N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide maleate in free base form, pharmaceutical formulation, method of manufacture and use thereof for the treatment of herpesvirus

Abstract

To provide an antiviral active substance.SOLUTION: The present invention relates to the field of an antiviral active substance, in particular a salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide, more particularly a free base maleate, a pharmaceutical formulation thereof, and a process for the preparation of these salts. The present invention also relates to the use of these salts and pharmaceutical formulations thereof, respectively, in a method of treatment and / or prevention of human herpes simplex virus infection, in particular infection caused by HSV-1 and HSV-2.SELECTED DRAWING: None

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the field of antiviral active substances, in particular salts, more particularly the maleate salt of the free base, of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide, (said acetamide compound may hereinafter also be called "Pritelivir"), their pharmaceutical formulations, and processes for the preparation of these salts. The present invention also relates to the use of said salts, in particular the maleate salt, and their pharmaceutical formulations, respectively, in the treatment and / or prevention of human herpes simplex virus infections. [Background technology]

[0002] background N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide (i.e., "Pritelivir"), its free base and mesylate salt, is a known antiviral compound that is used in the treatment of herpes simplex virus (herpes simplex virus 1 and 2, respectively; hereinafter abbreviated as HSV-1 and HSV-2), as disclosed, for example, in WO2006 / 103011A1.

[0003] WO01 / 47904A1 describes thiazolylamide derivatives, processes for their preparation and their use as medicaments, in particular as antiviral agents. WO03 / 000259A1 describes the topical application of substituted thiazolylamide compounds in the treatment of herpes infections in humans, preparations suitable for topical application and methods for their preparation.

[0004] The aforementioned WO2006 / 103011A1 describes pharmaceutical preparations for oral administration containing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide or its hydrates or solvates, as well as its acids. The document also relates to a method for producing said preparations, as well as their use for treating / preventing diseases mediated by herpes viruses, in particular diseases mediated by herpes simplex viruses.

[0005] WO2013 / 045491A1 describes crystalline mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide with well-defined particle size distribution and specific surface area range, which has demonstrated enhanced long-term stability and release kinetics from the pharmaceutical composition.Therefore, pharmaceutical compositions containing said crystalline mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide are also described therein.

[0006] Similarly, EP 2 598 502 A1 describes crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide with a well-defined particle size distribution and specific surface area range (which demonstrated enhanced long-term stability and release kinetics from pharmaceutical compositions), as well as pharmaceutical compositions containing said N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide monomesylate monohydrate with the aforementioned particle size distribution and specific surface area range.

[0007] WO2013 / 045479A1 describes an improved and shortened synthesis process of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide and its mesylate salt by using boronic acid derivatives or boronolane reagents while avoiding harmful organotin compounds. Moreover, a crystalline mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide with enhanced long-term stability and release kinetics from its pharmaceutical composition is also described therein.

[0008] Said Pritelivir is an innovative, highly active and specific inhibitor of herpes simplex virus (HSV) infection. As a compound derived from the chemical class of thiazolylamide, Pritelivir is active against both types of herpes simplex virus that cause labial and genital herpes, respectively, and maintains activity against viruses that have become resistant to marketed drugs. Pritelivir has a different mechanism of action from other antiviral substances currently used to treat HSV infection (i.e., nucleoside analogue acyclovir and its prodrug valacyclovir, and famciclovir (prodrug of penciclovir)). Whereas nucleoside analogues terminate ongoing DNA chain elongation by inhibiting viral DNA polymerase, Pritelivir prevents de novo synthesis of viral DNA by inhibiting helicase-primase complex. In addition, it does not require activation in HSV-infected cells by viral thymidine kinase, and therefore is also protective against non-infected cells.

[0009] HSV-1 and / or HSV-2 infections are pathogenic, e.g., herpes labialis (clinically manifested as cold sores, mainly due to infection with HSV-1), genital herpes (mainly due to HSV-2 infection), but also very rarely cause severe diseases, e.g., keratitis and encephalitis. The virus is ubiquitously distributed throughout the world. A well-known drug used to treat herpes simplex infections is acyclovir (i.e., 2-amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one), which is a specific inhibitor of viral DNA polymerase.

[0010] Thus, herpes simplex viruses are widespread in the human population (seropositivity rates up to 100%, depending on the geographical region and subpopulation) and are divided into herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Infection leads to lifelong persistence of the virus with frequent and sometimes painful recurrences. HSV-1 causes oral lesions (herpes labialis), HSV-2 appears in the genital area and is mainly transmitted sexually. In immunocompromised patients, HSV leads to severe complications. In immunocompetent individuals, the negative symptoms and visible facial lesions associated with genital herpes may cause psychological distress.

[0011] According to the WHO, approximately 3.7 billion people under the age of 50 worldwide, or 67% of the population, were infected with HSV-1 in 2012. The prevalence of infection was estimated to be highest in Africa (87%) and lowest in the Americas (40-50%).

[0012] Antiviral drugs against herpes viruses can be administered to patients in several ways, for example, systemically, orally, topically, parenterally.As with all drugs, when used in treatment and / or prophylaxis methods on or in patients, physico-chemical stability, storage stability and stability during use are of utmost importance.The physico-chemical stability of the compound pritelivir is already quite good, and the compound itself has been demonstrated to absorb ultraviolet light.

[0013] Thus, the object of the present invention is to provide a more stable, particularly light-stable compound that exhibits fewer impurities. The mesylate form of the compound pritelivir is an example of a fairly stable form, but residual impurities may be present in the normally produced product, which is another object of the present invention to overcome. The above and other objects have been achieved by the present invention. Summary of the Invention

[0014] The physico-chemical and photostability of the salts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide, and in particular the maleate salt of the free base, provided by the present invention ensures that the respective pharmaceutical compositions formulated to contain said salts, and in particular said maleate salts, have a substantially reduced amount of any decomposition / degradation products. In other words, said salts, and in particular the maleate salts of the present invention (hereinafter abbreviated as "API") as active pharmaceutical ingredients are provided with a higher purity (i.e., less degradation products) or the dosage of such API per volume unit is higher. These characteristics of these salts, and in particular the maleate salts of the present invention, make it possible to reduce the initial amount of API in the formulation of the pharmaceutical composition. Because, when directly compared to formulations that are not based on these salts, particularly the maleate salt of the free base form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide, the effective concentration per volume unit of a given drug is achieved at lower levels and maintained for longer periods of time, respectively.

[0015] In summary, the present invention provides a stable salt form of pritelivir, in particular a stable maleate salt of the free base of pritelivir, and thereby, surprisingly, with the addition of a weak acid, such as maleic acid, a salt of the free base pritelivir may be obtained which thus results in a higher intrinsic pH value without simultaneously reducing the dissolution properties, while still ensuring pharmaceutical use in topical application (higher pH reduces the skin irritation effect) and oral application (without alteration of the bioavailability properties).

[0016] Furthermore, the inventive manufacturing process described herein for the free base salts of pritelivir, particularly the maleate salt disclosed herein, ensures the substantial absence of impurities arising from the manufacturing process, such as from the solvents, or degradation products of either the maleate salt or other compounds as APIs used in the manufacturing process. In contrast, as mentioned above, mesylates of the active compound are an example of a substantially stable form, although they are known to contain potential residual impurities that occur in their conventionally produced products.

[0017] Therefore, the present invention provides, inter alia, a surprising and unexpected physico-chemically stable salt form of the free base N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide with maleic acid. Specifically, the maleate salt of the free base of pritelivir provided herein unexpectedly exhibits a higher inherent pH value without reducing the solubility properties.

[0018] Very surprisingly, the maleate salt of the present invention exhibits remarkable photostability, which is particularly advantageous for its use in topical formulations intended to be used in methods for treating / preventing infections caused by herpes infections. Pharmaceutical formulations of photostable APIs at higher pH simultaneously reduce the skin irritation effect and allow their stability even under light exposure. Moreover, due to the above-mentioned properties, the bioavailability properties of the maleate salt are not affected when said maleate salt is used as an API in oral dosage forms.

[0019] In addition, the present invention unexpectedly provides stable salt forms, particularly stable salt forms of the maleate salt of the free base form of pritelivir, which, when obtained directly from the manufacturing process disclosed herein, have a high degree of purity themselves and can be stored for extended periods of time due to their stability. Furthermore, in the formulation of these salts, particularly the maleate salt as the API, as pharmaceuticals and storage, the API is present in high concentrations with essentially no or very little degradation, ensuring that the therapeutically effective concentration per volume unit of the pharmaceutical provided by the present invention is maintained at a high level.

[0020] Abbreviation 2-Me-THF 2-Methyltetrahydrofuran ac acetone ACN Acetonitrile am. amorphous API Active Pharmaceutical Ingredient COX Cyclooxygenase DCM Dichloromethane DMSO Dimethyl sulfoxide DSC Differential Scanning Calorimetry HPLC High Performance Liquid Chromatography HP-β CD Hydroxypropyl-β-cyclodextrin Hept n-Heptane HSV Herpes simplex virus IPA Isopropanol LIMS-Sample / ID A unique number provided by the LIMS system for the analytical sample. LIMS-Task / ID A unique number provided by the LIMS system for the analysis task / measurement MVTR Water Vapor Transmission Rate MCH Methylcyclohexane MEK 2-butanone (methyl ethyl ketone) MIBK Methyl isobutyl ketone NSAIDs Nonsteroidal Anti-inflammatory Drugs NMP n-Methyl-2-pyrrolidone NMR nuclear magnetic resonance (spectroscopy) PSAs produce pressure sensitive adhesives. STX Saxitoxin TBME tert-butyl methyl ether (MtBE) TGA thermogravimetry THF Tetrahydrofuran Tol Toluene TTX Tetrodotoxin XRPD X-ray powder diffraction [Brief description of the drawings]

