 25(1) C(2D) 7333(1) 2011 (2) 1602(2) 27(1) C(3D) 6969(1) 2136(2) 1304(2) 26(1) C(4D) 6709(1) 1744(2) 1117(3) 32(1 ) C(5D) 6818(1) 1220(2) 1238(3) 32(1) C(6D) 7179(1) 1080(2) 1536(2) 24(1) C(7D) 7614(1) 338 (2) 1971(2) 22(1) C(8D) 7660(1) -209(2) 2063(2) 24(1) C(9D) 8001(1) -439(2) 2370(2) 25 (1) C(10D) 8302(1) -111(2) 2608(2) 24(1) C(11D) 8268(1) 437(2) 2537(2) 26(1) C(12D) 7925( 1) 662(2) 2212(2) 23(1) C(13D) 8743(1) -762(2) 3435(3) 43(1) C(14D) 8764(1) -504(2) 2294( 3) 31(1) C(15D) 6807(2) 2848(2) 397(3) 41(1) C(16D) 7078(1) 3086(2) 1700(3) 36(1) S(2) 525(1) 500(1) 1,331(1) 35(1) S(3) 827(1) 2,850(1) 152(1) 25(1) S(4) 1,743(1) 4,426(1) 389( 1) 29(1) 172 1246454 172 of 249 S(5) 3048(1) 3051(1) 1414(1) 30(1) S(6) 5663(1) 497(1) 1723(1) 33(1) S(7) 5874(1) 2562( 1) 455(1) 34(1) S(8) 8160(1) 2896(1) 1391(1) 23(1) S(9) 8481(1) 615(1) 291(1) 26(1) OR(1) 619(4) 884(5) 1948(7) 56(2) OR(2) 392(10) 52(10) 1452(19) 70(6) OR(3) 886(4) 594( 6) 1706(8) 55(2) O(1') 342(2) 769(3) 1689(4) 61(2) O(2') 419(6) -77(6) 1226(11) 70 (5) O(3') 893(2) 480(4) 1357(5) 58(2) O(4) 1009(1) 2335(1) 358(2) 35(1) O(5) 1031( 1) 3,269(1) 635(2) 41(1) OR(6) 718(1) 2,970(1) -613(2) 27(1) OR(7) 1,911(1) 3,966(1) 826(2 ) 45(1) OR(8) 1422(1) 4299(1) -282(2) 45(1) OR(9) 1667(1) 4851(1) 790(2) 30(1) OR(10) 3321(1) 2861(1) 1185(2) 41(1) OR(11) 2835(1) 2637(2) 1525(3) 68(1) OR(12) 3217(1) 3392(1) 2047( 2) 46(1) OR(13) 5318(1) 542(2) 1772(2) 56(1) OR(14) 5728(1) -26(1) 1506(2) 60(1) OR(15 ) 5964(1) 678(1) 2388(2) 42(1) OR(16) 5932(1) 2520(1) -212(2) 32(1) OR(17) 5774(1) 2071(2) 681(2) 57(1) 173 1246454 173 of 249 0(18) 6182(1) 2836(1) 1038(2) 39(1) 0(19) 8126(1) 2360(1) 1113(2) 31(1) 0(20) 8540(1) 3032( 1) 1876(2) 35(1) 0(21) 7918(1) 3019(1) 1720(2) 31(1) 0(22) 8264(1) 640(1) -494(2) 26(1 ) 0(23) 8590(1) 62(1) 534(2) 31(1) 0(24) 8786(1) 983(1) 553(2) 33(1) C(1S) 298(2) 782 (2) 463(4) 62(2) C(2S) 387(2) 1337(2) 396(3) 45(1) C(3S) 2064(1) 4682(2) 95(3) 30(1 ) C(4S) 1928(1) 5196(2) -337(3) 39(1) C(5S) 2748(1) 3452(2) 689(3) 37(1) C(6S) 2934(1) 3925(2) 551(3) 32(1) C(7S) 5504(1) 2984(2) 239(3) 39(1) C(8S) 5570(2) 3516(2) -63(4) 54 (2) C(9S) 5626(2) 921(2) 1016(3) 38(1) C(10S) 5990(3) 881(4) 989(5) 100(3) C(11S) 8047(1 ) 3340(2) 650(3) 28(1) C(12S) 7648(1) 3320(2) 118(3) 38(1) C(13S) 8200(1) 808(2) 708(3) 27 (1) C(14S) 7876(1) 454(2) 490(3) 34(1) C(15S) 414(1) 2769(2) 254(3) 36(1) C(16S) 186(2 ) 3261(2) 66(3) 49(2) 174 1246454 174 of 249 Table 3. Bond lengths [A] and angles [°] for LMT.2EsOH. S(1A)-C(1A) 1.756(5) S(1A)-C(12A) 1.759(5) N(1A)-C(7A) 1.390(6) N(1A)-C(6A) 1.389( 6) N(1A)-H(1AA) 0.8800 N(2A)-C(10A) 1.485(5) N(2A)-C(14A) 1.492(6) N(2A)-C(13A) 1.495 (6) N(2A)-H(2AA) 0.9300 N(3A)-C(3A) 1.474(5) N(3A)-C(16A) 1.489(6) N(3A)-C(15A) 1.494(6) N(3A)-H(3A) 0.9300 C(1A)-C(2A) 1.384(6) C(1A)-C(6A) 1.404(6) C(2A)-C(3A) ) 1.371(6) C(2A)-H(2A) 0.9500 C(3A)-C(4A) 1.384(6) C(4A)-C(5A) 1.389(6) C(4A)-H( 4A) 0.9500 C(5A)-C(6A) 1.384(6) C(5A)-H(5A) 0.9500 C(7A)-C(8A) 1.387(6) C(7A)-C( 12A) 1,399(6) 175 1246454 175 of 249 C(8A)-C(9A) 1.391(6) C(8A)-H(8A) 0.9500 C(9A)-C(10A) 1.384(6) C(9A)-H(9A) 0.9500 C(10A)-C(11A) 1.376(6) C(11A)-C(12A) 1.388(6) C(11A)-H(11A) 0.9500 C(13A)-H(13A) 0.9800 C(13A)-H(13B) 0.9800 C(13A)-H(13C) 0.9800 C(14A)-H(14A) 0.9800 C(14A)-H(14B) 0.9800 C( 14A)-H(14C) 0.9800 C(15A)-H(15A) 0.9800 C(15A)-H(15B) 0.9800 C(15A)-H(15C) 0.9800 C(16A) -H(16A) 0.9800 C(16A)-H(16B) 0.9800 C(16A)-H(16C) 0.9800 S(1B)-C(12B) 1.761(4) S(1B)- C(1B) 1.762(4) N(1B)-C(6B) 1.385(5) N(1B)-C(7B) 1.392(6) N(1B)-H(1B) 0.8800 N(2B) -C(10B) 1.474(6) 176 1246454 176 of 249 N(2B)-C(14B) 1.502(6) N(2B)-C(13B) 1.512(6) N(2B)-H(2BB) 0.9300 N(3B)-C(3B) 1.479(5 ) N(3B)-C(16B) 1.496(6) N(3B)-C(15B) 1.501(6) N(3B)-H(3B) 0.9300 C(1B)-C(2B) 1.392( 6) C(1B)-C(6B) 1.410(6) C(2B)-C(3B) 1.372(6) C(2B)-H(2B) 0.9500 C(3B)-C(4B) 1.391 (6) C(4B)-C(5B) 1.391(6) C(4B)-H(4B) 0.9500 C(5B)-C(6B) 1.389(6) C(5B)-H(5B) 0.9500 C(7B)-C(8B) 1.399(6) C(7B)-C(12B) 1.406(6) C(8B)-C(9B) 1.377(6) C(8B)-H(8B ) 0.9500 C(9B)-C(10B) 1.381(6) C(9B)-H(9B) 0.9500 C(10B)-C(11B) 1.384(6) C(11B)-C(12B ) 1.388(6) C(11B)-H(11B) 0.9500 177 1246454 177 of 249 C(13B)-H(13D) 0.9800 C(13B)-H(13E) 0.9800 C(13B)-H(13F) 0.9800 C(14B)-H(14D) 0.9800 C( 14B)-H(14E) 0.9800 C(14B)-H(14F) 0.9800 C(15B)-H(15D) 0.9800 C(15B)-H(15E) 0.9800 C(15B) -H(15F) 0.9800 C(16B)-H(16D) 0.9800 C(16B)-H(16E) 0.9800 C(16B)-H(16F) 0.9800 S(1C)-C (12C) 1.760(4) S(1C)-C(1C) 1.765(4) N(1C)-C(7C) 1.387(5) N(1C)-C(6C) 1.395(5) N(1C) -H(1C) 0.8800 N(2C)-C(10C) 1.469(5) N(2C)-C(14C) 1.498(5) N(2C)-C(13C) 1.503(5) N(2C )-H(2CC) 0.9300 N(3C)-C(3C) 1.482(5) N(3C)-C(15C) 1.494(6) N(3C)-C(16C) 1.497(6) N( 3C)-H(3C) 0.9300 178 1246454 178 of 249 C(1C)-C(2C) 1.377(6) C(1C)-C(6C) 1.411(6) C(2C)-C(3C) 1.380(6) C(2C)-H(2C) 0. 9500 C(3C)-C(4C) 1.381(6) C(4C)-C(5C) 1.390(6) C(4C)-H(4C) 0.9500 C(5C)-C(6C) 1.397( 6) C(5C)-H(5C) 0.9500 C(7C)-C(8C) 1.397(6) C(7C)-C(12C) 1.413(6) C(8C)-C(9C) 1.378 (6) C(8C)-H(8C) 0.9500 C(9C)-C(10C) 1.386(6) C(9C)-H(9C) 0.9500 C(10C)-C(11C) 1.384 (6) C(11C)-C(12C) 1.377(6) C(11C)-H(11C) 0.9500 C(13C)-H(13G) 0.9800 C(13C)-H(13H) 0 .9800 C(13C)-H(13I) 0.9800 C(14C)-H(14G) 0.9800 C(14C)-H(14H) 0.9800 C(14C)-H(14I) 0.9800 C(15C)-H(15G) 0.9800 179 1246454 179 of 249 C(15C)-H(15H) 0.9800 C(15C)-H(15I) 0.9800 C(16C)-H(16G) 0.9800 C(16C)-H(16H) 0.9800 C( 16C)-H(16I) 0.9800 S(1D)-C(12D) 1.760(4) S(1D)-C(1D) 1.761(5) N(1D)-C(7D) 1.381(6) N (1D)-C(6D) 1.389(6) N(1D)-H(1D) 0.8800 N(2D)-C(10D) 1.471(6) N(2D)-C(13D) 1.486(6) N(2D)-C(14D) 1.495(6) N(2D)-H(2D) 0.9300 N(3D)-C(3D) 1.483(6) N(3D)-C(15D) 1.495(6 ) N(3D)-C(16D) 1.504(6) N(3D)-H(3D) 0.9300 C(1D)-C(2D) 1.389(6) C(1D)-C(6D) 1.405( 6) C(2D)-C(3D) 1.379(6) C(2D)-H(2DD) 0.9500 C(3D)-C(4D) 1.381(6) C(4D)-C(5D) 1.385 (7) C(4D)-H(4D) 0.9500 180 1246454 180 of 249 C(5D)-C(6D) 1.377(6) C(5D)-H(5D) 0.9500 C(7D)-C(8D) 1.394(6) C(7D)-C(12D) 1.409(6 ) C(8D)-C(9D) 1.385(6) C(8D)-H(8D) 0.9500 C(9D)-C(10D) 1.384(6) C(9D)-H(9D) 0. 