[0021] [Figure 1] Representative Characteristic Properties of the Maleate Salt of the Free Base Form of Plitelivir of the Present Invention. [Diagram 2] Ortep plot for the maleate salt of the free base form of Priterivir. Crystal structure of the maleate salt of the free base form of Priterivir (Code: P071-02-ACE11-01-SCXRD-01). The thermal ellipsoid is shown with the electron density set at the 50% probability level. [Diagram 3] 1H NMR spectrum of the maleate salt of the free base form of pritelivir according to the present invention. [Figure 4] HPLC overlay of the free base form of pritelivir maleate (middle, 100.0% a / a); with the corresponding mother liquor (top, 75.64% a / a) and blank (bottom). [Diagram 5]DSC of the maleate salt of the free base form of pritelivir according to the present invention. Melting endotherm at 177°C. [Figure 6] TGA of the maleate salt of the free base form of pritelivir according to the present invention with a weight loss of 0.74% w / w up to 150° C. The next step shows the decomposition of maleic acid in the melt. [Figure 7] 1 is an XRPD of the maleate salt of the free base form of pritelivir according to the present invention, which shows a crystalline form. [Figure 8] 4 shows XRPD data for the maleate salt of the free base form of pritelivir according to the present invention. [Figure 9] 1 is an XRPD of the maleate salt of the free base form of pritelivir according to the present invention, which shows a crystalline form. [Figure 10] The table of Figure 10 shows the peak list of the PXRD pattern of the maleate salt of the free base form of pritelivir, which is further shown in Figure 11. The characteristic peaks of the maleate salt as described above are highlighted therein. [Figure 11] Characteristic peaks of the powder X-ray diffraction pattern of the free base form of pritelivir maleate salt (code: P071-02-PXRD-01), the characteristic peaks of each phase are marked with arrows. [Figure 12] 1H-NMR spectrum of the free base form of pritelivir maleate salt. [Figure 13] Peak list of the 1H-NMR spectrum of the maleate salt of the free base form of pritelivir in Figure 12. Legend: s=singlet; d=doublet; t=triplet; m=multiplet. [Figure 14] 13C-NMR spectrum of the free base maleate salt of pritelivir. [Figure 15] Peak list of the 13C-NMR spectrum (proton decoupled) of the maleate salt of the free base form of pritelivir in Figure 14. Legend: s=singlet; d=doublet; t=triplet; m=multiplet. [Figure 16] FTIR spectrum of the free base form of pritelivir maleate salt. [Figure 17]Peak list of the FTIR spectrum of the maleate salt of the free base form of pritelivir in Figure 16. Legend: s=sharp; b=broad; st=strong; me=medium; we=weak. [Figure 18] UV-Vis spectrum of the maleate salt of the free base form of pritelivir. [Figure 19] Figure 18 Peak list of the UV-Vis spectrum of the maleate salt of the free base form of pritelivir. [Figure 20] MS spectrum of the maleate salt of the free base form of pritelivir. [Figure 21] Relevant peaks in the MS spectrum of the maleate salt of the free base form of pritelivir in FIG. [Figure 22] 1H NMR spectrum of the sulfate salt of the free base form of pritelivir according to the present invention. [Diagram 23] HPLC overlay of the sulfate salt of the free base form of pritelivir according to the present invention (middle, 100.0% a / a); with the corresponding mother liquor (top, 73.83% a / a) and blank (bottom). [Figure 24] DSC of the sulfate salt of the free base form of pritelivir according to the present invention. No distinct melting point was observed, but there was a large endotherm due to water release (onset at 97° C.). [Diagram 25] TGA of the sulfate salt of the free base form of pritelivir according to the present invention with a weight loss of 6.3% w / w. [Figure 26] 4 shows XRPD of the sulfate salt of the free base form of pritelivir according to the present invention. [Figure 27] 4 shows XRPD data for the sulfate salt of the free base form of pritelivir according to the present invention. [Figure 28] 1H NMR spectrum of the hemiethane-1,2-disulfonic acid salt of the free base form of pritelivir according to the present invention. [Figure 29] HPLC overlay of the hemiethane-1,2-disulfonate salt of the free base form of pritelivir according to the present invention (middle, 100.0% a / a) with the corresponding mother liquor (top, 82.54% a / a) and blank (bottom). [Diagram 30]DSC of the hemiethane-1,2-disulfonate salt of the free base form of pritelivir according to the present invention. A large endotherm due to moisture release (onset at 100° C.) is seen, as well as a form transformation (180° C.) and a melting endotherm (250° C.). [Diagram 31] TGA of the hemiethane-1,2-disulfonic acid salt of the free base form of pritelivir according to the present invention with a weight loss of 3.4% w / w. [Diagram 32] The XRPD of the free base form of hemiethane-1,2-disulfonic acid salt of pritelivir according to the present invention shows a crystalline form. [Diagram 33] 4 shows XRPD data for the hemiethane-1,2-disulfonic acid salt of the free base form of pritelivir according to the present invention. [Diagram 34] 1H NMR spectrum of the benzenesulfonate salt of the free base form of pritelivir according to the present invention. [Diagram 35] HPLC overlay of the benzenesulfonate salt of the free base form of pritelivir according to the invention (middle, 99.64% a / a) with the corresponding mother liquor (top, 83.88% a / a) and blank (bottom). [Diagram 36] Figure 2: TGA of the benzenesulfonate salt of the free base form of pritelivir according to the present invention with a weight loss of 0.15% w / w. [Figure 37] The XRPD of the benzenesulfonate salt of the free base form of pritelivir according to the present invention shows a crystalline form. [Figure 38] 4 shows XRPD data for the benzenesulfonate salt of the free base form of pritelivir according to the present invention. [Figure 39] 1H NMR spectrum of the free base esylate salt of pritelivir according to the present invention. [Diagram 40] HPLC overlay of the free base form esylate of pritelivir according to the present invention (middle, 100.0% a / a); with the corresponding mother liquor (top, 63.06% a / a) and blank (bottom). [Diagram 41] DSC of the free base form esylate salt of pritelivir according to the present invention. Water release / form conversion endotherm around 150°C and melting endotherm at 223°C. [Diagram 42] TGA of the esylate salt of the free base form of pritelivir according to the present invention with a weight loss of 3.5% w / w by 200°C. [Diagram 43] The XRPD of the free base esylate salt of pritelivir according to the present invention shows a crystalline form. [Diagram 44] XRPD data of the free base esylate salt of pritelivir according to the present invention. [Diagram 45] Irradiated solutions of test articles and dark controls: Peak % areas of pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt. [Figure 46] Irradiated solutions of test articles and dark controls: Peak % areas of pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt. [Figure 47] Test items: Comparative dissolution profiles of pritelivir free base, its mesylate, its sulfonate, its maleate, its esylate, its monobenzenesulfonate, and its hemiethane-1,2-disulfonate salts using FaSSGF, FaSSIF, and FeSSIF. [Figure 48] Comparison of the solubility of the test items: pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt in water. [Figure 49] Comparison of the solubility of the test items: pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt in various pharmaceutical excipients. [Figure 50] Comparison of the stability of the test items: pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt in various pharmaceutical excipients when stored at ambient temperature for 2 weeks. [Figure 51] Comparison of the stability of the test items: pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt in various pharmaceutical excipients when stored at 50°C for 2 weeks. [Figure 52] Irradiated solutions of test articles and dark controls: Peak % areas of pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt. [Diagram 53] Irradiated solutions of test articles and dark controls: Peak % areas of pritelivir free base, its mesylate salt, its sulfonate salt, its maleate salt, its esylate salt, its monobenzenesulfonate salt, and its hemiethane-1,2-disulfonate salt. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description of the Invention Before describing the invention in detail, it may be convenient to provide definitions for certain terminology used throughout this specification. Although the invention will be described with reference to specific embodiments, this description should not be construed in a limiting sense. Before describing representative embodiments of the invention in detail, definitions that are important for understanding the invention are provided.

[0023] definition The term "pritelivir" in the context of the present invention refers to the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide itself. That is, for example, "free base of pritelivir" or similar expressions refer to the free base of the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide. Similarly, mesylate of pritelivir refers to the mesylate of the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide.

[0024] Similar expressions in the context of the present invention, all of which refer to the compound pritelivir, are "BAY57-1293", "AIC090096" and "AIC316". Similarly, the terms "pritelivir", "BAY57-1293", "AIC090096" and "AIC316" ​​or the compound "N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide" are intended throughout the text to represent a compound having the following structural formula:

[0025] [ka] .

[0026] The term "maleate salt" or similar terms refers to the maleate salt of the free base form of the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide.

[0027] In the context of the description, the expression "maleate" or similar expressions means the salt obtained from the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide when reacted with maleic acid. The maleate ion is the ionized form of maleic acid. Maleic acid or cis-butenedioic acid is an organic compound, i.e. a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCHCHCO2H. Maleic acid is the cis isomer of butenedioic acid, whereas fumaric acid is the trans isomer. Maleic acid is a less stable molecule than fumaric acid. Maleic acid is more soluble in water than fumaric acid. The melting point of maleic acid (135 °C) is also much lower than that of fumaric acid (287 °C). Both properties of maleic acid can be explained by the intramolecular hydrogen bonding that occurs in maleic acid at the expense of intermolecular interactions, which are not possible in fumaric acid for geometric reasons. In particular, maleic acid and the ionized form of maleic acid, i.e., the maleate ion, are further characterized by three double bonds.

[0028] As used in this specification and the appended claims, the singular forms "a" and "an" include the respective plural forms unless the context clearly dictates otherwise.

[0029] The term "photostability" or similar expressions refers to a material that has a light stability of at least 1.2 million Lux-hours under exposure to light of wavelengths between 300 nm and 800 nm and a light exposure of at least 200 Watt-hours / m 2Photostability refers to the physical-chemical stability of the maleate salt of the free base N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide, which does not undergo any medicamentically unacceptable changes upon exposure to light of 1000 nm. Photostability can be tested according to the ICH Topic Q1B guidance on Photostable Testing of New Active Substances and Medicinal Products, which is incorporated herein by reference.

[0030] In the context of the present invention, the terms "about" and "approximately" indicate an interval of accuracy that a person skilled in the art would understand to still ensure the technical effect of the feature in question. This term typically indicates a deviation of ±20%, preferably ±15%, more preferably ±10%, even more preferably ±5% from the indicated numerical value.

[0031] The term "comprising" should be understood as not limiting. In the present invention, the term "consisting of" should be considered as a preferred embodiment of the term "comprising of". Hereinafter, when a group is defined as comprising at least a certain number of embodiments, this means that the group preferably consists only of these embodiments.

[0032] Moreover, terms such as "first," "second," "third," or "(a)," "(b)," "(c)," "(d)," and the like, used herein and in the claims are used to distinguish between similar elements and not necessarily to describe a sequential or chronological order. The terms so used are interchangeable, under appropriate circumstances, and it should be understood that the embodiments of the invention described herein may be performed in orders other than those described or illustrated herein.

[0033] Where terms such as "first", "second", "third" or "(a)", "(b)", "(c)", "(d)" and the like refer to multiple steps of a method or use, unless otherwise indicated in the above or below application of this specification, the times or time intervals between those multiple steps may not be consistent, i.e., those multiple steps may be performed simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks, months or even years between such steps.

[0034] In the methods of the present invention, the phrase "antiviral effective amount" refers to the total amount of each active ingredient in the method sufficient to show a meaningful patient benefit, i.e., a cure of acute pathology characterized by suppression of herpes virus infection. When applied to an individual active ingredient administered alone, the phrase refers to that active ingredient alone. When applied to a combination of active ingredients, the phrase refers to the combined amount of each ingredient that produces a therapeutic effect, whether administered together, sequentially, or simultaneously.

[0035] In one embodiment, the term "prophylaxis" or "prevention" as used herein and in the claims refers to the administration or use of a compound or composition disclosed herein to protect, for example, an uninfected organism or, for example, uninfected cells of an organism from infection. However, in the context of the present invention, it also means that the organism may already be infected with a virus, but the spread of said virus within the organism (cell to cell) or within the organism's social environment is prevented by the salt of the present invention, in particular the maleate salt of the present invention. The organism may be a human or other mammal, whereby humans are preferred. Thus, in one embodiment of the present invention, the organism to which the compound or pharmaceutical composition is administered is a human infected with a herpes virus, for example HSV-1 and / or HSV-2, or at risk of being infected with such a virus. For further definitions of the "prophylaxis" embodiment of the present invention, see below.

[0036] The terms "treat", "treating" and "treatment" as used herein means to prevent or ameliorate a disease associated with a herpes virus infection.

[0037] The physical characterization of the salts of the invention referred to herein, in particular the maleate salt of the invention, was carried out using compendial methods in accordance with the European Pharmacopoeia (Ph.Eur) and / or the US Pharmacopeial Convention (USP).

[0038] Various embodiments of the invention are described in further detail herein below. Whenever reference is made to respective alternatives regarding the components of the composition, the type of pharmaceutical composition, the concentrations of the components, the duration of administration, the frequency of administration, the medical indication to be treated, the skilled artisan will immediately understand that, where technically possible, individual combinations can be made, or, where technically impossible, it has been expressly indicated otherwise.

[0039] Priterivir free base maleate salt In one embodiment, the present application relates to a maleate salt of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in free base form, having the molecular formula HO2CCHCHCO2H. The characteristic properties of the maleate salt of the present invention are shown in Figure 1. The Ortep Plot of the maleate salt is shown in Figure 2. The characteristic XRPD peaks are shown in Figures 10 and 11.

[0040] The maleate salt is further characterized by the compound of formula (I): [ka] .

[0041] As used herein, the term "storage stability" or "photostability" and corresponding terms indicate that the maleate salt of the present invention does not decompose or degrade over a long period of time. This is shown by standard measurement methods, such as HPLC, XRPD, etc., which allow the identification of said compound and / or its degradation products, showing a reference profile for the compound N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide (i.e., priterivir). 13 C- and 1 This means that the maleate concentration, as measured using 1 H-NMR spectroscopy, remains very high at all times.

[0042] The physico-chemical characterization of the salts of the invention, and in particular the maleate salts mentioned herein, is usually carried out using compendial methods in accordance with the European Pharmacopoeia (Ph.Eur) and / or the US Pharmacopeial Convention (USP).

[0043] Due to the general absence mentioned above of impurities (the salts of the present invention, in particular the maleate salt, either directly resulting from the manufacturing process or resulting from decomposition of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide), the purity of these salts, in particular the maleate salt of the free base form of pritelivir, as the manufactured product or in the formulation of a composition or medicament initially comprising these salts of the free base form of pritelivir is very high, i.e., a high concentration of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide per volume unit is achieved.

[0044] This is of great advantage when the salts of the invention are used in pharmaceutical and drug formulations, particularly topical formulations thereof, since the effective concentration of active compound per unit of volume is greatly increased.

[0045] This allows the amount of the salt of the present invention, particularly the maleate salt of the free base form of pritelivir, in the formulation to be reduced, while at the same time maintaining a suitably high effective amount of the active compound.This is particularly desirable for medicines used as topical compositions (as opposed to single unit dosage forms, essentially solid medicines, such as tablets, or - as another example - dosage forms for reconstitution in a pharma- ceutically acceptable medium or carrier for immediate use, as understood by those skilled in the art, for example for systemic or parenteral use), because the active ingredient in topically applied medicines is exposed to harsh environmental conditions with respect to temperature changes, light exposure, such as UV radiation, (relative) humidity, and mechanical stress when applied to the affected area of ​​the skin or mucous membrane.

[0046] Under such harsh conditions, it is important that a sufficiently high and therapeutically effective concentration of the API reaches as quickly as possible the cells forming the treatment surface and surface (e.g., the epidermis and dermal layers of the skin where the herpes virus damages the affected cells). When an effective antiviral concentration is quickly reached in the treatment area (cells, organs, e.g., skin, or parts thereof), the number of herpes viruses in the treatment area is reduced. This also reduces the number of affected viruses, especially herpes simplex viruses, that can infect neuronal cells, where these viruses persist in a latent state and can eventually be reactivated by physico-chemical stimuli, e.g., physiological stress, UV stress, or cellular changes due to other factors that shift the balance in the affected cells from herpes virus latency (and the expression of the polypeptides and / or polynucleotides encoded by the respective viruses) to herpes virus reactivation. Reactivation causes herpes viruses to leave the latent state and leave the cells forming a latent reservoir only to infect and productively grow there in cells that are subsequently destroyed by the virus itself or by host defense mechanisms, e.g., immune cells.

[0047] In the context of the above, a further embodiment of the present invention is a method for treating or inhibiting the occurrence of herpes simplex virus subtype 1 or 2 infection, or inhibiting the transmission of herpes simplex virus subtype 1 or 2 infection, comprising administering to a subject in need thereof an effective amount of a composition of the salt of the present invention, in particular the maleate salt in the free base form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide.

[0048] In another aspect of the present invention, the term "prophylaxis and / or prevention" or similar terms in the art pertinent to the present invention clearly means to the skilled artisan the inhibition or reduction of recurrence of infection with herpes simplex virus subtype 1 or 2, or the inhibition or reduction of transmission of infection.

[0049] In the context of the present invention, the term "prophylaxis and / or prevention" does not, even under its broadest reasonable interpretation, imply the complete and total absence of any infectious viral particles or infected cells in a patient. In accordance with the context of the present invention, such a position is appropriate in the art pertinent to the content disclosed herein. In support of these definitions of the term "prophylaxis and / or prevention", the following publications are incorporated herein by reference:

[0050] [ka]

[0051] These documents also support the art-documented correlation between helicase-primase inhibition and the prevention of herpes simplex virus infection or transmission.

[0052] Furthermore, Kleymann, 2002, mentioned above, teaches at the bottom of the left column on page 396 that recurrent disease and asymptomatic viral budding are almost completely suppressed by helicase-primase inhibitors, which should reduce person-to-person transmission, i.e., effectively prevent the transmission of HSV.

[0053] The above-referenced disclosure of Corey, 2004, at the bottom of page 11 and the first column of page 17, teaches that once-daily suppressive therapy with valacyclovir significantly reduced the risk of transmission of genital herpes between heterosexual, HSV-2 discordant couples, i.e., prevented transmission. The study obtained these results with a drug that was shown to inhibit budding of HSV type 2 (HSV-2) at genital mucosal surfaces. See top of page 11. Moreover, the frequency and amount of HSV shed asymptomatically at genital mucosal surfaces was found to be the primary source of transmissible infection. See citations 20-22 (which date back to 1997, 1998, and 1997, in citation order). Thus, approaches to reduce the frequency and amount of HSV shed asymptomatically at genital mucosal surfaces are ways to achieve herpes transmission prevention.

[0054] Karim, 2015, teaches at the bottom of page 530 based on a study therein, that pericoital application of tenofovir gel reduced HSV-2 acquisition in women, i.e., prevented HSV acquisition. The efficacy was a 51% reduction. See the second column on page 534. A previous study by the same group dating back to 2010 (see citation 6 in this reference) showed that pericoital application of a topical vaginal gel formulation of tenofovir reduced HIV acquisition. Although HIV is a different virus, it is not implausible to the skilled artisan in light of the above that a drug can prevent acquisition of a viral infection. Moreover, this is clearly confirmed by Karim to occur in the case of HSV. Since March 1987, Gold and Corey have supported the well-known effective preventive effect of acyclovir (i.e., a viral DNA polymerase inhibitor). In addition, since 2002, Tyring et al. have supported the efficacy of the prodrug valacyclovir (i.e., a viral DNA polymerase inhibitor).

[0055] In the case of HSV-1 and HSV-2, those skilled in the art will recognize that although the virus is present in the body due to infection, no symptoms will develop because the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide maleate salt effectively inhibits viral budding and proliferation ("preventing" or "inhibiting" the resulting symptoms of HSV-1 and HSV-2 infection).

[0056] In further support of the "treat prevention as suppression" aspect of the present invention, the previously mentioned references regarding valacyclovir (i.e., Tyring et al. 2002) and acyclovir (i.e., Gold et al. 1987) are repeated, which also establish that HSV infection is well established in asymptomatic form in healthy individuals, further implying in the art that preventative / suppressive therapy. Moreover, effective HSV prophylaxis has thus been clinically demonstrated in clinical trials.

[0057] In this regard, the poster of ICAAC 2014 on HSV-2 genital herpes indication is incorporated by reference (Wald et al., 2014, supra). Finally, the skilled person is aware that, by analogy with tenofovir, salts of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide as helicase-primase inhibitors, in particular the maleate salt of the free base, have an even higher antiviral effect than tenofovir in the case of HIV, which would lead the skilled person to expect that N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide would also have a more pronounced prophylactic efficacy. In this regard, the publications by Andrei et al. and Kleymann et al. mentioned above are particularly relevant. IC demonstrated therein for tenofovir 50The values ​​are significantly higher compared to the maleate salt of the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide.

[0058] As used herein, the term "anti-inflammatory agent", as defined in the preceding paragraph, generally refers to a compound or combination of compounds, such as steroids and nonsteroidal anti-inflammatory drugs (NSAIDs), which upon administration to an individual suffering from inflammation, tend to reduce such inflammation.

[0059] As used herein, "centrally and peripherally acting analgesics" includes opioid analgesics. Opioid analgesics include, for example, buprenorphine, physiologically acceptable salts or esters thereof, and suitable opioid analgesics include alfentanil, allylprozine, alphaprozine, anileridine, benzylmorphine, benzitramide, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, levororphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocin, methadone, metopon, morphine, mylophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalbuphine, nalorphine, naloxone, naltrexone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, profadol, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, and tramadol. Also included are esters, salts, and mixtures of any of the foregoing.

[0060] As used herein, non-opioid analgesics include, for example, NSAIDs, tricyclic antidepressants (e.g., amitriptyline), anticonvulsants (e.g., gabapentin), or antimigraine compounds (e.g., sumatriptan or naratriptan). NSAIDs can be cyclooxygenase (COX) inhibitors COX-1 or COX-2. Specific examples of NSAIDs include ibuprofen, flurbiprofen, diclofenac, indomethacin, piroxicam, ketoprofen, etodolac, diflucinal, meloxicam, aceclofenac, fenoprofen, naproxen, tiaprofenic acid, tolmetin, celecoxib, and rofecoxib, as well as physiologically acceptable salts and esters thereof. Suitable salts are alkali addition salts, such as potassium or sodium salts.

[0061] In the compositions of the present invention, long or short acting local and volatile anesthetics selected from the group including bupivacaine, lidocaine, xylocaine, tetrodotoxin (TTX), saxitoxin (STX), and the like, may be used.

[0062] Topical application Generally, rapid drug delivery through skin barrier is important for topical application.Since only dissolved drug can cross the stratum corneum of epidermis, suspended drug form may have significant effect on topical delivery properties.Drug in suspended form may deliver less locally because suspended drug must first enter into solution.This will also slow down the drug delivery of topical application.

[0063] In contrast, when a drug is applied topically in dissolved form, drug delivery should be faster and the extent of drug delivered should be determined by its IC 90 should be much higher compared to the value.

[0064] pH / apparent pH / topical formulations pH is an important parameter, especially for topical formulations, due to its influence on patient compliance, drug stability, and skin penetration of active moieties. Most traditional topical formulations are based on aqueous systems, such as gels, creams, and lotions, however, non-aqueous systems, such as oils, ointments, and the like, are also used for hydrophobic drugs. Accurate pH measurement of non-aqueous formulations is much more complicated than that of aqueous formulations.

[0065] Theoretically, while measuring the pH of an aqueous solution, some of the water molecules are converted to H + and O.H. - It is broken down into ions so that its pH value can be accurately obtained on a scale of 0 to 14. However, for non-aqueous systems, the 0 to 14 pH scale may not be appropriate.

[0066] Where pH is a measure of hydrogen ion activity in a solution using aprotic solvents, the concentration of hydrogen ions is significantly reduced or negligible. pH electrodes used in typical laboratory settings are calibrated using aqueous buffer solutions and are not calibrated for aqueous systems. + These pH electrodes are very suitable for recording ion concentrations. The electrochemistry of these electrodes is very similar to that of non-aqueous systems, H + It may not be suitable for recording ion concentrations.

[0067] Porras and Kenndler suggested that pH measurements of non-aqueous systems are possible using aqueous calibrations, however, the pH value must be considered as apparent pH, which provides the relative acidity / alkalinity of the system. Several practical difficulties can be encountered while measuring the apparent pH of non-aqueous systems.

[0068] Low H + Ion concentrations can cause inaccurate detection of the electrochemical potential between the glass pH indicator electrode and the test sample, which can result in oscillatory pH measurements, long response times, and inaccurate readings.

[0069] There are other factors that may contribute to these effects: Most pH electrodes are H + It relies on a hydrated gel layer on the outside of the glass beads to detect activity. Dehydration of the gel layer due to the low water content of non-aqueous samples results in slow response times and inaccurate measurements. Non-aqueous systems may have low electrical conductance, therefore H + This reduces the efficiency of the electrical components needed to detect changes in activity. Aqueous buffers used to calibrate pH meters may not be compatible with non-aqueous samples, so the results cannot be interpreted as such.

[0070] The inventors have surprisingly found that the salts of the invention as active ingredients, in particular the maleate salt of the invention, are more stable at pH ≧ 4.0, so the invention also provides, for example, ointment formulations with a pH of around 4.0 (although it is well known that this is the apparent pH due to the very low concentration of aqueous components).

[0071] In this regard, it is important to note that our stability analysis showed apparent pH values ​​ranging from 4 to 7 without any effect on the purity of the API. Therefore, the measured shift in apparent pH had no effect whatsoever on the assay and purity of the salt of the present invention of pritelivir free base form, e.g., in its ointment formulation.

[0072] Thus, in another embodiment, the application relates to a pharmaceutical composition as defined in any one or more of the embodiments further outlined below, wherein the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide maleate salt is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein said ointment is administered 5 times a day, and further wherein said ointment is administered for 4 days.

[0073] In another embodiment, the application relates to a pharmaceutical composition as defined in any one or more of the following embodiments, wherein the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide maleate salt is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is a gel, and wherein said gel is administered 5 times a day, and further wherein said gel is administered for 4 days.

[0074] In another embodiment, the application relates to a pharmaceutical composition as defined in any one or more of the following embodiments, wherein the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide maleate salt is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is a cream, and wherein said cream is administered 5 times a day, and further wherein said cream is administered for 4 days.

[0075] In another aspect of the present invention, the pharmaceutical compositions disclosed herein of the pritelivir salts of the present invention, particularly the maleate salt, may be suitably formulated for systemic, oral, topical or parenteral application.

[0076] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid free base maleate according to the present invention is a compound useful for use in methods for treating and / or preventing infectious diseases and / or in preventing the transmission of infectious diseases. Moreover, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base maleate has high activity in methods for treating / preventing herpes viruses and infections caused by herpes viruses and / or infections caused by the transmission of a herpes virus or multiple herpes viruses.

[0077] The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid free base maleate of the present invention is therefore useful for the preparation of pharmaceutical compositions to be used in methods of treatment and / or prevention of diseases caused by herpes viruses or caused by infection with a herpes virus or multiple herpes viruses.

[0078] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base maleate is particularly useful for use in methods of treating and / or preventing infection caused by herpes simplex virus or in preventing the transmission of a herpes virus or herpes viruses. Herpes simplex virus (HSV, subtypes 1 and 2) infections are classified into one of several distinct diseases based on the site of infection. Orofacial herpes virus infections, the visible symptoms of which are colloquially referred to as herpes simplex or fever blisters, affect the face and mouth. Orofacial herpes is the most common form of infection. Genital herpes is the second most common form of herpes simplex virus infection. Genital herpes is believed to be caused mostly exclusively by HSV-2, although genital HSV-1 infections are on the rise. Other diseases such as herpes simplex, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are also caused by herpes simplex viruses.

[0079] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base maleate is therefore useful in methods for the treatment and / or prevention of infections caused by herpes simplex viruses and / or for use in the prevention of herpes simplex virus transmission.

[0080] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base maleate of the present invention can be administered in combination with other medicamentously active ingredients, such as acetylsalicylic acid and anti-inflammatory agents such as acetaminophen, or (local) anesthetics, or other antiviral agents.

[0081] Combinations of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base maleate salt of the present invention with an anesthetic agent, as well as pharmaceutical compositions comprising such combinations, are another embodiment of the present invention.

[0082] In addition, in another embodiment, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base maleate of the present invention can be combined and used in combination with an antiviral agent. The antiviral agent is preferably an antimetabolite, most preferably a nucleobase analog drug, a nucleotide analog drug, or a nucleoside analog drug. It is more preferred that the antiviral agent is selected from the group of drugs useful against herpes viruses and / or against the transmission of a herpes virus or multiple herpes viruses, including but not limited to trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir or penciclovir or the prodrug of acyclovir, valacyclovir, the prodrug of penciclovir, famciclovir, or valganciclovir.

[0083] The combination of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base maleate salt of the present invention with further active agents such as anti-inflammatory agents, immunomodulators such as therapeutic vaccines, siRNAs, antisense oligonucleotides, nanoparticles, antiviral agents or viral uptake inhibitors such as n-docosanol, may be administered simultaneously in one single pharmaceutical composition or in more than one pharmaceutical composition, wherein each composition comprises at least one active agent.

[0084] The pharmaceutical composition of the present invention can be prepared in conventional solid and conventional pharmaceutical preparations and auxiliary agents in a known manner at appropriate dosage levels.Preferred preparations can be adapted for oral administration.These dosage forms include, for example, pills, tablets, film tablets, coated tablets, sustained release preparations, and capsules.