9500 C(10D)-C(11D) 1.391(6) C(11D)-C(12D) 1.388(6) C(11D)-H(11D) 0.9500 C(13D)-H(13J) 0. 9800 C(13D)-H(13K) 0.9800 C(13D)-H(13L) 0.9800 C(14D)-H(14J) 0.9800 C(14D)-H(14K) 0.9800 C (14D)-H(14L) 0.9800 C(15D)-H(15J) 0.9800 C(15D)-H(15K) 0.9800 C(15D)-H(15L) 0.9800 C(16D )-H(16J) 0.9800 C(16D)-H(16K) 0.9800 C(16D)-H(16L) 0.9800 S(2)-O(2) 1.32(3) S( 2)-O(3) 1.359(16) 181 1246454 181 of 249 S(2)-O(1') 1.423(7) S(2)-O(3') 1.481(8) S(2)-O(2') 1.510(16) S(2)-O(1 ) 1.503(13) S(2)-C(1S) 1.756(6) S(3)-O(5) 1.442(3) S(3)-O(6) 1.459(3) S(3)-O (4) 1.469(3) S(3)-C(15S) 1.795(5) S(4)-O(7) 1.446(4) S(4)-O(9) 1.461(3) S(4) -O(8) 1.466(3) S(4)-C(3S) 1.779(5) S(5)-O(11) 1.438(4) S(5)-O(12) 1.456(4) S( 5)-O(10) 1.463(3) S(5)-C(5S) 1.775(5) S(6)-O(14) 1.453(4) S(6)-O(15) 1.456(4) S(6)-O(13) 1.458(4) S(6)-C(9S) 1.749(5) S(7)-O(17) 1.442(4) S(7)-O(18) 1.479( 4) S(7)-O(16) 1.482(3) S(7)-C(7S) 1.744(5) 182 1246454 182 of 249 S(8)-O(21) 1.447(3) S(8)-O(19) 1.452(3) S(8)-O(20) 1.479(3) S(8)-C(11S) 1.776( 4) S(9)-O(24) 1.458(3) S(9)-O(22) 1.458(3) S(9)-O(23) 1.486(3) S(9)-C(13S) 1.765(5) O(1)-O(3) 1.56(2) C(1S)-C(2S) 1.470(8) C(1S)-H(1S1) 0.9900 C(1S)-H (1S2) 0.9900 C(2S)-H(2S1) 0.9800 C(2S)-H(2S2) 0.9800 C(2S)-H(2S3) 0.9800 C(3S)-C(4S ) 1.534(7) C(3S)-H(3S1) 0.9900 C(3S)-H(3S2) 0.9900 C(4S)-H(4S1) 0.9800 C(4S)-H(4S2) 0.9800 C(4S)-H(4S3) 0.9800 C(5S)-C(6S) 1.506(7) C(5S)-H(5S1) 0.9900 C(5S)-H(5S2) 0 .9900 C(6S)-H(6S1) 0.9800 183 1246454 183 of 249 C(6S)-H(6S2) 0.9800 C(6S)-H(6S3) 0.9800 C(7S)-C(8S) 1.550(7) C(7S)-H(7S1) 0.9900 C (7S)-H(7S2) 0.9900 C(8S)-H(8S1) 0.9800 C(8S)-H(8S2) 0.9800 C(8S)-H(8S3) 0.9800 C(9S )-C(10S) 1.511(10) C(9S)-H(9S1) 0.9900 C(9S)-H(9S2) 0.9900 C(10S)-H(10A) 0.9800 C(10S) -H(10B) 0.9800 C(10S)-H(10C) 0.9800 C(11S)-C(12S) 1.522(7) C(11S)-H(11E) 0.9900 C(11S)- H(11F) 0.9900 C(12S)-H(12A) 0.9800 C(12S)-H(12B) 0.9800 C(12S)-H(12C) 0.9800 C(13S)-C( 14S) 1.498(6) C(13S)-H(13M) 0.9900 C(13S)-H(13N) 0.9900 C(14S)-H(14M) 0.9800 C(14S)-H(14N ) 0.9800 184 1246454 184 of 249 C(14S)-H(14O) 0.9800 C(15S)-C(16S) 1.500(7) C(15S)-H(15M) 0.9900 C(15S)-H(15N) 0.9900 C (16S)-H(16M) 0.9800 C(16S)-H(16N) 0.9800 C(16S)-H(16O) 0.9800 C(1A)-S(1A)-C(12A) 102 .6(2) C(7A)-N(1A)-C(6A) 126.5(4) C(7A)-N(1A)-H(1AA) 116.8 C(6A)-N(1A )-H(1AA) 116.8 C(10A)-N(2A)-C(14A) 112.3(4) C(10A)-N(2A)-C(13A) 112.8(4) C (14A)-N(2A)-C(13A) 111.3(4) C(10A)-N(2A)-H(2AA) 106.7 C(14A)-N(2A)-H(2AA) 106.7 C(13A)-N(2A)-H(2AA) 106.7 C(3A)-N(3A)-C(16A) 114.4(3) C(3A)-N(3A)- C(15A) 111.3(4) C(16A)-N(3A)-C(15A) 110.1(4) C(3A)-N(3A)-H(3A) 106.8 C(16A )-N(3A)-H(3A) 106.8 C(15A)-N(3A)-H(3A) 106.8 C(2A)-C(1A)-C(6A) 120.3(4 ) C(2A)-C(1A)-S(1A) 116.7(3) 185 1246454 185 of 249 C(6A)-C(1A)-S(1A) 123.0(3) C(3A)-C(2A)-C(1A) 120.4(4) C(3A)-C(2A)- H(2A) 119.8 C(1A)-C(2A)-H(2A) 119.8 C(2A)-C(3A)-C(4A) 120.6(4) C(2A)-C (3A)-N(3A) 120.2(4) C(4A)-C(3A)-N(3A) 119.1(4) C(3A)-C(4A)-C(5A) 118, 8(4) C(3A)-C(4A)-H(4A) 120.6 C(5A)-C(4A)-H(4A) 120.6 C(6A)-C(5A)-C( 4A) 121.8(4) C(6A)-C(5A)-H(5A) 119.1 C(4A)-C(5A)-H(5A) 119.1 C(5A)-C(6A) )-N(1A) 119.7(4) C(5A)-C(6A)-C(1A) 118.0(4) N(1A)-C(6A)-C(1A) 122.3( 4) C(8A)-C(7A)-N(1A) 119.7(4) C(8A)-C(7A)-C(12A) 118.4(4) N(1A)-C(7A )-C(12A) 121.9(4) C(7A)-C(8A)-C(9A) 121.9(4) C(7A)-C(8A)-H(8A) 119.0 C (9A)-C(8A)-H(8A) 119.0 C(10A)-C(9A)-C(8A) 118.4(4) C(10A)-C(9A)-H(9A) 120.8 C(8A)-C(9A)-H(9A) 120.8 186 1246454 186 of 249 C(11A)-C(10A)-C(9A) 120.9(4) C(11A)-C(10A)-N(2A) 117.9(4) C(9A)-C(10A)- N(2A) 121.2(4) C(10A)-C(11A)-C(12A) 120.4(4) C(10A)-C(11A)-H(11A) 119.8 C(12A )-C(11A)-H(11A) 119.8 C(11A)-C(12A)-C(7A) 119.9(4) C(11A)-C(12A)-S(1A) 116, 5(3) C(7A)-C(12A)-S(1A) 123.5(3) N(2A)-C(13A)-H(13A) 109.5 N(2A)-C(13A) -H(13B) 109.5 H(13A)-C(13A)-H(13B) 109.5 N(2A)-C(13A)-H(13C) 109.5 H(13A)-C(13A )-H(13C) 109.5 H(13B)-C(13A)-H(13C) 109.5 N(2A)-C(14A)-H(14A) 109.5 N(2A)-C( 14A)-H(14B) 109.5 H(14A)-C(14A)-H(14B) 109.5 N(2A)-C(14A)-H(14C) 109.5 H(14A)-C (14A)-H(14C) 109.5 H(14B)-C(14A)-H(14C) 109.5 N(3A)-C(15A)-H(15A) 109.5 N(3A)- C(15A)-H(15B) 109.5 H(15A)-C(15A)-H(15B) 109.5 N(3A)-C(15A)-H(15C) 109.5 187 1246454 187 of 249 H(15A)-C(15A)-H(15C) 109.5 H(15B)-C(15A)-H(15C) 109.5 N(3A)-C(16A)-H(16A) 109, 5 N(3A)-C(16A)-H(16B) 109.5 H(16A)-C(16A)-H(16B) 109.5 N(3A)-C(16A)-H(16C) 109 .5 H(16A)-C(16A)-H(16C) 109.5 H(16B)-C(16A)-H(16C) 109.5 C(12B)-S(1B)-C(1B) 101.6(2) C(6B)-N(1B)-C(7B) 125.1(4) C(6B)-N(1B)-H(1B) 117.4 C(7B)-N( 1B)-H(1B) 117.4 C(10B)-N(2B)-C(14B) 111.3(3) C(10B)-N(2B)-C(13B) 114.6(4) C(14B)-N(2B)-C(13B) 110.7(4) C(10B)-N(2B)-H(2BB) 106.5 C(14B)-N(2B)-H(2BB ) 106.5 C(13B)-N(2B)-H(2BB) 106.5 C(3B)-N(3B)-C(16B) 113.0(3) C(3B)-N(3B) -C(15B) 111.8(3) C(16B)-N(3B)-C(15B) 111.1(4) C(3B)-N(3B)-H(3B) 106.9 C( 16B)-N(3B)-H(3B) 106.9 C(15B)-N(3B)-H(3B) 106.9 C(2B)-C(1B)-C(6B) 120.4( 4) 188 1246454 188 of 249 C(2B)-C(1B)-S(1B) 117.8(3) C(6B)-C(1B)-S(1B) 121.5(3) C(3B)-C(2B)- C(1B) 119.7(4) C(3B)-C(2B)-H(2B) 120.2 C(1B)-C(2B)-H(2B) 120.2 C(2B)-C (3B)-C(4B) 121.1(4) C(2B)-C(3B)-N(3B) 120.3(4) C(4B)-C(3B)-N(3B) 118, 7(4) C(5B)-C(4B)-C(3B) 119.2(4) C(5B)-C(4B)-H(4B) 120.4 C(3B)-C(4B) -H(4B) 120.4 C(4B)-C(5B)-C(6B) 121.1(4) C(4B)-C(5B)-H(5B) 119.5 C(6B)- C(5B)-H(5B) 119.5 N(1B)-C(6B)-C(5B) 120.1(4) N(1B)-C(6B)-C(1B) 121.4( 4) C(5B)-C(6B)-C(1B) 118.5(4) N(1B)-C(7B)-C(8B) 119.9(4) N(1B)-C(7B )-C(12B) 121.8(4) C(8B)-C(7B)-C(12B) 118.3(4) C(9B)-C(8B)-C(7B) 121.6( 4) C(9B)-C(8B)-H(8B) 119.2 C(7B)-C(8B)-H(8B) 119.2 C(8B)-C(9B)-C(10B) 119.0(4) C(8B)-C(9B)-H(9B) 120.5 189 1246454 189 of 249 C(10B)-C(9B)-H(9B) 120.5 C(9B)-C(10B)-C(11B) 121.4(4) C(9B)-C(10B)-N(2B ) 120.8(4) C(11B)-C(10B)-N(2B) 117.6(4) C(10B)-C(11B)-C(12B) 119.5(4) C(10B )-C(11B)-H(11B) 120.3 C(12B)-C(11B)-H(11B) 120.3 C(11B)-C(12B)-C(7B) 120.3(4 ) C(11B)-C(12B)-S(1B) 118.2(3) C(7B)-C(12B)-S(1B) 121.2(3) N(2B)-C(13B) -H(13D) 109.5 N(2B)-C(13B)-H(13E) 109.5 H(13D)-C(13B)-H(13E) 109.5 N(2B)-C(13B )-H(13F) 109.5 H(13D)-C(13B)-H(13F) 109.5 H(13E)-C(13B)-H(13F) 109.5 N(2B)-C( 