[0085] The pharmaceutical composition according to the invention may contain 5 to 70% by weight, more preferably 10 to 30% by weight, of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base maleate (all percentage data are weight percent based on the weight of the pharmaceutical preparation).

[0086] The pharmaceutical compositions of the invention may contain the following preservatives: phenoxyethanol, formaldehyde solution, parabens, pentanediol, or sorbic acid.

[0087] As pharma- ceutically acceptable carriers, excipients, and / or diluents, carriers such as preferably inert carriers such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid-filled capsules) can be used, suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycols, and waxes, sugars such as sucrose, starches from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate, and ammonium calcium alginate, cellulosic materials such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate; boric acid, sodium benzoate, sodium acetate, lubricants such as thorium, sodium chloride, magnesium, calcium or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as, for example, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol, and D,L-leucine; disintegrants such as, for example, starch, methylcellulose, guar gum, and modified starches such as, for example, sodium carboxymethyl starch, natural and synthetic gums such as, for example, carob, karaya, guar, tragacanth, and agar, cellulose derivatives such as, for example, methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose, and crosslinked microcrystalline cellulose such as, for example, croscarmellose sodium, alginates such as, for example, alginic acid and sodium alginate, clays such as, for example, bentonite, and effervescent mixtures; colorants, sweeteners, flavors, preservatives; glidents such as, for example, silicon dioxide and talc;Suitable adsorbents are clay, aluminum oxide, suitable diluents are water or water / propylene glycol solutions for parenteral injection, juices, sugars such as lactose, sucrose, mannitol and sorbitol, starches from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose;

[0088] patch The salt compounds according to the present invention, particularly the maleate salt, and pharmaceutical compositions thereof, can also be administered using a patch applied to a part of the body of an organism, e.g., a human, infected with a herpes virus, e.g., HSV-1 and / or HSV-2. More particularly, such a patch according to the present invention comprises a skin adhesive layer, a backing layer and a release liner, the adhesive layer comprising the salt compounds according to the present invention, particularly the maleate salt of the free base form of pritelivir according to the present invention, and / or other active compounds dissolved in a low volatility solvent, and a polymer adhesive soluble in a high volatility solvent. The salt compounds according to the present invention, particularly the maleate salt of the free base form of pritelivir according to the present invention, may be incorporated into the adhesive layer as an antiviral substance in a therapeutically and prophylactically effective amount dissolved in a low volatility solvent, e.g., 0.1-10% by weight of the dry adhesive layer.

[0089] "Solvents" can be classified according to the correlation of their physico-chemical properties. Among others, the basic properties include density, viscosity, dielectric constant, dipole moment, solubility and boiling point. "Solvents" are broadly classified according to the boiling temperature at 1 bar as low, medium or high boiling: low boiling: boiling range below 100°C; medium boiling: boiling range between 100°C and 150°C; high boiling: boiling range above 150°C. Low boiling solvents are highly volatile solvents, whereas high boiling solvents are solvents that tend to be difficult to distill off, such that they are defined as low volatility solvents. An example of a low volatility solvent according to the present invention is dimethyl sulfoxide, which may be present in an amount of 10-50% by weight of the dry adhesive layer. The adhesive polymer is selected from pectin, guar gum, acacia gum, xanthan gum, polyvinyl alcohol, polymethacrylic acid, polymethacrylate, acrylate / alkyl methacrylate copolymer, any acrylic acid ester copolymer, aminoalkyl methacrylate copolymer, polyvinylpyrrolidone, cellulose or a cellulose derivative, such as, for example, hydroxypropylcellulose, hydroxyethylcellulose or mixtures thereof. The adhesive layer may be formed from a solution of the adhesive polymer in a solvent that is highly volatile, i.e. has a low boiling point (in the range of 40°C to 100°C) and a high vapor pressure. The solvent is then usually evaporated off during the manufacturing process, even though a certain amount (up to 15% by weight) may be left in the adhesive layer after drying. The adhesive polymer or adhesive polymer mixture may be present in an amount of 20 to 50% by weight of the dried adhesive layer.

[0090] The patch of the invention may further contain citric acid, succinic acid, lactic acid and their esters as non-polymeric crystallization inhibitors, for example in an amount of 0.5-15% by weight of the dry adhesive layer. The patch may also contain other excipients, for example crosslinkers, penetration enhancers, plasticizers, preservatives, antioxidants, fragrances, emollients, etc. The backing layer may be permeable, semi-occlusive or occlusive, or oxygen permeable, and may have a thickness of, for example, 50-3500 g / m 2It consists of a polyurethane ether or ester film, polyethylene, ethylene vinyl acetate or polyolefin film, with a moisture vapor transmission rate (MVTR) of 100 / day and a thickness of 20-150 μm. The backing layer must be very flexible and soft, transparent or colored, and may be occlusive or sweat-resistant, providing a herpes masking effect. Moreover, it protects the damaged skin and viral lesions from external contact, thereby reducing the patient's pain and the possibility of further contamination or infection, and improving the re-epithelialization process. The adhesive layer is protected from the external environment through a release liner, which must be removed before applying the patch to the body site involved with the viral lesion. Once the patch is applied, through the self-adhesive layer, it delivers the active ingredients into and through the skin for up to 6-24 hours.

[0091] According to the invention, the patch is prepared by a process which involves mixing a solution of adhesive polymer in a highly volatile solvent together with other ingredients, and then casting the mixture on a silicone-coated liner film, followed by drying and final lamination. The highly volatile solvent is evaporated and an adhesive film remains on the release liner, whereas the less volatile solvent remains in the adhesive layer and prevents crystallization of the drug. The polymers used according to the invention are those normally used to manufacture pressure sensitive adhesives (PSAs) or bioadhesive films in organic or aqueous solutions, at concentrations ranging from 20 to 80%, preferably 20 to 50%, of the composition of the adhesive mixture, while the concentration of the highly volatile solvent is 10 to 50%.

[0092] According to the present invention, other components of the adhesive or reservoir layer include thickeners, chemical permeation enhancers, non-polymeric crystallization inhibitors, flavorings, surfactants, crosslinkers, buffers, plasticizers, preservatives, antioxidants, pigments. The selected solvent and polymer must, of course, be miscible with and form a homogeneous solution that can be cast evenly. The low boiling point solvent, i.e., a highly volatile solvent with a boiling point below 100°C, is preferably water, ethanol, methanol, isopropyl alcohol, ethyl acetate, and more preferably water.

[0093] Thus, according to the present invention, it is possible to prepare an anti-herpes patch having an effective amount of the salt compound of the present invention, in particular the maleate salt of the present invention, as an effective drug agent that can be continuously delivered to the application site. The low volatility solvent helps to avoid crystallization by maintaining the active agent in the matrix in a dissolved state so that it reaches the skin and the site of action, and also affects the diffusivity of the drug throughout the matrix. The matrix must be selected according to the physico-chemical properties of the low volatility solvent or solvent mixture. The polymer must provide good adhesion to the final product. The quantitative composition of the adhesive mixture is selected to have a film that is acceptable in thickness, adhesive properties, mechanical resistance, skin adhesion, peelability, and handling. The polymer mixture range in the dry matrix, solubilized in the low boiling point solvent or solvent mixture, is 5-50%, most preferably 20-35%. The solvent percentage ranges from 20-70%, preferably 35-55%, in the mixture to be cast to produce the adhesive layer or reservoir layer. The amount of low boiling point solvent in the dry matrix should not exceed 15% by weight. Instead, low volatility solvents are included in the dry matrix, entrapped in the polymer and dissolving the active ingredient. The amount of these solvents in the dry state is in the range of 10-50%, in particular in the range of 30-55%. Process for producing the salt of the present invention Priterivir free base maleate salt

[0094] [ka]

[0095] Synthesis scheme of the free base maleate salt of pritelivir In another aspect of the invention, a process for preparing the maleate salt of the free base form of pritelivir is provided.

[0096] The process includes the following steps: i) providing a mixing means, preferably a mixing means comprising an overhead stirrer; ii) charging 460-490 g of pritelivir free base into the mixing means of step i); iii) The free base of pritelivir from step ii) is suspended in 3 to 5 times the amount of water; iv) heating the suspension of step iii) to 45-55°C by suitable heating means; v) adding 225-240 g of solid maleic acid over a period of 40-90 minutes until a resulting solution is obtained; vi) Cool the solution obtained in step v) to 44-52°C; vii) introducing an aliquot of the solution of step vi) together with the maleate salt of the free base form of pritelivir; viii) Cooling the resulting suspension of step vii) to 18-24° C. for 1.5-2.5 hours; ix) The suspension of step viii) is subsequently stirred overnight; x) filtering the suspension of step ix) to obtain a resulting filter cake; xi) transferring the solid filter cake obtained in step x) to a mixing means, preferably a flask; xii) Followed by rotary evaporation of the mixture of step xi) for 25-32 hours to obtain a constant weight, applying the following conditions: a. Ambient temperature between 30 and 40 degrees Celsius; b. Pressure between 15 and 25 mbar; xiii) followed by homogenization, preferably using a mortar and pestle; xiv) Obtaining the maleate salt of the free base form of pritelivir according to the present invention.

[0097] In a preferred embodiment of the above process, said process comprises the following steps: i) Prepare a mixing flask equipped with an overhead stirrer; ii) charging about 475.4 g of pritelivir free base into the mixing flask of step i); iii) suspending the free base of pritelivir from step ii) in about 4 volumes of water; iv) heating the suspension of step iii) to about 51° C. by suitable heating means; v) adding about 232 g of solid maleic acid over a period of about 60 minutes until a resulting solution is obtained; vi) cooling the solution obtained in step v) to about 48° C.; vii) introducing an aliquot of the solution of step vi) together with the maleate salt of the free base form of pritelivir; viii) cooling the resulting suspension of step vii) to about 21° C. for about 2 hours; ix) The suspension of step viii) is subsequently stirred overnight; x) filtering the suspension of step ix) to obtain a resulting filter cake; xi) transferring the solid filter cake obtained in step x) to a mixing means, preferably a flask; xii) Followed by rotary evaporation of the mixture of step xi) for about 28 hours to obtain a constant weight, applying the following conditions: a. Ambient temperature of approximately 35°C; b. a pressure of approximately 20 mbar; xiii) followed by homogenization, preferably using a mortar and pestle; xiv) Obtaining the maleate salt of the free base form of pritelivir according to the present invention.

[0098] Other tested salts of the invention The free base form of pritelivir is N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide sulfate Manufacturing process for the sulfate free base form of pritelivir

[0099] [ka]

[0100] Synthesis scheme of the sulfate salt of the free base form of pritelivir General process description: All equivalents, volumes (L / kg) and weights (kg / kg) refer to the weight of the starting material free base of Pritelivir. Pritelivir free base (1 equivalent, 1 wt, 250.0 g) is suspended in water (4.0 vol.) and ethanol (4.0 vol.) in a 2.5 L sulfonation flask equipped with an overhead stirrer. The suspension is heated to 50° C. A solution of sulfuric acid (96%, 1.05 equivalents, 0.256 wt) in water (0.256 vol.) is prepared and the 15% solution is added to the suspension at 50° C. After 5 minutes at 50° C., the suspension turns into a more viscous suspension, which is stirred at 50° C. for an additional 150 minutes. The remaining aqueous sulfuric acid solution is added to the suspension during 75 minutes at 50° C. The suspension is cooled to 21° C. during 3 hours and stirred at 21° C. for 13 hours. The suspension is filtered and the filter cake is washed with a mixture of water (0.8 vol.) and ethanol (0.8 vol.). After desolvation of the filter cake on the filter, the solid is transferred to a flask and dried to constant weight by rotary evaporator (35° C., <20 mbar, 6 h).

[0101] IPC: 93.59% dry mass (160°C). 294.43 g of the sulfate salt of pritelivir free base (94.7% yield not corrected for assay).

[0102] Characterization of the sulfate free base form of pritelivir. Ethanol content by NMR: <100 ppm (below limit of quantification). Water content by Karl Fischer titration: 6.33% w / w (monohydrate 3.5%, dihydrate 6.7% w / w). Assay by NMR: 95.3% w / w as monosulfate (estimated monosulfate content by NMR is higher than Karl Fischer titration). 76.6% w / w as pritelivir free base. Sulfate: 18.1% w / w, theoretical (monohydrate monosulfate): 18.9% w / w, (estimated, (different free base) vs. (100%-water content)). 19.4% w / w (estimated from elemental analysis and NMR assay) (priterivir free base).

[0103] Elemental analysis: [Table 1]

[0104] Special process description for the sulfate salt of pritelivir free base The free base of pritelivir suspended in 1 L of ethanol and 1 L of water is heated to a temperature of 50° C. 0.16 equivalents of sulfuric acid are added during 1 minute. After about 5 minutes, a viscous suspension is formed. Stirring for about another 2 hours is followed to obtain a stirred suspension, and 0.9 equivalents of sulfuric acid are added during 75 minutes at a temperature of 50° C. The suspension is cooled to room temperature and stirred for a further 18 hours. Filtration, washing with 0.4 L of ethanol / water 1 / 1 (v / v) and drying in vacuum are followed.

[0105] result: Crude sulfate salt of pritelivir free base was obtained: 294.4 g of a white solid (dry mass: 93.6% (160° C.), <100 ppm ethanol). Sulfate Content: Not determined (estimated from elemental analysis). NMR: 85.7% w / w estimated as monosulfate TGA: 6.48% weight loss Karl Fischer: 6.23% w / w water Grade (purity): 250G Product (% theory): 94.7 (uncorrected)

[0106] The free base form of pritelivir is N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide hemiethane-1,2-disulfonate Manufacturing process for the ethane-1,2-disulfonate salt of the free base form of pritelivir

[0107] [ka]

[0108] Synthesis scheme of the ethane-1,2-disulfonate salt of the free base form of pritelivir Overview of the manufacturing process for the ethane-1,2-disulfonate salt of the free base form of pritelivir:

[0109] All equivalents, volumes (L / kg) and weights (kg / kg) refer to the weight of the starting material free base of Pritelivir. Pritelivir free base (1 equivalent, 1 wt, 250.0 g) is suspended in water (4.0 vol.) and ethanol (4.0 vol.) in a 2.5 L sulfonation flask equipped with an overhead stirrer. The suspension is heated to 53° C. A solution of ethane-1,2-disulfonic acid (0.60 equivalent, 0.312 wt) in water (0.31 vol.) is prepared and a 15% solution is added to the suspension at 53° C. The suspension is introduced (0.02% w / w) and after 45 minutes the addition of the acid solution is continued for 10 minutes. The suspension is stirred at 53° C. for 90 minutes, cooled to 21° C. during 3 hours and stirred at 21° C. for 13 hours. The suspension is filtered and the filter cake is washed with a mixture of water (0.8 vol.) and ethanol (0.8 vol.). After desolvation of the filter cake on the filter, the solid is transferred to a flask and dried to constant weight by rotary evaporator (35° C., <20 mbar, 3 h).

[0110] result: IPC: 96.84% dry mass (160°C). 305.12 g of crude pritelivir free base form ethane-1,2-disulfonic acid salt (98.7% yield not corrected for assay). Characterization of the ethane-1,2-disulfonate free base form of pritelivir Ethanol content by NMR: Not detected. Water content by Karl Fischer titration: 3.48% w / w (monohydrate 1.8%, dihydrate 3.5% w / w). Assay by NMR: 95.6% w / w as the hemisulfonate salt. 77.3% w / w as the free base.

[0111] Special process description for the ethane-1,2-disulfonate salt of the free base form of pritelivir The free base of pritelivir is suspended in 1 L of ethanol and 1 L of water and heated to a temperature of 54° C. 0.09 equivalents of ethane-1,2-disulfonic acid (11.6 g) are dissolved in 11.6 g of water and filtered through a syringe filter. The ethane-1,2-disulfonic acid solution is added to the free base suspension during 1 minute. Ethane-1,2-disulfonic acid salt seeds are added. The suspension is stirred for 40 minutes at 54° C. 0.51 equivalents of ethane-1,2-disulfonic acid (66.4 g) are dissolved in water (66 g, syringe filtered) at 54° C. during 1 hour. Stirring at 54° C. for 90 minutes follows. The mixture is cooled to room temperature and stirred at room temperature for an additional 18 hours. Filtration, washing with ethanol / water 1 / 1 (v / v, 0.4 L) and drying in vacuum are followed.

[0112] result: Crude ethane-1,2 disulfonate: 305.1 g white solid (dry mass: 96.8% at 160 °C, no ethanol visible by NMR). Ethane-1,2-disulfonic acid content: 0.53 equivalents (NMR) NMR: 95.6% w / w estimated as the hemi-salt. Karl Fischer: 3.48% w / w water Grade (purity): 250g Product (% theory): 98.7 (uncorrected)

[0113] The free base form of pritelivir is N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamidobenzenesulfonate Manufacturing process for the benzenesulfonate salt of the free base form of pritelivir

[0114] [ka]

[0115] 1. Synthesis scheme of the benzenesulfonate salt of the free base form of pritelivir. Overview of the manufacturing process for the benzenesulfonate salt of the free base form of pritelivir

[0116] All equivalents, volumes (L / kg) and weights (kg / kg) refer to the weight of the starting material, pritelivir free base. In a 2.5 L sulfonation flask equipped with an overhead stirrer, pritelivir free base (1 equivalent, 1 wt, 250.0 g) is suspended in water (4.0 vol.) and ethanol (4.0 vol.). The suspension is heated to 53° C. A solution of benzenesulfonic acid monohydrate (1.0 equivalent, 0.442 wt) in water (0.15 vol.) is prepared and a 15% solution is added to the suspension at 50° C. The suspension is introduced (0.02% w / w) and after 30 minutes the addition of the acid solution is continued for 90 minutes. The suspension is cooled to 21° C. during 3 hours and stirred at said 21° C. for 14 hours. The suspension is filtered and the filter cake is washed with a mixture of water (0.8 vol.) and ethanol (0.8 vol.). After desolvation of the filter cake on the filter, the solid was transferred to a flask and dried to constant weight by rotary evaporator (35° C., <20 mbar, 4 h).

[0117] result: IPC: 99.63% dry mass (160°C). 322.51 g of the benzenesulfonate salt of the free base form of pritelivir (92.6% yield not corrected for assay). Characterization of the free base benzenesulfonate salt of pritelivir. Ethanol content by NMR: 500 ppm Water content by Karl Fischer titration: 0.17% w / w (monohydrate 3.1% w / w) Assay by NMR: 102.1% w / w as the benzenesulfonate salt. 73.4% w / w as free base

[0118] Description of the special process for the benzenesulfonate salt of the free base form of pritelivir The free base of pritelivir is suspended in 1 L of ethanol and 1 L of water and heated to a temperature of 52°C. 0.15 equivalents of benzenesulfonic acid (16.4 g) are added as a solution in water (6.3 g) during 1 minute. Seeds of the benzenesulfonate salt of the free base form of pritelivir are added and stirred for 30 minutes at a temperature of 52°C. 0.85 equivalents of benzenesulfonic acid (94.0 g) are added as a solution in water (30.5 g) during 90 minutes. The mixture is cooled to room temperature. Stirring at room temperature for about 18 hours is then followed by filtration, washing with 0.4 L of ethanol / water 1 / 1 (v / v) and drying in vacuum.

[0119] result: Crude benzenesulfonate salt of the free base form of pritelivir: 322.5 g of white solid (dry mass: 99.6% (160° C.)). 500ppm ethanol Benzenesulfonic acid content: 0.93 equivalents (NMR) NMR: 102.1% w / w estimated as monosulfate TGA: 0.15% weight loss Karl Fischer: 0.17% w / w water Grade (purity): 250g Product (% theory): 92.6 (uncorrected)

[0120] The free base form of pritelivir is N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide ethanesulfonate Manufacturing process for the ethanesulfonate salt of the free base form of pritelivir

[0121] [ka]

[0122] Synthesis scheme of the ethanesulfonate salt of the free base form of pritelivir Overview of the manufacturing process for the ethanesulfonate free base salt of pritelivir

[0123] All equivalents, volumes (L / kg) and weights (kg / kg) refer to the weight of the starting free base of Plitelivir. Plitelivir free base (1 equivalent, 1 wt, 250.0 g) is suspended in water (4.0 vol.) and ethanol (4.0 vol.) in a 2.5 L sulfonation flask equipped with an overhead stirrer. The suspension is heated to 55°C. Ethanesulfonic acid (1.56 equiv., 0.427 wt.) is dissolved in water (0.43 vol.) and added during 50 min. The suspension is cooled to 21° C. during 3 h (at around 38° C. a viscous suspension may form) and is followed by further stirring at 21° C. for 14 h. The suspension is filtered and the filter cake is washed with a mixture of water (0.8 vol.) and ethanol (0.8 vol.). After desolvation of the filter cake on the filter, the solid is transferred to a flask and dried to constant weight by rotary evaporator (35° C., <20 mbar, 4 h).

[0124] result: IPC: 96.31% dry mass (160°C). 314.28 g of crude ethanesulfonate salt of the free base form of pritelivir (98.7% yield not corrected for assay). Characterization: Ethanol content by NMR: 220 ppm Water content by Karl Fischer titration: 3.35% w / w (monohydrate 3.4% w / w). Assay by NMR: 95.0% w / w as the maleate salt. 72.1% w / w as the free base.

[0125] Description of the manufacturing process for the ethanesulfonate salt of the free base form of pritelivir The free base of pritelivir is suspended in 1 L of ethanol and 1 L of water and heated to a temperature of 60° C. 1.56 equivalents of ethanesulfonic acid (106.8 g) are dissolved in water (107 g) and added to the suspension during 50 min. The suspension is cooled to room temperature and further stirred for 18 h. It is followed by filtration, washing with 0.4 L of ethanol / water 1 / 1 (v / v) and drying in vacuum.

[0126] result: Crude ethanesulfonate salt of the free base form of pritelivir: 314.3 g white solid (dry mass: 96.3% (160°C)) 200ppm Ethanol (NMR) 1 equivalent of ethanesulfonic acid (NMR) NMR: 95.0% w / w estimated as monoesylate salt TGA: 3.46% weight loss Karl Fischer: 3.35% w / w water Grade (purity): 250g Product (% theory): 98.7 (uncorrected)

[0127] Conclusion: In addition to the maleate salt of the free base form of pritelivir of the present invention, the inventors have further surprisingly discovered four additional salts, which are as follows: i) They are all crystalline; ii) all contain water; iii) NMR data showed no residual ethanol present which would be outside the scope of this specification. iv) DSC shows expected morphological changes for all salts, and v) All of the identified salt forms of the present invention are physico-chemically stable at 40° C. / 75% relative humidity for 4 weeks.

[0128] In accordance with the above context, the following consecutively numbered embodiments provide other specific aspects of the present invention:

[0129] 1. The maleate salt of the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide.

[0130] In addition to embodiment 1, the present invention also provides the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir.

[0131] 2. The maleate salt is resistant to light exposure at wavelengths ranging from 300 nm to 800 nm for at least 29 hours, at a light exposure of at least 1.2 million Lux hours, and at least 200 Wh / m 2 The maleate salt of embodiment 1, characterized by a photostability of at least 70% retention of the free base of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide after light exposure to a light exposure energy of 100 nm, wherein said photostability is measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0132] 3. The maleate salt of any one of the preceding embodiments, further characterized by having characteristic XRPD peaks at 6.6, 15.9, 16.2, 18.1, 20.5, 22.5, 26.1, and 28.6 2θ, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0133] 4. The maleate salt according to any one of the preceding embodiments, wherein the maleate salt is physico-chemically stable, characterized by a recovery of at least 85% of the starting concentration of the maleate salt after storage for 2 weeks in aqueous solution at room temperature and a pH of 3.5 to 7.0, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0134] 5. The maleate salt according to any one of the preceding embodiments, wherein the maleate salt is characterized by a solubility in water of about 0.48 mg / mL, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0135] 6. 6. The pharmaceutical composition comprising the maleate salt according to any one of embodiments 1 to 5, wherein the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient.

[0136] In addition to embodiment 6, the pharmaceutical formulations disclosed herein also provide the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir.

[0137] 7. A photostable pharmaceutical composition obtainable by formulating the maleate salt according to any one of embodiments 1 to 5 together with at least one pharma- ceutically acceptable excipient.

[0138] 8. The pharmaceutical composition according to embodiment 6 or 7, further comprising another medicament active ingredient selected from the group consisting of anti-inflammatory agents, antiviral agents, centrally or peripherally acting analgesics, (local) anesthetics.

[0139] In addition to embodiment 8, similarly, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir disclosed herein may also be combined into a pharmaceutical formulation with another pharma- ceutical active ingredient selected from the group consisting of anti-inflammatory agents, antiviral agents, centrally or peripherally acting analgesics, and (local) anesthetics.

[0140] 9. The pharmaceutical composition of embodiment 8, wherein the local anesthetic is lidocaine.

[0141] 10. The pharmaceutical composition according to any one of embodiments 6 to 8, further comprising an ultraviolet light blocking agent selected from the group comprising: Octisalate, titanium dioxide, zinc oxide, PABA, homosalate, trolamine salicylate, dioxybenzone, sulisobenzone, oxybenzone, avobenzone, ecamsule, melazimate, cinoxate, octocrylene.

[0142] In addition to embodiment 10, similarly, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir disclosed herein may also be combined in a pharmaceutical formulation with an ultraviolet light blocking agent selected from the group including Octisalate, titanium dioxide, zinc oxide, PABA, homosalate, trolamine salicylate, dioxybenzone, sulisobenzone, oxybenzone, avobenzone, ecamsule, melazimate, cinoxate, octocrylene.

[0143] 11. A topical pharmaceutical formulation comprising the maleate salt according to any one of embodiments 1 to 5, wherein the formulation further comprises a formulation for patch administration, a cream, an ointment, an ointment, a gel, a skin lotion, a wax formulation, a lipstick, a tonic, a mousse, a foam, a film, an emulsion, a paste, a solution, an oil, and a lipogel.

[0144] In addition to embodiment 11, in another aspect of the present invention, the free base forms of pritelivir sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate may also be further included in the formulations for patch administration, creams, ointments, salves, gels, skin lotions, wax formulations, lipsticks, tonics, mousses, foams, films, emulsions, pastes, solutions, oils, and lipogels.