14B)-H(14D) 109.5 N(2B)-C(14B)-H(14E) 109.5 H(14D)-C(14B)-H(14E) 109.5 N(2B)-C (14B)-H(14F) 109.5 H(14D)-C(14B)-H(14F) 109.5 H(14E)-C(14B)-H(14F) 109.5 N(3B)- C(15B)-H(15D) 109.5 N(3B)-C(15B)-H(15E) 109.5 H(15D)-C(15B)-H(15E) 109.5 190 1246454 190 of 249 N(3B)-C(15B)-H(15F) 109.5 H(15D)-C(15B)-H(15F) 109.5 H(15E)-C(15B)-H(15F) 109, 5 N(3B)-C(16B)-H(16D) 109.5 N(3B)-C(16B)-H(16E) 109.5 H(16D)-C(16B)-H(16E) 109 .5 N(3B)-C(16B)-H(16F) 109.5 H(16D)-C(16B)-H(16F) 109.5 H(16E)-C(16B)-H(16F) 109.5 C(12C)-S(1C)-C(1C) 101.7(2) C(7C)-N(1C)-C(6C) 125.4(4) C(7C)-N( 1C)-H(1C) 117.3 C(6C)-N(1C)-H(1C) 117.3 C(10C)-N(2C)-C(14C) 114.9(3) C(10C )-N(2C)-C(13C) 110.2(3) C(14C)-N(2C)-C(13C) 111.2(3) C(10C)-N(2C)-H(2CC ) 106.7 C(14C)-N(2C)-H(2CC) 106.7 C(13C)-N(2C)-H(2CC) 106.7 C(3C)-N(3C)-C( 15C) 111.2(4) C(3C)-N(3C)-C(16C) 112.9(4) C(15C)-N(3C)-C(16C) 111.5(4) C( 3C)-N(3C)-H(3C) 106.9 C(15C)-N(3C)-H(3C) 106.9 C(16C)-N(3C)-H(3C) 106.9 191 1246454 191 of 249 C(2C)-C(1C)-C(6C) 120.3(4) C(2C)-C(1C)-S(1C) 117.7(3) C(6C)-C(1C)- S(1C) 121.8(3) C(1C)-C(2C)-C(3C) 119.7(4) C(1C)-C(2C)-H(2C) 120.2 C(3C )-C(2C)-H(2C) 120.2 C(2C)-C(3C)-C(4C) 121.8(4) C(2C)-C(3C)-N(3C) 118, 6(4) C(4C)-C(3C)-N(3C) 119.5(4) C(3C)-C(4C)-C(5C) 118.7(4) C(3C)-C (4C)-H(4C) 120.7 C(5C)-C(4C)-H(4C) 120.7 C(4C)-C(5C)-C(6C) 120.9(4) C( 4C)-C(5C)-H(5C) 119.5 C(6C)-C(5C)-H(5C) 119.5 N(1C)-C(6C)-C(5C) 119.9( 4) N(1C)-C(6C)-C(1C) 121.3(4) C(5C)-C(6C)-C(1C) 118.7(4) N(1C)-C(7C )-C(8C) 119.9(4) N(1C)-C(7C)-C(12C) 122.0(4) C(8C)-C(7C)-C(12C) 118.1( 4) C(9C)-C(8C)-C(7C) 121.5(4) C(9C)-C(8C)-H(8C) 119.2 C(7C)-C(8C)-H (8C) 119.2 C(8C)-C(9C)-C(10C) 119.3(4) 192 1246454 192 of 249 C(8C)-C(9C)-H(9C) 120.3 C(10C)-C(9C)-H(9C) 120.3 C(11C)-C(10C)-C(9C) 120, 5(4) C(11C)-C(10C)-N(2C) 117.5(4) C(9C)-C(10C)-N(2C) 121.9(4) C(12C)-C (11C)-C(10C) 120.4(4) C(12C)-C(11C)-H(11C) 119.8 C(10C)-C(11C)-H(11C) 119.8 C( 11C)-C(12C)-C(7C) 120.1(4) C(11C)-C(12C)-S(1C) 118.4(3) C(7C)-C(12C)-S( 1C) 121.3(3) N(2C)-C(13C)-H(13G) 109.5 N(2C)-C(13C)-H(13H) 109.5 H(13G)-C(13C )-H(13H) 109.5 N(2C)-C(13C)-H(13I) 109.5 H(13G)-C(13C)-H(13I) 109.5 H(13H)-C( 13C)-H(13I) 109.5 N(2C)-C(14C)-H(14G) 109.5 N(2C)-C(14C)-H(14H) 109.5 H(14G)-C (14C)-H(14H) 109.5 N(2C)-C(14C)-H(14I) 109.5 H(14G)-C(14C)-H(14I) 109.5 H(14H)- C(14C)-H(14I) 109.5 N(3C)-C(15C)-H(15G) 109.5 N(3C)-C(15C)-H(15H) 109.5 193 1246454 193 of 249 H(15G)-C(15C)-H(15H) 109.5 N(3C)-C(15C)-H(15I) 109.5 H(15G)-C(15C)-H(15I) 109, 5 H(15H)-C(15C)-H(15I) 109.5 N(3C)-C(16C)-H(16G) 109.5 N(3C)-C(16C)-H(16H) 109 .5 H(16G)-C(16C)-H(16H) 109.5 N(3C)-C(16C)-H(16I) 109.5 H(16G)-C(16C)-H(16I) 109.5 H(16H)-C(16C)-H(16I) 109.5 C(12D)-S(1D)-C(1D) 102.4(2) C(7D)-N(1D)- C(6D) 126.5(4) C(7D)-N(1D)-H(1D) 116.7 C(6D)-N(1D)-H(1D) 116.7 C(10D)-N (2D)-C(13D) 114.5(4) C(10D)-N(2D)-C(14D) 111.3(3) C(13D)-N(2D)-C(14D) 110, 7(4) C(10D)-N(2D)-H(2D) 106.6 C(13D)-N(2D)-H(2D) 106.6 C(14D)-N(2D)-H( 2D) 106.6 C(3D)-N(3D)-C(15D) 111.2(4) C(3D)-N(3D)-C(16D) 114.3(4) C(15D)- N(3D)-C(16D) 111.2(4) C(3D)-N(3D)-H(3D) 106.5 C(15D)-N(3D)-H(3D) 106.5 194 1246454 194 of 249 C(16D)-N(3D)-H(3D) 106.5 C(2D)-C(1D)-C(6D) 120.2(4) C(2D)-C(1D)-S(1D ) 117.4(3) C(6D)-C(1D)-S(1D) 122.4(3) C(3D)-C(2D)-C(1D) 119.7(4) C(3D )-C(2D)-H(2DD) 120.1 C(1D)-C(2D)-H(2DD) 120.1 C(2D)-C(3D)-C(4D) 120.7(4 ) C(2D)-C(3D)-N(3D) 120.7(4) C(4D)-C(3D)-N(3D) 118.4(4) C(3D)-C(4D) -C(5D) 119.2(5) C(3D)-C(4D)-H(4D) 120.4 C(5D)-C(4D)-H(4D) 120.4 C(6D)- C(5D)-C(4D) 121.5(4) C(6D)-C(5D)-H(5D) 119.2 C(4D)-C(5D)-H(5D) 119.2 C (5D)-C(6D)-N(1D) 118.7(4) C(5D)-C(6D)-C(1D) 118.6(4) N(1D)-C(6D)-C (1D) 122.7(4) N(1D)-C(7D)-C(8D) 119.7(4) N(1D)-C(7D)-C(12D) 121.5(4) C (8D)-C(7D)-C(12D) 118.7(4) C(9D)-C(8D)-C(7D) 121.8(4) C(9D)-C(8D)-H (8D) 119.1 C(7D)-C(8D)-H(8D) 119.1 195 1246454 195 of 249 C(10D)-C(9D)-C(8D) 118.3(4) C(10D)-C(9D)-H(9D) 120.9 C(8D)-C(9D)-H(9D ) 120.9 C(9D)-C(10D)-C(11D) 121.7(4) C(9D)-C(10D)-N(2D) 121.0(4) C(11D)-C (10D)-N(2D) 117.1(4) C(12D)-C(11D)-C(10D) 119.5(4) C(12D)-C(11D)-H(11D) 120, 3 C(10D)-C(11D)-H(11D) 120.3 C(11D)-C(12D)-C(7D) 120.0(4) C(11D)-C(12D)-S( 1D) 116.4(3) C(7D)-C(12D)-S(1D) 123.4(3) N(2D)-C(13D)-H(13J) 109.5 N(2D)- C(13D)-H(13K) 109.5 H(13J)-C(13D)-H(13K) 109.5 N(2D)-C(13D)-H(13L) 109.5 H(13J) -C(13D)-H(13L) 109.5 H(13K)-C(13D)-H(13L) 109.5 N(2D)-C(14D)-H(14J) 109.5 N(2D )-C(14D)-H(14K) 109.5 H(14J)-C(14D)-H(14K) 109.5 N(2D)-C(14D)-H(14L) 109.5 H( 14J)-C(14D)-H(14L) 109.5 H(14K)-C(14D)-H(14L) 109.5 N(3D)-C(15D)-H(15J) 109.5 196 1246454 196 of 249 N(3D)-C(15D)-H(15K) 109.5 H(15J)-C(15D)-H(15K) 109.5 N(3D)-C(15D)-H(15L) 109, 5 H(15J)-C(15D)-H(15L) 109.5 H(15K)-C(15D)-H(15L) 109.5 N(3D)-C(16D)-H(16J) 109 .5 N(3D)-C(16D)-H(16K) 109.5 H(16J)-C(16D)-H(16K) 109.5 N(3D)-C(16D)-H(16L) 109.5 H(16J)-C(16D)-H(16L) 109.5 H(16K)-C(16D)-H(16L) 109.5 O(2)-S(2)-O(3 ) 118.5(17) O(2)-S(2)-O(1') 87.9(12) O(3)-S(2)-O(1') 108.0(8) O (2)-S(2)-O(3') 117.2(14) O(3)-S(2)-O(3') 31.5(6) O(1')-S(2 )-O(3') 138.3(6) O(2)-S(2)-O(2') 23.8(18) O(3)-S(2)-O(2') 115 .1(10) O(1')-S(2)-O(2') 110.6(8) O(3')-S(2)-O(2') 101.4(8) O (2)-S(2)-O(1) 111.9(14) O(3)-S(2)-O(1) 65.7(9) O(1')-S(2)- O(1) 42.6(5) O(3')-S(2)-O(1) 95.8(7) 197 1246454 197 of 249 O(2')-S(2)-O(1) 134.1(9) O(2)-S(2)-C(1S) 117.0(16) O(3)-S(2) -C(1S) 118.1(6) O(1')-S(2)-C(1S) 99.1(4) O(3')-S(2)-C(1S) 97.8 (4) O(2')-S(2)-C(1S) 104.8(8) O(1)-S(2)-C(1S) 114.6(5) O(5)-S (3)-O(6) 113.5(2) O(5)-S(3)-O(4) 112.5(2) O(6)-S(3)-O(4) 111, 9(2) O(5)-S(3)-C(15S) 107.5(2) O(6)-S(3)-C(15S) 106.2(2) O(4)-S (3)-C(15S) 104.6(2) O(7)-S(4)-O(9) 113.8(2) O(7)-S(4)-O(8) 113, 4(2) O(9)-S(4)-O(8) 111.3(2) O(7)-S(4)-C(3S) 106.0(2) O(9)-S (4)-C(3S) 106.6(2) O(8)-S(4)-C(3S) 104.9(2) O(11)-S(5)-O(12) 112, 3(3) O(11)-S(5)-O(10) 114.1(3) O(12)-S(5)-O(10) 109.9(2) O(11)-S (5)-C(5S) 107.4(2) O(12)-S(5)-C(5S) 107.2(2) O(10)-S(5)-C(5S) 105, 5(2) 198 1246454 198 of 249 O(14)-S(6)-O(15) 112.2(2) O(14)-S(6)-O(13) 113.4(3) O(15)-S(6)- O(13) 111.4(2) O(14)-S(6)-C(9S) 105.6(2) O(15)-S(6)-C(9S) 108.3(2) O(13)-S(6)-C(9S) 105.4(3) O(17)-S(7)-O(18) 114.0(2) O(17)-S(7)- O(16) 114.2(2) O(18)-S(7)-O(16) 110.7(2) O(17)-S(7)-C(7S) 105.8(3) O(18)-S(7)-C(7S) 105.3(2) O(16)-S(7)-C(7S) 106.0(2) O(21)-S(8)- O(19) 114.3(2) O(21)-S(8)-O(20) 111.7(2) O(19)-S(8)-O(20) 111.95(19) O(21)-S(8)-C(11S) 106.3(2) O(19)-S(8)-C(11S) 108.1(2) O(20)-S(8)- C(11S) 103.7(2) O(24)-S(9)-O(22) 113.23(19) O(24)-S(9)-O(23) 112.94(19) O(22)-S(9)-O(23) 111.07(18) O(24)-S(9)-C(13S) 106.1(2) O(22)-S(9)- C(13S) 107.7(2) O(23)-S(9)-C(13S) 105.3(2) S(2)-O(1)-O(3) 52.7(7) 199 1246454 199 of 249 S(2)-O(3)-O(1) 61.6(8) C(2S)-C(1S)-S(2) 115.9(5) C(2S)-C(1S)- H(1S1) 108.3 S(2)-C(1S)-H(1S1) 108.3 C(2S)-C(1S)-H(1S2) 108.3 S(2)-C(1S) -H(1S2) 108.3 H(1S1)-C(1S)-H(1S2) 107.4 C(1S)-C(2S)-H(2S1) 109.5 C(1S)-C(2S )-H(2S2) 109.5 H(2S1)-C(2S)-H(2S2) 109.5 C(1S)-C(2S)-H(2S3) 109.5 H(2S1)-C( 2S)-H(2S3) 109.5 H(2S2)-C(2S)-H(2S3) 109.5 C(4S)-C(3S)-S(4) 111.3(3) C(4S )-C(3S)-H(3S1) 109.4 S(4)-C(3S)-H(3S1) 109.4 C(4S)-C(3S)-H(3S2) 109.4 S( 4)-C(3S)-H(3S2) 109.4 H(3S1)-C(3S)-H(3S2) 108.0 C(3S)-C(4S)-H(4S1) 109.5 C (3S)-C(4S)-H(4S2) 109.5 H(4S1)-C(4S)-H(4S2) 109.5 C(3S)-C(4S)-H(4S3) 109.5 H(4S1)-C(4S)-H(4S3) 109.5 H(4S2)-C(4S)-H(4S3) 109.5 200 1246454 200 of 249 C(6S)-C(5S)-S(5) 112.7(3) C(6S)-C(5S)-H(5S1) 109.0 S(5)-C(5S)-H(5S1 ) 109.0 C(6S)-C(5S)-H(5S2) 109.0 S(5)-C(5S)-H(5S2) 109.0 H(5S1)-C(5S)-H( 5S2) 107.8 C(5S)-C(6S)-H(6S1) 109.5 C(5S)-C(6S)-H(6S2) 109.5 H(6S1)-C(6S)-H (6S2) 109.5 C(5S)-C(6S)-H(6S3) 109.5 H(6S1)-C(6S)-H(6S3) 109.5 H(6S2)-C(6S)- H(6S3) 109.5 C(8S)-C(7S)-S(7) 110.6(4) C(8S)-C(7S)-H(7S1) 109.5 S(7)-C (7S)-H(7S1) 109.5 C(8S)-C(7S)-H(7S2) 109.5 S(7)-C(7S)-H(7S2) 109.5 H(7S1)- C(7S)-H(7S2) 108.1 C(7S)-C(8S)-H(8S1) 109.5 C(7S)-C(8S)-H(8S2) 109.5 H(8S1) -C(8S)-H(8S2) 109.5 C(7S)-C(8S)-H(8S3) 109.5 H(8S1)-C(8S)-H(8S3) 109.5 H(8S2 )-C(8S)-H(8S3) 109.5 C(10S)-C(9S)-S(6) 104.5(5) 201 1246454 201 of 249 C(10S)-C(9S)-H(9S1) 110.8 S(6)-C(9S)-H(9S1) 110.8 C(10S)-C(9S)-H(9S2) 110, 8 S(6)-C(9S)-H(9S2) 110.8 H(9S1)-C(9S)-H(9S2) 108.9 C(9S)-C(10S)-H(10A) 109 .5 C(9S)-C(10S)-H(10B) 109.5 H(10A)-C(10S)-H(10B) 109.5 C(9S)-C(10S)-H(10C) 109.5 H(10A)-C(10S)-H(10C) 109.5 H(10B)-C(10S)-H(10C) 109.5 C(12S)-C(11S)-S(8 ) 113.0(3) C(12S)-C(11S)-H(11E) 109.0 S(8)-C(11S)-H(11E) 109.0 C(12S)-C(11S) -H(11F) 109.0 S(8)-C(11S)-H(11F) 109.0 H(11E)-C(11S)-H(11F) 107.8 C(11S)-C(12S )-H(12A) 109.5 C(11S)-C(12S)-H(12B) 109.5 H(12A)-C(12S)-H(12B) 109.5 C(11S)-C( 12S)-H(12C) 109.5 H(12A)-C(12S)-H(12C) 109.5 H(12B)-C(12S)-H(12C) 109.5 C(14S)-C (13S)-S(9) 111.6(3) C(14S)-C(13S)-H(13M) 109.3 202 1246454 202 of 249 S(9)-C(13S)-H(13M) 109.3 C(14S)-C(13S)-H(13N) 109.3 S(9)-C(13S)-H(13N) 109, 3 H(13M)-C(13S)-H(13N) 108.0 C(13S)-C(14S)-H(14M) 109.5 C(13S)-C(14S)-H(14N) 109 .5 H(14M)-C(14S)-H(14N) 109.5 C(13S)-C(14S)-H(14O) 109.5 H(14M)-C(14S)-H(14O) 109.5 H(14N)-C(14S)-H(14O) 109.5 C(16S)-C(15S)-S(3) 112.7(4) C(16S)-C(15S)- H(15M) 109.0 S(3)-C(15S)-H(15M) 109.0 C(16S)-C(15S)-H(15N) 109.0 S(3)-C(15S) -H(15N) 109.0 H(15M)-C(15S)-H(15N) 107.8 C(15S)-C(16S)-H(16M) 109.5 C(15S)-C(16S )-H(16N) 109.5 H(16M)-C(16S)-H(16N) 109.5 C(15S)-C(16S)-H(16O) 109.5 H(16M)-C( 16S)-H(16O) 109.5 H(16N)-C(16S)-H(16O) 109.5 Symmetry transformations used to generate equivalent atoms: Table 4. Anisotropic displacement parameters (A2x 103) for LMT.2EsOH. The exponent of the anisotropic displacement factor takes the 203 1246454 203 of 249 form of: -2π2[ h2a^U11+ ... + 2 h k a* b* U12] U11 U22 U33 U23 U13 U12 S(1A) 18(1) 21(1) 121(2) 12(1) -15(1) -2(1) N(1A) 15(2) 24(2) 36( 2) 1(2) 0(2) -3(2) N(2A) 19(2) 20(2) 27(2) 5(2) 1(2) 0(2) N(3A) 17(2 ) 23(2) 27(2) -1(2) 3(2) 1(2) C(1A) 20(3) 22(2) 39(3) 3(2) -4(2) -1( 2) C(2A) 17(2) 24(2) 39(3) 2(2) -4(2) -1(2) C(3A) 22(2) 22(2) 25(2) -1 (2) 7(2) -2(2) C(4A) 17(2) 29(2) 31(3) -5(2) 7(2) 2(2) C(5A) 15(2) 28 (2) 37(3) -6(2) 9(2) -6(2) C(6A) 18(2) 23(2) 26(2) -2(2) 3(2) -3(2 ) C(7A) 22(2) 23(2) 25(2) 0(2) 5(2) -2(2) C(8A) 21(2) 25(2) 21(2) -3(2 ) 6(2) -7(2) C(9A) 25(2) 22(2) 24(2) 2(2) 7(2) -3(2) C(10A) 19(2) 24(2 ) 22(2) 3(2) 4(2) 2(2) C(11A) 19(2) 23(2) 33(3) 2(2) 1(2) -8(2) C(12A) 20(3) 22(2) 42(3) 6(2) 2(2) -1(2) C(13A) 28(3) 39(3) 30(3) 15(2) 0(2) - 2(2) C(14A) 34(3) 44(3) 37(3) 1(2) 7(2) 13(2) C(15A) 96(5) 26(3) 36(3) 3( 2) 37(3) 2(3) C(16A) 32(3) 26(2) 30(3) -9(2) 4(2) 6(2) S(1B) 17(1) 18(1 ) 39(1) 3(1) 7(1) -1(1) N(1B) 21(2) 16(2) 25(2) -2(2) 8(2) -3(2) N( 2B) 29(2) 24(2) 20(2) 4(2) 1(2) 6(2) 204 1246454 204 of 249 N(3B) 21(2) 19(2) 21(2) -2(2) 3(2) 2(2) C(1B) 17(2) 20(2) 18(2) 0(2) 5 (2) 0(2) C(2B) 21(2) 23(2) 16(2) -3(2) 3(2) -4(2) C(3B) 22(2) 18(2) 18 (2) -2(2) 6(2) 1(2) C(4B) 16(2) 23(2) 20(2) -1(2) 3(2) 0(2) C(5B) 16 (2) 21(2) 21(2) -1(2) 5(2) -4(2) C(6B) 25(2) 20(2) 17(2) 0(2) 9(2) 1 (2) C(7B) 22(2) 24(2) 20(2) -3(2) 9(2) 0(2) C(8B) 29(3) 19(2) 27(2) 0( 2) 17(2) -2(2) C(9B) 32(3) 20(2) 25(2) 3(2) 16(2) 4(2) C(10B) 31(3) 24(2 ) 14(2) 1(2) 7(2) 9(2) C(11B) 24(2) 23(2) 19(2) -2(2) 6(2) -1(2) C(12B ) 28(3) 18(2) 20(2) 0(2) 9(2) 2(2) C(13B) 53(3) 30(3) 26(3) 14(2) 11(2) 17 (2) C(14B) 22(2) 30(2) 27(3) 1(2) 4(2) 6(2) C(15B) 42(3) 22(2) 35(3) 3(2 ) 15(2) 3(2) C(16B) 39(3) 30(3) 25(3) -8(2) 2(2) 10(2) S(1C) 16(1) 21(1) 34(1) 2(1) 6(1) 0(1) N(1C) 15(2) 22(2) 31(2) -8(2) 4(2) -5(2) N(2C) 16(2) 19(2) 23(2) 0(2) 6(2) 0(1) N(3C) 21(2) 28(2) 27(2) 1(2) 7(2) 5( 2) C(1C) 16(2) 25(2) 15(2) -1(2) 2(2) 0(2) C(2C) 20(2) 24(2) 17(2) -2( 2) 6(2) -1(2) C(3C) 21(2) 20(2) 19(2) 1(2) 6(2) 5(2) C(4C) 20(2) 34(3 ) 20(2) -2(2) 7(2 ) 4(2) 205 1246454 205 of 249 C(5C) 20(2) 26(2) 20(2) -1(2) 6(2) -1(2) C(6C) 22(2) 24(2) 15(2) -4(2 ) 7(2) -1(2) C(7C) 18(2) 29(2) 17(2) -4(2) 6(2) 2(2) C(8C) 17(2) 22(2 ) 27(2) -8(2) 9(2) -6(2) C(9C) 21(2) 20(2) 22(2) -3(2) 10(2) -2(2) C (10C) 14(2) 25(2) 18(2) -3(2) 5(2) 1(2) C(11C) 15(2) 24(2) 21(2) -5(2) 6 (2) -7(2) C(12C) 18(2) 19(2) 21(2) -4(2) 7(2) 2(2) C(13C) 17(2) 30(2) 29 (3) 2(2) 9(2) 3(2) C(14C) 23(2) 23(2) 23(2) 2(2) 7(2) -2(2) C(15C) 46( 3) 45(3) 56(4) 22(3) 