[0145] 12. The topical pharmaceutical formulation according to embodiment 11, wherein said maleate salt has an average recovery percentage of about 95-105% when measured according to ICH guideline Q1B.

[0146] 13. 13. The topical pharmaceutical formulation according to any one of embodiments 11-12, wherein said maleate salt has an average purity ranging from 95-105%, preferably about 100% area / area, as measured according to ICH guideline Q1B.

[0147] 14. 14. The pharmaceutical composition or topical pharmaceutical formulation according to any one of embodiments 6 to 13, wherein said maleate salt is present in dissolved form in an amount of 0.1 to 10% w / w as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0148] 15. 15. The pharmaceutical composition or topical pharmaceutical formulation according to any one of embodiments 6 to 14, wherein said maleate salt is present in an amount of 3.0-8% w / w as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0149] 16. 16. The pharmaceutical composition or topical pharmaceutical formulation according to any one of embodiments 6 to 15, wherein said maleate salt is present in an amount of 4-7% w / w as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0150] 17. 17. The pharmaceutical composition or topical pharmaceutical formulation according to any one of embodiments 6 to 16, wherein said maleate salt is present in an amount of 5.0% w / w as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0151] 18. 18. The topical pharmaceutical formulation according to any one of embodiments 11 to 17, wherein said maleate salt is present in an amount of 1.0 to 10% w / w, in particular 5.0% w / w, and wherein said topical pharmaceutical formulation is an ointment, and wherein said ointment is administered 1 to 10 times per day, 2 to 10 times per day, 3 to 8 times per day, 3 to 7 times per day, 4 to 6 times per day, or 5 times per day.

[0152] 19. 19. The topical pharmaceutical formulation according to any one of embodiments 11-18, wherein said maleate salt is present in an amount of 1.0-7.5% w / w, in particular 5.0% w / w, and wherein said topical pharmaceutical formulation is an ointment, and wherein said ointment is administered 1-10 times per day, 2-10 times per day, 3-8 times per day, 3-7 times per day, 4-6 times per day or 5 times per day, and wherein said ointment is administered for a period of 2-14 days, 3-10 days, 3-7 days, 4-5 days, or for 5 or 4 days.

[0153] 20. 20. The topical pharmaceutical formulation according to any one of embodiments 11-19, wherein said maleate salt is present in an amount of 5.0% w / w and said topical pharmaceutical formulation is an ointment and said ointment is administered 5 times a day and said ointment is administered for a period of 4 days.

[0154] In an embodiment adjacent to embodiment 20, the maleate salt is present in an amount of 5.0% w / w and the topical pharmaceutical formulation is a gel and the gel is administered five times daily and the gel is administered for a period of four days.

[0155] In an embodiment adjacent to embodiment 20, the maleate salt is present in an amount of 5.0% w / w and the topical pharmaceutical formulation is a cream and the cream is administered 5 times daily and the cream is administered for a period of 4 days.

[0156] Further to embodiment 20, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also present in an amount of 5.0% w / w, and said topical pharmaceutical formulation is either an ointment, gel, or cream, and said ointment, gel, or cream is administered five times a day, and said ointment, gel, or cream is administered for a period of four days.

[0157] twenty one. The topical pharmaceutical formulation of any one of embodiments 11-20, wherein the maleate salt is present in an amount sufficient to achieve a concentration of at least > 10 nM in the epidermis and dermis at least 1 hour after application to a subject individual in a topical treatment method with the composition, as measured using a compendial method according to "Ph. Eur" and / or "USP" methods.

[0158] twenty two. The topical pharmaceutical formulation according to any one of embodiments 11 to 21, wherein said topical pharmaceutical formulation has an apparent pH of 3.5 to 7.0, in particular 4.0 to 5.0, when measured using a compendial method according to "Ph. Eur" and / or "USP" methods.

[0159] twenty three. A topical pharmaceutical formulation according to any one of embodiments 11 to 22, wherein said maleate salt has a physico-chemical stability of at least 85% after 2 weeks of storage at room temperature and at an apparent pH of 3.5 to 7.0, in particular 4.0 to 5.0, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

[0160] twenty four. The maleate salt according to any one of embodiments 1 to 5, for use as a medicament.

[0161] In addition to embodiment 24, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use as a medicament.

[0162] twenty five. The maleate salt according to any one of embodiments 1 to 5, for use in a method for the treatment and / or prophylaxis of herpes infections.

[0163] Further to embodiment 25, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in methods for the treatment and / or prevention of herpes infections.

[0164] 26. The maleate salt according to any one of embodiments 1 to 5, for use in the treatment and / or prevention of herpes infections, wherein said herpesvirus is selected from the order Simplex Virales.

[0165] In addition to embodiment 26, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in a method for the treatment and / or prophylaxis of a herpes infection, wherein the herpesvirus is selected from the order Simplex Viridae.

[0166] 27. The maleate salt for use according to any one of embodiments 25 to 26, wherein the simplex virus is selected from herpes simplex virus 1 or herpes simplex virus 2.

[0167] In addition to embodiment 27, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in a method for the treatment and / or prophylaxis of a herpes infection, wherein the herpesvirus is selected from the order Simplex Viridae.

[0168] 28. A method for treating or inhibiting the occurrence of, or inhibiting the transmission of, herpes simplex virus subtype 1 or 2 infection, comprising administering to a subject in need thereof an effective amount of the free base form of the maleate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] as defined in any one of embodiments 1 to 5.

[0169] Further to embodiment 28, there is provided a method for treating or suppressing the occurrence of, or suppressing the transmission of, herpes simplex virus subtype 1 or 2 infection, comprising administering to a subject in need thereof an effective amount of a salt selected from the group consisting of sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate of the free base form of pritelivir disclosed herein.

[0170] 29. The maleate salt according to any one of embodiments 1 to 5, for use in an oral pharmaceutical formulation in the treatment of a subject in need thereof.

[0171] In addition to embodiment 29, the free base forms of sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate of pritelivir are also provided for use in oral pharmaceutical formulations in treating subjects in need thereof.

[0172] 30. The maleate salt according to any one of embodiments 1 to 5, for use in an oral pharmaceutical formulation in the treatment and / or prevention of herpes infections, and in particular herpes simplex infections, in a subject in need thereof.

[0173] In addition to embodiment 30, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in oral pharmaceutical formulations in the treatment and / or prevention of herpes infections, particularly herpes simplex infections, in subjects in need thereof.

[0174] 31. The maleate salt according to any one of embodiments 1 to 5, for use in a topical pharmaceutical formulation in the treatment of a subject in need thereof.

[0175] In addition to embodiment 31, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in topical pharmaceutical formulations in treating subjects in need thereof.

[0176] 32. The maleate salt according to any one of embodiments 1 to 5, for use in topical administration to a subject in need thereof, wherein said topical administration includes application to the skin and mucosal surfaces, such as application to the face, lips, genitals, and eyes.

[0177] In addition to embodiment 32, the free base forms of sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate of pritelivir are also provided for use in topical administration to a subject in need thereof, wherein said topical administration includes application to the skin and mucosal surfaces, e.g., application to the face, lips, genitals, and eyes.

[0178] 33. The maleate salt according to any one of embodiments 1 to 5, for use in systemic administration to a subject in need thereof.

[0179] In addition to embodiment 33, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in systemic administration to a subject in need thereof.

[0180] 34. The maleate salt according to any one of embodiments 1 to 5, for use in a method for the treatment and / or prevention of recurrent herpes labialis.

[0181] Further to embodiment 34, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for use in methods for the treatment and / or prevention of recurrent herpes labialis.

[0182] 35. The maleate salt according to any one of embodiments 1 to 5 for use in a method for the treatment and / or prevention of recurrent herpes labialis selected from the group of patients showing signs of the prodromal stage of herpes labialis, patients suffering from erythema, patients showing labial papules, patients suffering from labial vesicles, patients suffering from ulcers and / or soft crusts on the lips, patients suffering from hard crusts on the lips, patients suffering from residual labial erythema.

[0183] In addition to embodiment 35, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts in the free base form of pritelivir are also provided for use in a method for the treatment and / or prevention of recurrent herpes labialis selected from the group of patients exhibiting signs of the prodromal stage of herpes labialis, patients suffering from erythema, patients exhibiting labial papules, patients suffering from labial vesicles, patients suffering from ulcers and / or soft crusts on the lips, patients suffering from hard crusts on the lips, patients suffering from residual labial erythema.

[0184] 36. The maleate salt according to any one of embodiments 1 to 5, for use in a method for the treatment and / or prevention of vulvar herpes.

[0185] 37. The maleate salt according to any one of embodiments 1 to 5 for use in the treatment and / or prevention of herpetic keratitis.

[0186] 38. The maleate salt according to any one of embodiments 1 to 5, for use in the treatment and / or prophylaxis of herpes meningitis and / or herpes encephalitis.

[0187] 39. The maleate salt according to any one of embodiments 1 to 5, for use in the treatment and / or prevention of herpes infections in newborns.

[0188] 40. The maleate salt according to any one of embodiments 1 to 5, for use in the treatment and / or prevention of herpes infections in immunocompetent and / or immunocompromised individuals.

[0189] Similarly, in addition to the contents of embodiments 36 to 40, the free base forms of pritelivir sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate also apply.

[0190] 41. The maleate salt according to any one of embodiments 1 to 5, wherein said immunocompromised individual is selected from the group comprising organ transplant recipients, individuals suffering from another viral or bacterial infection, in particular an infection by HIV and / or another herpes virus, and individuals infected with a herpes simplex virus that is resistant to at least one antiviral action.

[0191] 42. A method for the treatment and / or prevention of herpes infections, comprising administering to a subject in need thereof a maleate salt according to any one of embodiments 1 to 5.

[0192] In addition to embodiment 42, the sulfate, hemiethane-1,2-disulfonate, benzenesulfonate, and ethanesulfonate salts of the free base form of pritelivir are also provided for the aforementioned uses and methods of treatment.

[0193] 43. A process for the preparation of the maleate salt of the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide according to any one of the first to fifth embodiments, said process comprising the steps of: i) providing a mixing means, preferably a mixing means comprising an overhead stirrer; ii) charging 460-490 g of pritelivir free base into the mixing means of step i); iii) The free base of pritelivir from step ii) is suspended in 3 to 5 times the amount of water; iv) heating the suspension of step iii) to 45-55°C by suitable heating means; v) adding 225-240 g of solid maleic acid over a period of 40-90 minutes until a resulting solution is obtained; vi) Cool the solution obtained in step v) to 44-52°C; vii) introducing an aliquot of the solution of step vi) together with the crude maleate salt of the free base form of pritelivir; viii) Cooling the resulting suspension of step vii) to 18-24° C. for 1.5-2.5 hours; ix) The suspension of step viii) is subsequently stirred overnight; x) filtering the suspension of step ix) to obtain a resulting filter cake; xi) transferring the solid filter cake obtained in step x) to a mixing means, preferably a flask; xii) Followed by rotary evaporation of the mixture of step xi) for 25-32 hours to obtain a constant weight, applying the following conditions: a. Ambient temperature between 30 and 40 degrees Celsius; b. Pressure between 15 and 25 mbar; xiii) followed by homogenization, preferably using a mortar and pestle; xiv) Obtaining the maleate salt of the free base form of pritelivir according to the present invention.

[0194] 44. The process of embodiment 43, comprising the steps of: i) Prepare a mixing flask equipped with an overhead stirrer; ii) charging about 475.4 g of pritelivir free base into the mixing flask of step i); iii) suspending the free base of pritelivir from step ii) in about 4 volumes of water; iv) heating the suspension of step iii) to about 51° C. by suitable heating means; v) adding about 232 g of solid maleic acid over a period of about 60 minutes until a resulting solution is obtained; vi) cooling the solution obtained in step v) to about 48° C.; vii) introducing an aliquot of the solution of step vi) together with the crude maleate salt of the free base form of pritelivir; viii) cooling the resulting suspension of step vii) to about 21° C. for about 2 hours; ix) The suspension of step viii) is subsequently stirred overnight; x) filtering the suspension of step ix) to obtain a resulting filter cake; xi) transferring the solid filter cake obtained in step x) to a mixing means, preferably a flask; xii) Followed by rotary evaporation of the mixture of step xi) for about 28 hours to obtain a constant weight, applying the following conditions: a. Ambient temperature of approximately 35°C; b. a pressure of approximately 20 mbar; xiii) followed by homogenization, preferably using a mortar and pestle; xiv) Obtaining the maleate salt of the free base form of pritelivir according to the present invention.

[0195] The following examples are included to demonstrate preferred embodiments of the present invention. It should be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques disclosed by the inventors to function well in the practice of the present invention, and therefore can be considered to follow preferred modes for said practice.