29(3) 11(3) C(16C) 38(3) 33(3) 46(3) -18(2) -4(3) 8( 2) S(1D) 25(1) 23(1) 46(1) -3(1) 13(1) -4(1) N(1D) 26(2) 23(2) 36(2) -4 (2) 11(2) -4(2) N(2D) 22(2) 35(2) 23(2) 2(2) 7(2) 2(2) N(3D) 27(2) 24( 2) 34(2) 0(2) 16(2) 2(2) C(1D) 28(3) 28(2) 20(2) -3(2) 10(2) 0(2) C(2D ) 30(3) 29(2) 23(2) -5(2) 13(2) -4(2) C(3D) 33(3) 24(2) 24(2) -1(2) 13( 2) 1(2) C(4D) 27(3) 31(3) 33(3) 0(2) 10(2) -1(2) C(5D) 26(3) 29(3) 36(3 ) -6(2) 8(2) -6(2) C(6D) 29(3) 24(2) 19(2) -3(2) 10(2) 0(2) C(7D) 23( 2) 27(2) 16(2) 0(2) 9(2) -1(2) C(8D) 30(3) 27(2) 19(2) 0(2) 15(2) -3( 2) C(9D) 29(3) 2 9(2) 16(2) 3(2) 9(2) -2(2) 206 1246454 206 of 249 C(10D) 24(2) 30(2) 17(2) -2(2) 8(2) 0(2) C(11D) 26(3) 32(2) 17(2) -6(2) 7(2) -6(2) C(12D) 28(3) 24(2) 18(2) -5(2) 11(2) -1(2) C(13D) 33(3) 60(4 ) 33(3) 19(3) 11(2) 10(3) C(14D) 30(3) 33(3) 32(3) 3(2) 16(2) 5(2) C(15D) 51 (3) 34(3) 41(3) 6(2) 23(3) 10(2) C(16D) 35(3) 26(2) 47(3) -12(2) 19(3) -3 (2) S(2) 36(1) 27(1) 45(1) 9(1) 18(1) 2(1) S(3) 23(1) 22(1) 24(1) -3( 1) 4(1) -1(1) S(4) 16(1) 23(1) 40(1) -4(1) 4(1) -1(1) S(5) 23(1) 24 (1) 41(1) 8(1) 12(1) 4(1) Y(6) 42(1) 19(1) 29(1) 0(1) 9(1) -2(1) Y( 7) 31(1) 28(1) 39(1) 4(1) 12(1) 1(1) S(8) 20(1) 19(1) 24(1) 0(1) 4(1) -1(1) S(9) 23(1) 23(1) 27(1) -1(1) 7(1) 4(1) O(1) 67(4) 53(4) 52(5) 19(4) 29(4) 10(4) OR(2) 56(6) 25(9) 107(14) 17(8) 13(8) -20(7) OR(3) 55(4) 54 (4) 57(5) 23(4) 25(4) 8(3) O(1') 79(5) 68(4) 48(4) 25(3) 39(4) 31(4) O( 2') 53(4) 20(7) 109(13) 14(6) 9(7) -4(5) O(3') 35(3) 71(5) 68(5) 41(4) 21 (4) 9(3) OR(4) 26(2) 26(2) 44(2) 3(2) 7(2) 2(1) OR(5) 40(2) 33(2) 35(2 ) -10(2) 0(2) -8(2) OR(6) 23(2) 31(2) 26(2) -2(1) 9(1) -6(1) OR(7) 27 (2) 27(2) 72( 3) 11(2) 11(2) 0(2) 207 1246454 207 of 249 O(8) 16(2) 42(2) 57(2) -18(2) -3(2) -2(2) O(9) 24(2) 29(2) 38(2) -2( 1) 14(2) -3(1) OR(10) 43(2) 49(2) 33(2) 12(2) 18(2) 30(2) OR(11) 37(2) 48(2 ) 95(4) 34(2) 4(2) -11(2) OR(12) 78(3) 30(2) 34(2) -2(2) 28(2) 3(2) OR(13 ) 52(3) 72(3) 56(3) -16(2) 35(2) -33(2) O(14) 94(3) 25(2) 35(2) -2(2) 3( 2) 13(2) OR(15) 37(2) 40(2) 35(2) -9(2) 1(2) 5(2) OR(16) 23(2) 37(2) 36(2 ) -16(2) 13(2) -8(1) OR(17) 59(3) 36(2) 68(3) 23(2) 21(2) -5(2) OR(18) 28( 2) 52(2) 32(2) -9(2) 9(2) 0(2) OR(19) 33(2) 19(2) 34(2) -1(1) 7(2) -2 (1) OR(20) 20(2) 24(2) 45(2) -4(2) -1(2) -2(1) OR(21) 32(2) 34(2) 28(2) 3(1) 14(2) 2(1) OR(22) 26(2) 27(2) 24(2) -2(1) 9(1) -2(1) OR(23) 26(2) 23(2) 39(2) 3(1) 9(2) 8(1) OR(24) 26(2) 25(2) 42(2) -5(2) 8(2) -4(1) C(1S) 60(4) 50(4) 56(4) 14(3) 5(3) 6(3) C(2S) 48(3) 52(3) 36(3) 10(3) 19( 3) -2(3) C(3S) 20(2) 37(3) 30(3) -4(2) 6(2) 5(2) C(4S) 32(3) 57(3) 28( 3) 14(2) 12(2) 8(2) C(5S) 23(3) 31(3) 50(3) 11(2) 9(2) 8(2) C(6S) 37(3) 32(3) 26(3) 6(2) 13(2) 3(2) C(7S) 32(3) 47(3) 38(3) -2(2) 14(2) 1(2) C (8S) 48(4) 22 (3) 73(4) 9(3) 8(3) -3(2) 208 1246454 208 of 249 C(9S) 45(3) 31(3) 43(3) 11(2) 24(3) 7(2) C(10S) 118(8) 88(6) 104(7) -11(5) 58 (6) -22(6) C(11S) 30(3) 25(2) 30(3) 3(2) 14(2) -2(2) C(12S) 40(3) 40(3) 30 (3) 3(2) 11(2) 2(2) C(13S) 29(3) 25(2) 26(2) 0(2) 11(2) 1(2) C(14S) 35(3 ) 32(3) 37(3) -2(2) 18(2) -2(2) C(15S) 38(3) 39(3) 35(3) 2(2) 19(2) -2( 2) C(16S) 51(4) 50(3) 63(4) 5(3) 40(3) 4(3) Table 5. Hydrogen coordinates ( x 104) and isotropic shift parameters (Á2x 10 3) for LMT.2EsOH. ___________________________________ x y z U(eq) H(1AA) -585 2958 1019 35 H(2AA) 1142 2510 2886 30 H(3A) -993 5379 587 30 H(2A) -112 4894 1482 38 H(4A) -1173 4519 414 32 H (5A) -1024 3623 616 33H(8A) -239 2190 1412 29H(9A) 327 1779 2005 30H(11A) 801 3220 2506 34H(13A) 956 2107 3668 55H(13B) 1268 53 58H (13C) 853 1592 3162 55 H(14A) 950 1606 2041 62 H(14B) 1350 1846 2447 62 209 1246454 209 of 249 H(14C) 1048 2153 1770 62 H(15A) -399 5529 288 75 H(15B) -759 5883 -21 75 H(15C) -775 5281 -280 75 H(16A) -638 5607 1762 49 H(16B) -652 6075 1222 49H(16C) -306 5694 1555 49H(1B) 2048 25 885 25H(2BB) 3779 -238 2945 33H(3B) 1492 2364 765 27H(2B) 2408 2001 14(44 2B ) 1368 1494 658 26H(5B) 1566 616 765 25H(8B) 2428 -704 1523 28H(9B) 3012 -1036 2140 29H(11B) 3416 453 2358 28H(13D) 3579 -8789 57H(350 13E) 3953 -1033 3472 57H(13F) 3582 -1293 2905 57H(14D) 3650 -952 1829 43H(14E) 4042 -744 2383 43H(14F) 3758 -345 1811 43H(15D) 1271396 2099 50 H(15E) 1729 3039 363 50 H(15F) 1737 2500 -42 50 210 1246454 210 of 249 H(16D) 1800 2460 1997 53 H(16E) 1763 3014 1591 53 H(16F) 2137 2692 1883 53 H(1C) 4627 2587 1195 30 H(2CC) 6358 2390 3285 24 H(09 3905 406 406 2C) 4971 4574 1649 25H(4C) 3932 4060 845 30H(5C) 4137 3182 1006 27H(8C) 5015 1871 1821 26H(9C) 5601 1557 2480 25H(11C) 3H(11G2) 5 3987 273525 6256 1619 2248 39 h (13h) 6636 1887 2761 39 h (13i) 6327 2230 2142 39 h (14g) 6168 1769 3891 36 h (14h) 6544 1621 3871 36 h (14i) 6177 1339 3323 36 h (15g) 4636 5189 631 70H(15H) 4280 5544 406 70H(15I) 4252 4970 55 70H(16G) 4450 5092 2174 70H(16H) 4333 5614 1683 70H(16I) 4723 5354 1894 4 20 3818 70H( 211 1246454 211 of 249 H(2D) 8828 -56 3133 33 H(3D) 6618 2711 1123 32 H(2DD) 7510 2283 1724 32 H(4D) 6459 1833 909 38 H(5D) 6639 950 1112 38 H(8D) 7452 -412 2 8 H(9D) 8028 -812 2416 30 H(11D) 8478 655 2709 31 H(13J) 8654 -656 3792 65 H(13K) 9004 -828 3683 65 H(13L) 8618 -1085 3187 65 H(14J) 8622 - 820 2060 46H(14K) 9023 -587 2493 46H(14L) 8707 -220 1935 46H(15J) 7042 2819 377 61H(15K) 6720 3214 295 61H(15L) 6632 2612 31 61H7(101) 2976 2179 54H(16K) 6965 3437 1582 54H(16L) 7320 3101 1708 54H(1S1) 354 568 117 74H(1S2) 34 756 315 74H(2S1) 348 1552 757 67H(2) 6 -632 93 67 H(2S3) 641 1363 479 67 212 1246454 212 of 249 H(3S1) 2296 4750 523 36 H(3S2) 2109 4415 -213 36 H(4S1) 1692 5133 -749 59 H(4S2) 2102 5315 -517 59 H(4S3) 1901 5469 -21 59 H(5S1) 32351 241 44H(5S2) 2548 3575 803 44H(6S1) 3029 4152 984 48H(6S2) 2760 4126 137 48H(6S3) 3134 3806 444 48H(7S1) 5283 2814 -129 47H(7S1) 7 516 52) 7 546 52) 47H(8S1) 5796 3675 290 81H(8S2) 5368 3758 -148 81H(8S3) 5587 3453 -521 81H(9S1) 5428 806 551 46H(9S2) 5579 1289 1119 46H(10A) 9 8 6 150H(10B) 5993 1119 613 150H(10C) 6028 516 875 150H(11E) 8109 3705 840 33H(11F) 8195 3253 387 33H(12A) 7581 2956 -55 57H(12B) 3 556305 39 57 H(12C) 7500 3438 363 57 213 1246454 213 of 249 H(13M) 8341 797 1242 33 H(13N) 8118 1177 569 33 H(14M) 7744 447 -41 52 H(14N) 7716 589 698 52 H(14O) 7955 95 671 52 H(15M) 272 447 -63 4476 H(15N) 475 2669 763 44 H(16M) 317 3544 407 74 H(16N) -43 3188 97 74 H(16O) 135 3371 -430 74 Crystallographic data for LMT.2MsOH (Figure 17c) Table 1. Crystal data and structure refinement for LMT.2MsOH. Identification code 64412SC171 Empirical formula C18 H27 N3 O6 S3 Formula weight 477.61 Temperature 150(2) K Wavelength 0.71073 A Crystal system Triclinic Space group P-1 Unit cell dimensions a = 11.6401(6) At α= 104.682(2)°. b = 12.0744(6) A β= 92.386(2)°. c = 18.4846(9) A γ = 116.151(2)°. Volume 2220.42(19) A3 Z 4 214 1246454 214 of 249 Density (calculated) 1.429 Mg / m3 Absorption coefficient 0.374 mm-1 F(000) 1008 Crystal size 0.30 x 0.18 x 0.04 mm3 Theta range for data collection 1.16 to 27.57°. Index ranges -15<=h<=15, -15<=k<=15, -24<=l<=24 Collected reflections 42564 Independent reflections 10184 [R(int) = 0.0662] Extension to theta = 25 .00° 99.6 % Semi-empirical absorption correction from equivalents Transmission max and min. 0.9852 and 0.8962 Refinement Method Full Matrix Least Squares for F2 Data / Constraints / Parameters 10184 / 198 / 552 Goodness of Fit for F2 1.071 Final R Indices [I>2sigma(I)] R1 = 0.0593, 215 1246454 215 of 249 wR2 = 0.1399 R Indices (all data) R1 = 0.0909, wR2 = 0.1566 Largest peak and orifice difference 1.192 and -0.905 e.A-3 Table 2. Atomic coordinates ( x 104) and isotropic displacement parameters (A2x 103) for eul1_0m. U(eq) is defined as one third of the trace of the orthogonalized tensor Uj. _______________________________________________ x y z U(eq) C(1A) 2847(3) 7453(4) 3069(2) 28(1) C(2A) 2545(3) 8117(3) 2643(2) 27(1) C(3A) 3528 (3) 9173(4) 2496(2) 29(1) C(4A) 4823(3) 9566(4) 2760(2) 37(1) C(5A) 5121(3) 8863(4) 3154(2 ) 39(1) C(6A) 4156(3) 7809(4) 3317(2) 34(1) C(7A) 3630(5) 5911(5) 3768(2) 48(1) C(8A) 4139 (5) 5179(5) 4015(2) 55(1) C(9A) 3314(5) 4011(5) 4119(2) 58(1) C(10A) 1978(5) 3531(5) 3953(2 ) 52(1) C(11A) 1451(5) 4217(4) 3678(2) 45(1) C(12A) 2292(4) 5408(4) 3601(2) 42(1) C(13A) 3947 (4) 10426(4) 1555(2) 39(1) C(14A) 3035(4) 10981(4) 2698(2) 36(1) C(15A) 479(5) 2617(4) 4788(2 ) 56(1) C(16A) 422(9) 1431(7) 3338(3) 21(2) 216 1246454 216 of 249 C(16') -175(7) 1295(6) 3509(4) 38(2) C(1B) 1734(3) 3733(3) 1573(2) 20(1) C(2B) 467(3) 2802(3) 1532(2) 20(1) C(3B) -556(3) 2949(3) 1228(2) 20(1) C(4B) -328(3) 4011(3) 986(2) 21(1) C(5B) 938(3) 4959(3) 1054(2) 22(1) C(6B) 1992(3) 4819(3) 1335(2) 21(1) C(7B) 4382( 3) 5861(3) 1707(2) 21(1) C(8B) 5559(3) 6955(3) 1766(2) 22(1) C(9B) 6724(3) 7111(3) 2126(2) 22(1) C(10B) 6691(3) 6167(3) 2435(2) 20(1) C(11B) 5535(3) 5073(3) 2382(2) 20(1) C(12B) 4385( 3) 4907(3) 2011(2) 20(1) C(13B) -2276(3) 1245(3) 1673(2) 27(1) C(14B) -2081(3) 892(3) 317( 2) 27(1) C(15B) 8932(3) 7573(3) 3209(2) 26(1) C(16B) 8431(3) 5579(3) 2180(2) 29(1) C(1S) 3536(4) 59(4) 4695(2) 38(1) C(2S) 8797(4) 7948(3) 434(2) 33(1) C(3S) 5403(4) 3853(4) 327( 2) 40(1) C(4S) 6718(6) 3037(5) 4356(2) 67(2) N(1A) 4480(3) 7134(4) 3726(2) 46(1) N(2A) 3126(3) 9915(3) 2118(2) 29(1) N(3A) 1056(5) 2317(4) 4117(2) 68(1) N(1B) 3245(2) 5734(3) 1338( 2) 24(1) 217 1246454 217 of 249 N(2B) -1895(2) 1871(3) 1060(1) 21(1) N(3B) 7903(2) 6237(2) 2774(2) 21(1) O(1S) 1876(5) 153 (5) 5602(3) 31(1) O(2S) 1457(5) 367(5) 4352(3) 27(1) O(3S) 3166(4) 2156(4) 5329(3) 28(1 ) O(2S') 3198(4) 1901(4) 4683(3) 26(1) O(1S') 2515(5) 924(5) 5683(3) 25(1) O(3S') 1291( 5) -191(6) 4380(3) 27(1) OR(4S) 10898(2) 10147(2) 1042(1) 34(1) OR(5S) 9224(3) 9462(3) 1796(2 ) 40(1) O(6S) 10527(2) 8353(2) 1521(2) 39(1) O(7S) 6954(2) 2997(3) -257(1) 34(1) O(8S) 6130(2) 2435(2) 845(1) 31(1) O(9S) 4703(3) 1484(2) -383(2) 44(1) O(10S) 7552(3) 4905(3) 3786 (2) 53(1) O(11S) 8403(4) 3384(4) 3483(2) 73(1) O(12S) 6252(3) 2791(3) 2924(2) 57(1) S(1 ) 2478(1) 713(1) 4948(1) 30(1) S(2) 9944(1) 9074(1) 1257(1) 23(1) S(3) 5818(1) 2588(1) 111 (1) 22(1) S(4) 7286(1) 3562(1) 3574(1) 26(1) S(1A) 1567(1) 6322(1) 3376(1) 32(1) S(1B ) 2994(1) 3393(1) 1838(1) 26(1) Table 3. Bond lengths [A] and angles [°] for eul1_0m. C(1A)-C(2A) 1,390(5) 218 1246454 218 of 249 C(1A)-C(6A) 1.408(4) C(1A)-S(1A) 1.753(4) C(2A)-C(3A) 1.388(5) C(2A)-H(2A) 0. 9500 C(3A)-C(4A) 1.388(5) C(3A)-N(2A) 1.472(5) C(4A)-C(5A) 1.387(6) C(4A)-H(4A) 0 .9500 C(5A)-C(6A) 1.390(6) C(5A)-H(5A) 0.9500 C(6A)-N(1A) 1.393(5) C(7A)-C(12A) 1.386 (6) C(7A)-N(1A) 1.394(6) C(7A)-C(8A) 1.409(5) C(8A)-C(9A) 1.380(7) C(8A)-H(8A ) 0.9500 C(9A)-C(10A) 1.387(7) C(9A)-H(9A) 0.9500 C(10A)-C(11A) 1.399(5) C(10A)-N(3A ) 1.502(7) C(11A)-C(12A) 1.386(7) C(11A)-H(11A) 0.9500 C(12A)-S(1A) 1.768(3) C(13A)-N( 2A) 1.506(4) C(13A)-H(13A) 0.9800 219 1246454 219 of 249 C(13A)-H(13B) 0.9800 C(13A)-H(13C) 0.9800 C(14A)-N(2A) 1.499(5) C(14A)-H(14A) 0.9800 C (14A)-H(14B) 0.9800 C(14A)-H(14C) 0.9800 C(15A)-N(3A) 1.477(6) C(15A)-H(15A) 0.9800 C( 15A)-H(15B) 0.9800 C(15A)-H(15C) 0.9800 C(16A)-N(3A) 1.482(6) C(16A)-H(16H) 0.9800 C(16A )-H(16I) 0.9800 C(16A)-H(16J) 0.9800 C(16')-N(3A) 1.563(6) C(16')-H(16K) 0.9800 C( 16')-H(16L) 0.9800 C(16')-H(16M) 0.9800 C(1B)-C(2B) 1.390(4) C(1B)-C(6B) 1.398(4) C(1B)-S(1B) 1.770(3) C(2B)-C(3B) 1.394(4) C(2B)-H(2B) 0.9500 C(3B)-C(4B) 1.384(4 ) C(3B)-N(2B) 1.479(4) 220 1246454 220 of 249 C(4B)-C(5B) 1.386(4) C(4B)-H(4B) 0.9500 C(5B)-C(6B) 1.407(4) C(5B)-H(5B) 0.9500 C(6B)-N(1B) 1.387(4) C(7B)-N(1B) 1.391(4) C(7B)-C(8B) 1.397(4) C(7B)-C(12B) 1.405( 4) C(8B)-C(9B) 1.398(4) C(8B)-H(8B) 0.9500 C(9B)-C(10B) 1.385(4) C(9B)-H(9B) 0 .9500 C(10B)-C(11B) 1.387(4) C(10B)-N(3B) 1.478(4) C(11B)-C(12B) 1.386(4) C(11B)-H(11B) 0.9500 C(12B)-S(1B) 1.766(3) C(13B)-N(2B) 1.494(4) C(13B)-H(13D) 0.9800 C(13B)-H(13E) 0.9800 C(13B)-H(13F) 0.9800 C(14B)-N(2B) 1.503(4) C(14B)-H(14D) 0.9800 C(14B)-H(14E) 0 .9800 C(14B)-H(14F) 0.9800 221 1246454 221 of 249 C(15B)-N(3B) 