[0196] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this specification. Thus, this specification is to be construed as illustrative only and is intended to teach those skilled in the art the general manner of carrying out the invention. It can be understood that the forms of the invention shown and described herein can be considered as examples of embodiments. After utilizing this specification of the invention in its entirety, elements and materials may be substituted for those illustrated and described herein, parts and steps may be interchanged, and certain features of the invention may be utilized independently, as will likely be apparent to those skilled in the art. EXAMPLES

[0197] Common analytical methods applied: Melting point by DSC Principle: Differential scanning calorimetry with power compensation. Equipment: DSC system (DSC822e-Mettler Toledo) / analytical microbalance. Procedure: A precisely weighed amount of sample (typically 1-5 mg) is placed into a clean, dry aluminum crucible and closed with a drilled aluminum cap. The second crucible is a reference crucible. Conditions: Starting temperature: 20℃ Heating rate: 10℃ / min End temperature: 300℃ Atmosphere: N2 (flow rate 20 mL / min)

[0198] TGA volatiles Principle: Thermogravimetric method. Apparatus: TGA851e instrument including oven, oven temperature sensor and sample temperature sensor / aluminum oxide pan / analytical microbalance. Procedure: An empty aluminum oxide pan is used to obtain a background curve. Then, a precisely weighed amount of sample (typically 10 mg) is placed into a clean, dry pan. The counting is performed as described in the analytical instructions. Conditions: Starting temperature: 25℃ Heating rate: 5℃ / min End temperature: 300℃ Atmosphere: N2 (flow rate 50 mL / min)

[0199] 1 H NMR Equipment:Bruker AVANCE 400MHz Solvent: DMSO-D6 or CDCl3 Internal standard: tetramethylsilane (TMS) or solvent peak Decoupling: Inverse gated decoupling Assay: The assay is measured using a macro in ACD / Spac Manager 9 by comparing the integrated area of ​​the compound with that of an internal standard (typically hydroquinone dimethyl ether).

[0200] Optical microscopy using a hot stage Equipment: Olympus BX41 with Di-Li 5MP camera and grab and measure software; Hotstage Mettler Toledo FP90 with FP82 heating table. Method: Samples are prepared with a brush on the objective holder. Observations are made at 40, 100, 200 or 400x magnification, using unpolarized light or polarized light with two polarizing filters. Photographs are taken by software and exported as JPEG, scale is only approximate and not verified.

[0201] X-ray powder diffraction Apparatus: Rigaku Corporation MiniFlex (diameter 24 mm, pit 0.2 mm) using a silicon low background sample holder. Tube: Cu, λ=1.54056Å, 15kV method: Angle: 2θ=2Å~2θ=40Å Sampling width 0.02[2θ] Measurement time: 75 minutes. Preparation: When a sufficient amount has been isolated, the sample is ground using a mortar and pestle; this leads to more consistent results, less preferential orientation, and better handling of materials with large grain sizes. The solid placed on the sample holder is prepared using grease and flattened using a glass disc.

[0202] HPLC Common in-house methods are used to estimate purity and measure solubility in solution. Column: Phenomenex Luna 3μm C18 (50×4.6mm) Detection: DAD detector, recorded at 254 nm Diluent: 0.5mg / mL in ACN / H2O 1:1 + 1% TFA Eluate: A = "H2O + 0.05% CF3COOH" B = "CH3CN + 0.05% CF3COOH" method: Injection: 5μL Flow rate: 1.0mL / min

[0203] Min eluate 0.00% A=90.0 % B=10.0 0.10% A=90.0 % B=10.0 10.1% A=10.0 % B=90.0 12.1% A=10.0 % B=90.0 13.1% A=90.0 % B=10.0 15.1% A=90.0 % B=10.0

[0204] Example Identification of the free base form of the maleate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide

[0205] Structural confirmation by single crystal XRD (SCXRD) Concentrated solutions of the maleate salt of the present invention were subjected to various crystallization experiments, including various techniques such as, for example, by cooling, by distillation, by vapor diffusion, or by crystallization from the melt.

[0206] I.1 Powder X-ray diffraction pattern of the free base maleate of pritelivir Apparatus and methods used Sample preparation: To obtain the powder diffraction pattern of the resulting maleate solid, a sample of about 20 mg was prepared in a standard sample holder using two pieces of polyacetate foil.

[0207] Data collection: Powder diffraction patterns were acquired on a Bruker D8 Advance Series 2 Theta / Theta powder diffraction system using CuKα1 radiation (1.54060 A) in transmission geometry. The system was equipped with a VANTEC-1 single-photon counting PSD, a Germanium monochromator, a 90-position autotranslating sample stage, a fixed divergence slit, and a radial solar.

[0208] Programs used: Data collection with DIFFRAC and XRD Commander V.2.4.1 and evaluation with EVA V.12.0 and Microsoft Excel™. Samples were measured in a 20 min scan in the 2θ range of 4°-40° (step size: 0.016°), see Figures 7-11. The characteristic peaks in Figures 10-11, for example, allow one skilled in the art to verify that the maleate salt is a pure crystalline solid.

[0209] The physical characterization of the free base maleate salt of pritelivir referred to herein was performed using compendial methods in accordance with the European Pharmacopoeia (Ph. Eur) and / or the US Pharmacopeial Convention (USP).

[0210] All experiments provided solids by crystallization, but most were powders or at best very small single crystals (aggregated into clusters) that were not suitable for SCXRD analysis. Suitable small crystals were obtained by cooling crystallization in acetone and used for SCXRD measurements, but larger crystals were obtained by vapor diffusion after some weeks (Methyl Ethyl Ketone / Ethyl Acetate, Methyl Ethyl Ketone / Diethyl Ether and Acetone / Diethyl Ether, not used for SCXRD measurements).

[0211] Data for structure determination were collected at low temperature (100 K). The asymmetric unit contains one molecule of a cationic organic compound and one molecule of a maleate anion. The structure is apparently a salt with maleic acid.

[0212] In the maleate molecule of the present invention, one of the carboxyl groups showed a clearly different bond distance from the oxygen atom (1.22 vs. 1.32 Å), suggesting a protonation reaction of the oxygen atom with a longer bond. The experimental residual electron density confirmed the presence of a hydrogen atom because it was clearly localized at the expected position. Meanwhile, the second carboxyl group of the maleate showed a bond distance consistent with an oxygen atom (1.26 vs. 1.27 Å), but the electron density was not localized at the distance expected for a hydrogen atom. Both the identical bond distance and the missing electron density confirm the presence of a carboxylate group. In the organic molecule, a hydrogen atom can be clearly identified from the residual electron density, located at the expected position close to the nitrogen atom of the pyridine ring, confirming the cationic form of the molecule.

[0213] The maleate salt of the present invention forms an intramolecular hydrogen bond between both carboxyl groups, which should stabilize the structure and its anionic form. In addition, the carboxylate forms a hydrogen bond with the hydrogen of the pyridine ring. In the crystal packing, it can be observed that the maleate salt of the present invention creates several additional weak interactions with the organic molecule, which should further stabilize the structure. The structure is of excellent quality (R1: 3.81%). All relevant hydrogen atoms were experimentally localized from the residual electron density.

[0214] The PXRD pattern simulated from the single crystal data closely resembles the experimental PXRD pattern of the maleate salt of the present invention during phase 1 (see Figures 7-11), demonstrating that the bulk and measured single crystal correspond to the same crystalline phase.

[0215] A series of crystallization experiments of the maleate salt of the present invention were carried out in various solvents. One cooling crystallization experiment and three vapor diffusion experiments provided crystals suitable for SCXRD.

[0216] Table 1: List of solvents used for single crystal XRD experiments [Table 2]

[0217] The crystal structure of the maleate salt of the present invention was analyzed to confirm that the molecule is a salt. The predicted PXRD pattern from single crystal measurements corresponds to that of the maleate salt of the present invention, a Phase 1 standard.

[0218] I.2 The maleate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide offers advantages over the free base and the mesylate salt

[0219] Various salts according to the invention, namely: sulfate, ethanesulfonate, maleate, benzenesulfonate, hemiethane-1,2-disulfonate, free base and mesylate of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide, were successfully scaled up and subsequently tested in more detail with regard to their solubility and stability properties.

[0220] I.3 Solubility characteristics of the free base form of pritelivir maleate in water and related formulation vehicles (for oral route of administration)

[0221] [Table 3]

[0222] I.4 Determination of solubility in various pharmaceutical excipients The purpose of the study was to determine the solubility of pritelivir free base, its mesylate, its sulfate, its monoethanesulfonate, its maleate, its monobenzenesulfonate and its hemiethane-1,2-disulfonate in 30% Captisol®, 30% hydroxypropyl-β-cyclodextrin (HP-β CD), ethanol, propylene glycol (PG), and polyethylene glycol (PEG 400) at ambient temperature. Dimethyl sulfoxide (DMSO) served as the control solvent.

[0223] material Test items Reference item: Priterivir free base MW free form: 402.5g / mol Purity: 99% Batch number: BX01AWL Micronized Test items: Priterivir mesylate free base Priterivir free base sulfonate Priterivir free base monoethanesulfonate salt Priterivir free base maleate salt Priterivir free base monobenzenesulfonate salt Priterivir free base form hemiethane-1,2-disulfonate

[0224] method Sample preparation Suspensions were prepared by weighing the test items into glass vials and adding the appropriate solvent. The suspensions were vortex mixed briefly and shaken overhead for 22 hours. An aliquot (500 μL) was transferred to a filtration device equipped with a polyvinylidene fluoride membrane and the solids were separated by centrifugation. The filtrate was diluted (1:100) with acetonitrile / methanol / water / acetic acid (25+25+50+0.5, v+v+v+v).

[0225] Control solutions of all salts were prepared in DMSO at a concentration of 20 mg / mL and treated as described above. Solubility was determined by concentration measurements of diluted filtrates of supersaturated solutions.

[0226] Calibration and QC Samples Calibration samples were prepared covering the range of 20.0-1001 μg / L. QCs were prepared at three different concentration levels (50.0, 300, and 801 μg / mL) for within-batch control.

[0227] Chromatography and detection Chromatographic separation was performed on a Phenomenex Luna C18(2), 5 μm column (150×2 mm) by gradient elution with 1% acetic acid and acetonitrile / methanol (1+1, v+v) containing 1% acetic acid. A diode array detector was used for detection. Absorbance was recorded at a wavelength of 300 nm. A detailed method description was filed in the source data folder.

[0228] Data Evaluation All calculations were performed in Microsoft Excel 2010. Average data were presented as arithmetic means.

[0229] result: Priterivir free base, its mesylate, its sulfonate, its monoethanesulfonate, its maleate, its monobenzenesulfonate, and its hemiethane-1,2-disulfonate were dissolved in Captisol®, HP-β-cyclodextrin (HP-β CD), ethanol, propylene glycol (PG), and polyethylene glycol (PEG400) at ambient temperature. Dimethyl sulfoxide (DMSO) served as the control solvent.

[0230] The highest solubilities were found in 30% Captisol® and 30% β-cyclodextrin solutions for all salts. In Captisol®, the maximum soluble concentrations under the applied test conditions ranged from 18.5 to 37.6 mg / mL. Similar concentrations were found in β-cyclodextrin ranging from 21.0 to 37.7 mg / mL. The free base of pritelivir showed significantly lower solubility with values ​​of 1.79 and 1.91 mg / mL in Captisol® and β-cyclodextrin, respectively.

[0231] The lowest concentrations were observed in ethanol and were similar for the free base and all salts, ranging from 0.197 to 0.485 mg / mL. Greater variations in solubility were measured in PG and PEG. The sulfate salt showed the highest concentration in PG at 12.5 mg / mL, followed by the mesylate salt at 11.6 mg / mL, the monoethanesulfonate salt, and the maleate salt at 5 to 6 mg / mL. The lowest solubility was measured in the hemiethane-1,2-disulfonate salt at 0.769 mg / mL. In PEG, the free base of pritelivir showed the highest concentration at 89.6 mg / mL. The solubility of the maleate salt in PEG was found to be 32.2 mg / mL. All other salts showed values ​​≤15.2 mg / mL. Recoveries from DMSO solutions ranged from 93.0 to 109%, confirming the suitability of the assay.

[0232] The highest solubilities were found in 30% Captisol® and 30% β-cyclodextrin solutions for all salts. In Captisol®, the maximum soluble concentrations under the applied test conditions ranged from 18.5 to 37.6 mg / mL. Similar concentrations were found in β-cyclodextrin ranging from 21.0 to 37.7 mg / mL. The free base of pritelivir showed significantly lower solubility with values ​​of 1.79 and 1.91 mg / mL in Captisol® and β-cyclodextrin, respectively.

[0233] The lowest concentrations were observed in ethanol and were similar for the free base and all salts, ranging from 0.197 to 0.485 mg / mL. Greater variations in solubility were measured in PG and PEG. The sulfate showed the highest concentration in PG at 12.5 mg / mL, followed by the mesylate at 11.6 mg / mL, the monoethanesulfonate and the maleate at 5 to 6 mg / mL. The lowest solubility was measured in the hemiethane-1,2-disulfonate at 0.769 mg / mL. In PEG, the free base showed the highest concentration at 89.6 mg / mL. The solubility of the maleate salt in PEG was found to be 32.2 mg / mL. All other salts showed values ​​≦15.2 mg / mL. For details, see Figures 48-49.

[0234] I.5 Solubility in simulated gastric and intestinal fluids (n=3, unless otherwise stated): The objective of this study was to determine the relative solubilities of monoethanesulfonate, maleate, monobenzenesulfonate and hemiethane-1,2-disulfonate in fasted-state simulated gastric fluid (FaSSGF), fed-state simulated intestinal fluid (FeSSIF) and fasted-state simulated intestinal fluid (FaSSIF). The relative solubility of pritelivir free base and its mesylate salt was determined in more detail and used as a benchmark.