1.497(4) C(15B)-H(15D) 0.9800 C(15B)-H(15E) 0.9800 C(15B)-H(15F) 0.9800 C (16B)-N(3B) 1.503(4) C(16B)-H(16A) 0.9800 C(16B)-H(16B) 0.9800 C(16B)-H(16C) 0.9800 C( 1S)-S(1) 1.755(4) C(1S)-H(1S1) 0.9800 C(1S)-H(1S2) 0.9800 C(1S)-H(1S3) 0.9800 C(2S )-S(2) 1.768(3) C(2S)-H(2S1) 0.9800 C(2S)-H(2S2) 0.9800 C(2S)-H(2S3) 0.9800 C(3S) -S(3) 1.755(4) C(3S)-H(3S1) 0.9800 C(3S)-H(3S2) 0.9800 C(3S)-H(3S3) 0.9800 C(4S)- S(4) 1.762(4) C(4S)-H(4S1) 0.9800 C(4S)-H(4S2) 0.9800 C(4S)-H(4S3) 0.9800 N(1A)-H (1A) 0.8800 222 1246454 222 of 249 N(2A)-H(2A1) 0.9300 N(3A)-H(3A) 0.9300 N(1B)-H(1B) 0.8800 N(2B)-H(2B1) 0.9300 N( 3B)-H(3B) 0.9300 O(1S)-S(1) 1.573(5) O(2S)-S(1) 1.422(5) O(3S)-S(1) 1.508(5) O (2S')-S(1) 1.528(5) O(1S')-S(1) 1.312(5) O(3S')-S(1) 1.473(5) O(4S)-S(2) 1.449(2) O(5S)-S(2) 1.447(3) O(6S)-S(2) 1.472(2) O(7S)-S(3) 1.458(2) O(8S)-S( 3) 1.467(2) O(9S)-S(3) 1.433(3) O(10S)-S(4) 1.451(3) O(11S)-S(4) 1.417(3) O(12S)- S(4) 1.443(3) C(2A)-C(1A)-C(6A) 119.8(3) C(2A)-C(1A)-S(1A) 117.7(2) C( 6A)-C(1A)-S(1A) 122.0(3) C(3A)-C(2A)-C(1A) 120.3(3) C(3A)-C(2A)-H( 2A) 119.9 223 1246454 223 of 249 C(1A)-C(2A)-H(2A) 119.9 C(2A)-C(3A)-C(4A) 120.5(4) C(2A)-C(3A)-N(2A ) 116.9(3) C(4A)-C(3A)-N(2A) 122.3(3) C(5A)-C(4A)-C(3A) 118.9(4) C(5A )-C(4A)-H(4A) 120.5 C(3A)-C(4A)-H(4A) 120.5 C(4A)-C(5A)-C(6A) 121.7(3 ) C(4A)-C(5A)-H(5A) 119.1 C(6A)-C(5A)-H(5A) 119.1 C(5A)-C(6A)-N(1A) 120 .6(3) C(5A)-C(6A)-C(1A) 118.6(4) N(1A)-C(6A)-C(1A) 120.8(4) C(12A)- C(7A)-N(1A) 122.0(3) C(12A)-C(7A)-C(8A) 118.7(5) N(1A)-C(7A)-C(8A) 119 .3(4) C(9A)-C(8A)-C(7A) 120.2(5) C(9A)-C(8A)-H(8A) 119.9 C(7A)-C(8A )-H(8A) 119.9 C(8A)-C(9A)-C(10A) 120.1(4) C(8A)-C(9A)-H(9A) 120.0 C(10A) -C(9A)-H(9A) 120.0 C(9A)-C(10A)-C(11A) 120.6(5) C(9A)-C(10A)-N(3A) 121.4 (4) C(11A)-C(10A)-N(3A) 117.8(4) 224 1246454 224 of 249 C(12A)-C(11A)-C(10A) 118.5(4) C(12A)-C(11A)-H(11A) 120.7 C(10A)-C(11A)-H(11A ) 120.7 C(7A)-C(12A)-C(11A) 121.8(4) C(7A)-C(12A)-S(1A) 121.7(4) C(11A)-C (12A)-S(1A) 116.2(3) N(2A)-C(13A)-H(13A) 109.5 N(2A)-C(13A)-H(13B) 109.5 H( 13A)-C(13A)-H(13B) 109.5 N(2A)-C(13A)-H(13C) 109.5 H(13A)-C(13A)-H(13C) 109.5 H (13B)-C(13A)-H(13C) 109.5 N(2A)-C(14A)-H(14A) 109.5 N(2A)-C(14A)-H(14B) 109.5 H(14A)-C(14A)-H(14B) 109.5 N(2A)-C(14A)-H(14C) 109.5 H(14A)-C(14A)-H(14C) 109, 5 H(14B)-C(14A)-H(14C) 109.5 N(3A)-C(15A)-H(15A) 109.5 N(3A)-C(15A)-H(15B) 109 .5 H(15A)-C(15A)-H(15B) 109.5 N(3A)-C(15A)-H(15C) 109.5 H(15A)-C(15A)-H(15C) 109.5 H(15B)-C(15A)-H(15C) 109.5 N(3A)-C(16A)-H(16H) 109.5 225 1246454 225 of 249 N(3A)-C(16A)-H(16I) 109.5 N(3A)-C(16A)-H(16J) 109.5 N(3A)-C(16')-H(16K) 109 .5 N(3A)-C(16')-H(16L) 109.5 H(16K)-C(16')-H(16L) 109.5 N(3A)-C(16')-H (16M) 109.5 H(16K)-C(16')-H(16M) 109.5 H(16L)-C(16')-H(16M) 109.5 C(2B)-C(1B )-C(6B) 121.3(3) C(2B)-C(1B)-S(1B) 116.9(2) C(6B)-C(1B)-S(1B) 121.5( 2) C(1B)-C(2B)-C(3B) 118.7(3) C(1B)-C(2B)-H(2B) 120.7 C(3B)-C(2B)-H (2B) 120.7 C(4B)-C(3B)-C(2B) 121.2(3) C(4B)-C(3B)-N(2B) 118.7(3) C(2B) -C(3B)-N(2B) 119.5(3) C(3B)-C(4B)-C(5B) 119.7(3) C(3B)-C(4B)-H(4B) 120.1 C(5B)-C(4B)-H(4B) 120.1 C(4B)-C(5B)-C(6B) 120.4(3) C(4B)-C(5B)- H(5B) 119.8 C(6B)-C(5B)-H(5B) 119.8 N(1B)-C(6B)-C(1B) 122.5(3) N(1B)-C (6B)-C(5B) 118.7(3) 226 1246454 226 of 249 C(1B)-C(6B)-C(5B) 118.7(3) N(1B)-C(7B)-C(8B) 119.3(3) N(1B)-C(7B)- C(12B) 121.7(3) C(8B)-C(7B)-C(12B) 119.0(3) C(7B)-C(8B)-C(9B) 120.9(3) C(7B)-C(8B)-H(8B) 119.5 C(9B)-C(8B)-H(8B) 119.5 C(10B)-C(9B)-C(8B) 118, 7(3) C(10B)-C(9B)-H(9B) 120.6 C(8B)-C(9B)-H(9B) 120.6 C(9B)-C(10B)-C( 11B) 121.4(3) C(9B)-C(10B)-N(3B) 121.0(3) C(11B)-C(10B)-N(3B) 117.4(3) C( 12B)-C(11B)-C(10B) 119.7(3) C(12B)-C(11B)-H(11B) 120.1 C(10B)-C(11B)-H(11B) 120 .1 C(11B)-C(12B)-C(7B) 120.2(3) C(11B)-C(12B)-S(1B) 117.6(2) C(7B)-C(12B )-S(1B) 121.8(2) N(2B)-C(13B)-H(13D) 109.5 N(2B)-C(13B)-H(13E) 109.5 H(13D) -C(13B)-H(13E) 109.5 N(2B)-C(13B)-H(13F) 109.5 H(13D)-C(13B)-H(13F) 109.5 H(13E )-C(13B)-H(13F) 109.5 227 1246454 227 of 249 N(2B)-C(14B)-H(14D) 109.5 N(2B)-C(14B)-H(14E) 109.5 H(14D)-C(14B)-H(14E) 109, 5 N(2B)-C(14B)-H(14F) 109.5 H(14D)-C(14B)-H(14F) 109.5 H(14E)-C(14B)-H(14F) 109 .5 N(3B)-C(15B)-H(15D) 109.5 N(3B)-C(15B)-H(15E) 109.5 H(15D)-C(15B)-H(15E) 109.5 N(3B)-C(15B)-H(15F) 109.5 H(15D)-C(15B)-H(15F) 109.5 H(15E)-C(15B)-H(15F ) 109.5 N(3B)-C(16B)-H(16A) 109.5 N(3B)-C(16B)-H(16B) 109.5 H(16A)-C(16B)-H( 16B) 109.5 N(3B)-C(16B)-H(16C) 109.5 H(16A)-C(16B)-H(16C) 109.5 H(16B)-C(16B)-H (16C) 109.5 S(1)-C(1S)-H(1S1) 109.5 S(1)-C(1S)-H(1S2) 109.5 H(1S1)-C(1S)- H(1S2) 109.5 S(1)-C(1S)-H(1S3) 109.5 H(1S1)-C(1S)-H(1S3) 109.5 H(1S2)-C(1S) -H(1S3) 109.5 S(2)-C(2S)-H(2S1) 109.5 228 1246454 228 of 249 S(2)-C(2S)-H(2S2) 109.5 H(2S1)-C(2S)-H(2S2) 109.5 S(2)-C(2S)-H(2S3) 109, 5 H(2S1)-C(2S)-H(2S3) 109.5 H(2S2)-C(2S)-H(2S3) 109.5 S(3)-C(3S)-H(3S1) 109 .5 S(3)-C(3S)-H(3S2) 109.5 H(3S1)-C(3S)-H(3S2) 109.5 S(3)-C(3S)-H(3S3) 109.5 H(3S1)-C(3S)-H(3S3) 109.5 H(3S2)-C(3S)-H(3S3) 109.5 S(4)-C(4S)-H(4S1 ) 109.5 S(4)-C(4S)-H(4S2) 109.5 H(4S1)-C(4S)-H(4S2) 109.5 S(4)-C(4S)-H( 4S3) 109.5 H(4S1)-C(4S)-H(4S3) 109.5 H(4S2)-C(4S)-H(4S3) 109.5 C(6A)-N(1A)-C (7A) 124.8(3) C(6A)-N(1A)-H(1A) 117.6 C(7A)-N(1A)-H(1A) 117.6 C(3A)-N( 2A)-C(14A) 110.2(3) C(3A)-N(2A)-C(13A) 114.9(3) C(14A)-N(2A)-C(13A) 111.1 (3) C(3A)-N(2A)-H(2A1) 106.7 C(14A)-N(2A)-H(2A1) 106.7 229 1246454 229 of 249 C(13A)-N(2A)-H(2A1) 106.7 C(15A)-N(3A)-C(10A) 111.1(3) C(15A)-N(3A)-C(16A ) 130.2(6) C(10A)-N(3A)-C(16A) 101.3(4) C(15A)-N(3A)-C(16') 102.0(5) C( 10A)-N(3A)-C(16') 119.1(4) C(16A)-N(3A)-C(16') 28.2(3) C(15A)-N(3A)- H(3A) 103.9 C(10A)-N(3A)-H(3A) 103.9 C(16A)-N(3A)-H(3A) 103.9 C(16')-N(3A )-H(3A) 116.0 C(6B)-N(1B)-C(7B) 125.8(3) C(6B)-N(1B)-H(1B) 117.1 C(7B) -N(1B)-H(1B) 117.1 C(3B)-N(2B)-C(13B) 114.9(2) C(3B)-N(2B)-C(14B) 109.1 (2) C(13B)-N(2B)-C(14B) 111.1(3) C(3B)-N(2B)-H(2B1) 107.1 C(13B)-N(2B)- H(2B1) 107.1 C(14B)-N(2B)-H(2B1) 107.1 C(10B)-N(3B)-C(15B) 114.9(2) C(10B)-N (3B)-C(16B) 110.6(2) C(15B)-N(3B)-C(16B) 110.8(2) C(10B)-N(3B)-H(3B) 106, 7 C(15B)-N(3B)-H(3B) 106.7 230 1246454 230 of 249 C(16B)-N(3B)-H(3B) 106.7 O(1S')-S(1)-O(2S) 131.2(3) O(1S')-S(1)-O (3S') 123.5(3) O(2S)-S(1)-O(3S') 25.1(2) O(1S')-S(1)-O(3S) 71.7( 3) O(2S)-S(1)-O(3S) 110.8(3) O(3S')-S(1)-O(3S) 134.9(3) O(1S')-S (1)-O(2S') 116.5(3) O(2S)-S(1)-O(2S') 84.3(3) O(3S')-S(1)-O(2S ') 107.5(3) O(3S)-S(1)-O(2S') 45.0(2) O(1S')-S(1)-O(1S) 33.5(2) O(2S)-S(1)-O(1S) 109.1(3) O(3S')-S(1)-O(1S) 93.0(3) O(3S)-S(1) -O(1S) 103.3(3) O(2S')-S(1)-O(1S) 148.0(3) O(1S')-S(1)-C(1S) 107.0 (2) O(2S)-S(1)-C(1S) 114.7(2) O(3S')-S(1)-C(1S) 102.3(2) O(3S)-S (1)-C(1S) 113.6(2) O(2S')-S(1)-C(1S) 95.2(2) O(1S)-S(1)-C(1S) 104 .4(2) O(4S)-S(2)-O(5S) 112.76(15) O(4S)-S(2)-O(6S) 111.68(16) O(5S)- S(2)-O(6S) 112.07(17) 231 1246454 231 of 249 O(4S)-S(2)-C(2S) 108.24(17) O(5S)-S(2)-C(2S) 106.71(17) O(6S)-S(2)- C(2S) 104.86(16) O(9S)-S(3)-O(7S) 112.41(17) O(9S)-S(3)-O(8S) 113.91(16) O(7S)-S(3)-O(8S) 111.12(14) O(9S)-S(3)-C(3S) 105.99(19) O(7S)-S(3)- C(3S) 107.38(18) O(8S)-S(3)-C(3S) 105.42(16) O(11S)-S(4)-O(12S) 112.8(2) O(11S)-S(4)-O(10S) 114.1(2) O(12S)-S(4)-O(10S) 110.8(2) O(11S)-S(4)- C(4S) 106.2(3) O(12S)-S(4)-C(4S) 107.6(2) O(10S)-S(4)-C(4S) 104.6(2) C(1A)-S(1A)-C(12A) 100.76(19) C(12B)-S(1B)-C(1B) 101.93(14) Symmetry transformations used to generate equivalent atoms: Table 4. Anisotropic displacement parameters (A2x 103) for eul1_0m. The exponent of the anisotropic displacement factor takes the form of: -2π2[ h2a*2^1+ ... + 2 h k a* b* U12]___________________________________________ U11 U22 U33 U23 U13 U12 C(1A) 22(1) 45(2) 19(1) 2(1) 1(1) 21(1) C(2A) 17(1) 41(2) 20(1) 4(1) 0(1) 14(1) C(3A) 19(1) 46(2) 15(1) 2(1) 1(1) 12(1) 232 1246454 232 of 249 C(4A) 19(1) 57(2) 19(1) -4(1) 2(1) 12(1) C(5A) 19(1) 66(2) 20(1) -6(1) -2(1) 21(1) C(6A) 23(1) 59(2) 17(1) -4(1) -2(1) 26(1) C(7A) 75(2) 90(2 ) 15(1) 8(2) 5(1) 73(2) C(8A) 86(2) 98(2) 19(1) 6(2) 0(1) 83(2) C(9A) 101 (2) 92(2) 20(2) 6(2) -2(2) 86(2) C(10A) 100(2) 76(2) 18(1) 9(1) 3(2) 78( 2) C(11A) 86(2) 71(2) 16(1) 14(1) 7(1) 69(2) C(12A) 75(2) 75(2) 15(1) 15(1) 8(1) 67(2) C(13A) 27(2) 44(2) 20(2) 8(2) 4(2) -3(2) C(14A) 39(2) 30(2) 25 (2) 7(2) 10(2) 5(2) C(15A) 104(4) 34(2) 28(2) 4(2) -10(2) 34(3) C(1B) 17( 1) 22(1) 18(1) 4(1) 3(1) 10(1) C(2B) 21(1) 22(1) 18(1) 6(1) 4(1) 10(1) C(3B) 19(1) 23(1) 19(1) 5(1) 4(1) 10(1) C(4B) 20(1) 23(1) 22(1) 6(1) 3( 1) 12(1) C(5B) 22(1) 21(1) 24(1) 7(1) 4(1) 11(1) C(6B) 18(1) 22(1) 23(1) 5(1) 6(1) 10(1) C(7B) 21(1) 20(1) 23(1) 6(1) 6(1) 11(1) C(8B) 23(1) 19( 1) 26(1) 6(1) 6(1) 11(1) C(9B) 21(1) 19(1) 26(1) 5(1) 7(1) 9(1) C(10B) 19(1) 21(1) 19(1) 3(1) 4(1) 10(1) C(11B) 20(1) 21(1) 20(1) 5(1) 5(1) 10( 1) C(12B) 18(1) 20(1) 20(1) 6(1) 5(1) 8(1) C(13B) 21(2) 30(2) 2 4(2) 10(2) 4(1) 7(1) 233 1246454 233 of 249 C(14B) 24(2) 26(2) 21(2) 0(1) 0(1) 6(1) C(15B) 24(2) 22(2) 25(2) 0(1) 0( 1) 8(1) C(16B) 27(2) 31(2) 27(2) 0(2) 2(1) 18(2) C(1S) 33(2) 49(2) 28(2) 7(2) 0(2) 20(2) C(2S) 35(2) 29(2) 26(2) 2(2) -6(2) 12(2) C(3S) 62(3) 44 (2) 31(2) 12(2) 9(2) 40(2) C(4S) 95(4) 51(3) 30(2) 16(2) 22(2) 11(3) N(1A ) 42(2) 88(3) 23(2) 2(2) -6(1) 52(2) N(2A) 20(1) 32(2) 19(1) 5(1) 2(1) 0(1) N(3A) 159(4) 58(2) 17(2) 1(2) -12(2) 84(3) N(1B) 18(1) 25(1) 34(2) 17 (1) 7(1) 9(1) N(2B) 17(1) 25(1) 21(1) 6(1) 2(1) 10(1) N(3B) 18(1) 20(1 ) 21(1) 2(1) 1(1) 8(1) O(4S) 39(2) 25(1) 33(1) 10(1) 12(1) 9(1) O(5S) 37 (2) 35(2) 34(2) 0(1) 14(1) 10(1) O(6S) 30(1) 27(1) 54(2) 14(1) -11(1) 8( 1) OR(7S) 27(1) 48(2) 42(2) 28(1) 16(1) 22(1) OR(8S) 33(1) 42(1) 34(1) 23(1) 13(1) 25(1) O(9S) 33(2) 28(1) 53(2) 7(1) -5(1) 3(1) O(10S) 96(2) 27(1) 26 (1) 4(1) -11(2) 24(2) O(11S) 84(3) 128(3) 45(2) 25(2) 15(2) 82(3) O(12S) 43( 2) 54(2) 28(2) 2(1) -5(1) -11(1) S(1) 21(1) 19(1) 45(1) 13(1) -12(1) 5 (1) S(2) 23(1) 22(1) 20(1) 5(1) 3(1) 9(1) S(3) 19(1) 22(1) 28(1) 10(1) 6(1) 11(1) 2. 3. 4 1246454 234 of 249 S(4) 29(1) 22(1) 18(1) 6(1) 2(1) 4(1) S(1A) 29(1) 43(1) 39(1) 19(1) 5( 1) 26(1) S(1B) 17(1) 22(1) 39(1) 15(1) 1(1) 7(1) Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (A2x 10 3) for eul1_0m. _____________________________________ x y z U(eq) H(2A) 1662 7847 2452 32 H(4A) 5495 10304 2671 45 H(5A) 6007 9108 3318 47 H(8A) 5053 5489 4110 66 H(9A) 3662 3536 4304 69 H( 3874 3547 54 H (13A) 4800 11131 1827 58 h (13b) 3517 10752 1260 58 h (13c) 4057 9728 1211 58 h (14a) 2513 10627 3064 54 h (14b) 2623 11370 2445 54 h (14c) 3910 11643 2966 2966 54H(15A) 1173 3266 5213 84H(15B) -13 1828 4928 84H(15C) -105 2958 4669 84H(16H) -60 541 3357 32H(16I) 1086 1487 3019 32H(16J) -179 1679 3122 32 H(16K) -683 569 3701 56 235 1246454 235 of 249 H(16L) 94 977 3039 56 H(16M) -708 1698 3407 56 H(2B) 301 2081 1708 24 H(4B) -1035 4090 775 25 H(5B) 1095 5709 911 26 H(8B) 5567 7602 2 7 H(9B) 7524 7850 2158 27 H(11B) 5531 4439 2601 24 H(13D) -1727 843 1744 41 H(13E) -3189 582 1529 41 H(13F) -2161 1901 2148 41 H(14D) -192 -87 41H(14E) -2973 184 197 41H(14F) -1468 547 355 41H(15D) 9282 8071 2855 39H(15E) 9634 7519 3485 39H(15F) 8555 8004 3570 39H(15D) 4713 1898 43H(16B) 9145 5506 2426 43H(16C) 8752 6089 1829 43H(1S1) 4324 513 5083 56H(1S2) 3770 163 4204 56H(1S3) 3106 -861 6 839 65 4H655 210 50 H(2S2) 8124 7229 571 50 236 1246454 236 of 249 H(2S3) 9237 7616 64 50 H(3S1) 5170 3997 -144 60 H(3S2) 6146 4646 652 60 H(3S3) 4661 3623 594 60 H(4S1) 6520 2129 4255 100 H(4S2) 14 43 012 5930 (4S3) 7389 3569 4811 100H(1A) 5282 7506 3975 55H(2A1) 2289 9350 1848 35H(3A) 1596 2011 4279 82H(1B) 3327 6282 1083 29H(2 269 2B1) -24 3B) 7679 5766 3119 25 References: Abrahamson, M., Jonsdottir, S., Olafsson, I. & Grubb, A. 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Proceedings of the National Academy of Sciences 106, 7607-7612. 248 1246454 248 of 249 MIGUEL NORBERTO ARMANDO - 20109002225 Digitally signed by PORTALTRAM ITES - INPI Date: 2021.01.11 13:52:38-03:00 Reason: Digitally Signed by INPI Location: Buenos Aires, Argentina 1246454 249 of 249

Claims

1. A compound, characterized in that it has the following formula: FORMULA 1. 16 Claims follow