[0235] material Test items Test item: Monoethanesulfonate MW monoethanesulfonate: 530.6g / mol MW free form: 402.5g / mol Purity: 99% Batch number: Carbogen-NE-023931-Z-0-2-VV4 Test item: Maleate MW Maleate: 939.1 g / mol MW free form: 402.5g / mol Purity: 99% Batch number: Carbogen-NE-023931-Z-0-2-VV3 Test item: Monobenzenesulfonate MW monobenzenesulfonate: 578.7g / mol MW free form: 402.5g / mol Purity: 99% Batch number: Carbogen-NE-023931-Z-0-2-VV2 Test item: Hemiethane-1,2-disulfonate MW hemiethane-1,2-disulfonate: 1013.2g / mol MW free form: 402.5g / mol Purity: 99% Batch number: Carbogen-NE-023931-Z-0-2-VV1

[0236] Reference item: Priterivir free base MW Priterivir free base form: 402.5 g / mol Purity:nd Batch number: BHC-BXO1AWL Micronized Reference item: Mesylate MW Mesylate: 516.2 g / mol MW free form: 402.5g / mol Purity: 99.8% Batch number: BHC-BXR3NC1 Micronized

[0237] Matrix Fasted state artificial gastric juice (FaSSGF) SIF Powder Original was added to sodium chloride solution (34.2 mM, pH 1.6) to obtain a final concentration of 0.06 g / L.

[0238] Fasted state simulated intestinal fluid (FaSSIF) A buffer consisting of 10.5 mM sodium hydroxide (MW 40), 28.7 mM sodium dihydrogen phosphate (MW 119.98) and 106 mM sodium chloride (MW 58.44) was prepared. The pH was adjusted to 6.5 by the addition of 1 N hydrochloric acid. SIF Powder Original was added to obtain a final concentration of 2.24 g / L.

[0239] Feed-state simulated intestinal fluid (FeSSIF) A buffer consisting of 101 mM sodium hydroxide (MW 40), 144 mM glacial acetic acid (MW 60.05) and 203 mM sodium chloride (MW 58.44) was prepared. The pH was adjusted to 5 by the addition of 1 N hydrochloric acid. SIF Powder Original was added to obtain a final concentration of 11.2 g / L.

[0240] method All samples were prepared in triplicate with three separate initial weights.

[0241] Sample preparation Suspensions of monoethanesulfonate, maleate, monobenzenesulfonate, hemiethane-1,2-disulfonate, mesylate or pritelivir free base were prepared in triplicate by weighing approximately 12 mg of test item and adding 600 μL of FaSSGF, FaSSIF or FeSSIF (final concentration 20 mg / mL). The suspensions were incubated at 37°C. After 0, 0.5, 1 and 2 hours, aliquots (100 μL) were transferred to centrifugation devices (polyvinylidene difluoride membrane, 0.2 μm) for removal of solids (approximately 15000×g and 37°C for 10 min). FaSSGF filtrate was diluted with acetonitrile to a final dilution of 1:1000. FaSSIF filtrate was diluted with acetonitrile to a final dilution of 1:50 and FeSSIF filtrate was diluted with acetonitrile to a final dilution of 1:100.

[0242] Calibration and QC-Samples Calibration and quality control solutions of the mesylate free base form of pritelivir were prepared in acetonitrile / DMSO 4+1 (v+v). 10 μL calibration or quality control solution was added to methanol / water (1+1, v+v) containing an internal standard (i.e., stable isotope of pritelivir free base, 1000 μg / L in methanol / water (1+1, v+v) + 1% acetic acid). Calibration samples were prepared in the range of 10-1000 μg / L. Quality control samples were prepared at three different levels (25, 300, and 800 μg / L) as within-batch controls.

[0243] Chromatography and detection Chromatographic separation was performed on a Phenomenex Luna PFP(2), 3 μm column (100×2 mm) by gradient elution with 1% acetic acid and acetonitrile / methanol (1 / 1, v / v) containing 1% acetic acid as the mobile phase. For detection, a triple stage mass spectrometer (3200 QTrap) was used and operated in positive multi-stage reaction observation mode (MRM transition 403.6→196.3).

[0244] The samples were analyzed for their free base content of pritelivir. Since the pH of the artificial fluid did not change significantly with the addition of small amounts of sample, the stability of the free base in the medium was not considered, and therefore differences in the rate of hydrolysis of the base were not expected. Since no hydrolysis products were detected, only the relative solubility was used for further evaluation of the results.

[0245] Results and Discussion The relative solubilities of monoethanesulfonate, maleate, monobenzenesulfonate, hemiethane-1,2-disulfonate, free base of pritelivir and its mesylate salt were measured in FaSSGF, FaSSIF and FeSSIF during 2 hours of incubation at 37°C. The monoethanesulfonate salt showed the highest relative solubility of all test items in the investigated media FaSSGF, FaSSIF and FeSSIF. The solubility of hemiethane-1,2-disulfonate salt in FaSSGF was found to be higher than that of maleate and monobenzenesulfonate salts. In FaSSIF and FeSSIF, maleate, monobenzenesulfonate and hemiethane-1,2-disulfonate salts showed essentially similar concentrations. The abnormal concentration decrease over time in FaSSGF and FaSSIF may be partly explained by the hydrolysis of the free base observed in some experimental settings. Since the hydrolysis products were not measured, only the relative solubility should be used for further evaluation of the results. The solubility of the reference articles pritelivir free base and its mesylate salt was found to be as expected and in good agreement with previous studies. The summarized results are shown in FIG.

[0246] According to the data presented in FIG. 47, the tested salts demonstrate a significant advantage over the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide under FeSSIF conditions, where their solubility profile is significantly higher than that of the free base.

[0247] In contrast, under FaSSIF conditions, only the test salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide demonstrated benefits over the free base in terms of enhanced dissolution properties only over a short period of time, i.e., 30 minutes.

[0248] The solubility of the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide salt was also determined in water and in the presence of different pharmaceutical excipients in comparison to its free base.

[0249] The free base showed the lowest solubility of 0.00130 mg / mL in water. The sulfate, monoethanesulfonate, maleate, monobenzenesulfonate and hemiethane-1,2-disulfonate salts showed similar solubilities with a range ranging from 0.175 to 0.606 mg / mL. The corresponding pH ranged from 3.03 to 3.69. The highest solubility was measured for the mesylate salt, which was found to dissolve in water up to 1.20 mg / mL at a pH of 2.8. These results indicate that pH has a large effect on solubility. Counterions with higher acidity led to lower pH and higher solubility. See Figure 47 herein for results.

[0250] The free base, mesylate, sulfate, ethanesulfonate, maleate, benzenesulfonate and hemiethane-1,2-disulfonate salts were also tested for their solubility characteristics in Captisol®, hydroxypropyl-β-cyclodextrin (hereafter abbreviated HP-β CD), ethanol, propylene glycol (hereafter abbreviated PG) and polyethylene glycol 400 (hereafter abbreviated PEG 400) at ambient temperature. Dimethyl sulfoxide (hereafter abbreviated DMSO) served as the control solvent.

[0251] Surprisingly, the inventors found that the salts tested exhibited significantly higher (i.e., more than 10-fold higher) solubility in aqueous cyclodextrin solutions when the salts contained 30% Captisol® and 30% hydroxypropyl-β-cyclodextrin (HP-β CD).

[0252] The highest solubilities were seen for all tested salts in 30% Captisol® and 30% HP-β CD solutions. In Captisol®, the maximum soluble concentrations at the applied test conditions ranged from 18.5 to 37.6 mg / mL. Similar concentrations were seen in HP-β CD with values ​​ranging from 21.0 to 37.7 mg / mL. The free base showed significantly lower solubilities in Captisol® and HP-β CD with values ​​of 1.79 and 1.91 mg / mL, respectively.

[0253] The lowest concentrations were observed in ethanol and were similar for the free base and all salts tested, ranging from 0.197 to 0.485 mg / mL. Greater changes in dissolution properties were measured with PG and PEG.

[0254] The sulfate salt showed the highest concentration in PG at 12.5 mg / mL, followed by the mesylate salt at 11.6 mg / mL, the monoethanesulfonate salt and the maleate salt at 5-6 mg / mL. The lowest solubility was measured for hemiethane-1,2-disulfonic acid at 0.769 mg / mL. In PEG400, the free base of pritelivir showed the highest concentration at 89.6 mg / mL. The solubility of the maleate salt in PEG was found to be 32.2 mg / mL. All other salts showed values ​​≤15.2 mg / mL. Recoveries from DMSO solutions ranged from 93.0 to 109%, confirming the suitability of the test assay. For detailed results, see Figure 47.

[0255] Example II - Stability Measurements The objective of the study was to determine the stability of pritelivir free base and its mesylate, sulfate, monoethanesulfonate, maleate, monobenzenesulfonate and hemiethane-1,2-disulfonate salts in 30% Captisol®, 30% hydroxypropyl-β-cyclodextrin (HP-β CD), ethanol, propylene glycol (PG) and polyethylene glycol (PEG400) at ambient temperature and 50° C. over a period of two weeks. Additionally, the solubility of pritelivir free base and the aforementioned salts in water was determined and the resulting pH was measured.

[0256] material Test items Reference item: Priterivir free base MW free form: 402.5g / mol Purity: 99% Batch number: BX01AWL Micronized Test items: Priterivir mesylate free base Priterivir free base sulfonate Priterivir free base monoethanesulfonate salt Priterivir free base maleate salt Priterivir free base monobenzenesulfonate salt Priterivir free base form hemiethane-1,2-disulfonate

[0257] method Sample preparation Suspensions were prepared by weighing the test items into glass vials and adding the appropriate solvent. The suspensions were vortex mixed briefly and shaken overhead for 22 hours. Aliquots (500 μL) were transferred to filtration devices equipped with polyvinylidene fluoride membranes and the solids were separated by centrifugation. The filtrates were diluted (1:50 to 1:500) with acetonitrile / methanol / water / acetic acid (25+25+50+0.5, v+v+v+v). Stability and solubility were determined by concentration measurements of the diluted filtrates of supersaturated solutions.

[0258] Calibration and QC Samples Calibration samples were prepared covering the range of 20.0-1001 μg / L. QCs were prepared at three different concentrations (50.0, 300, and 801 μg / mL) for within-batch control.

[0259] Chromatography and detection Chromatographic separation was performed on a Phenomenex Luna C18(2), 5 μm column (150×2 mm) by gradient elution with 1% acetic acid and acetonitrile / methanol (1+1, v+v) containing 1% acetic acid. A diode array detector was used for detection. Absorbance was recorded at a wavelength of 300 nm.

[0260] Data Evaluation All calculations were performed in Microsoft Excel 2010. Average data were presented as arithmetic means. Recoveries were calculated relative to the measured starting concentration (t0).

[0261] II.1 Short-term stability of the free base and various salts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in pharmaceutical excipients:

[0262] All investigated salts and the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide showed stability over 2 weeks in 30% Captisol®, 30% HP-β CD, ethanol, propylene glycol and polyethylene glycol when stored at ambient temperature and protected from light for 2 weeks. Only the free base showed a slight decrease in ethanol, PEG and propylene glycol after 2 weeks.

[0263] Surprisingly, all tested salts showed sufficient solubility in all pharmaceutical excipients after two weeks at ambient temperature; see FIG. 50.

[0264] After storage at 50°C, the free base showed stability in aqueous media containing 30% Captisol® and 30% HP-β CD, with recoveries relative to the measured starting concentration of 103% and 88.9%, respectively. Minor decomposition was observed in polyethylene glycol, with a recovery of 78.3%. More significant instability was noted in ethanol and propylene glycol, where recoveries of 21.3% and 0% were observed after 2 weeks at 50°C. After storage at 50°C, the mesylate, sulfate, monoethanesulfonate, maleate, monobenzenesulfonate, and hemiethane-1,2-disulfonate salts were found to be stable in 30% Captisol®, 30% HP-β CD, ethanol, and propylene glycol, with recoveries relative to the measured starting concentration of ≧85% after 2 weeks.

[0265] The ethanesulfonate, benzenesulfonate, and hemiethane-1,2-disulfonate salts showed degradation in polyethylene glycol after 2 weeks of storage at 50° C. Recoveries were measured at 80.1%, 74.7%, and 75.4% for the ethanesulfonate, benzenesulfonate, and hemiethane-1,2-disulfonate salts, respectively. The mesylate, sulfate, and benzenesulfonate salts showed stability in polyethylene glycol after 2 weeks of storage at 50° C.

[0266] Surprisingly, the tested salts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mentioned above, including the maleate salt, showed improved stability in pharmaceutical excipients even after 2 weeks of storage at accelerated conditions at 50° C.; see FIG. 51 for further details.

[0267] Example III - Photostability study of the free base and tested salts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide

[0268] The test objective is 2000Wh / m 2 The objective of this study was to determine the photostability of priterivir free base according to the present invention versus its salts, i.e., mesylate, sulfate, monoethanesulfonate, maleate, monobenzenesulfonate, and hemiethane-1,2-disulfonate, after exposure to UV light (at a wavelength of >310 nm for approximately 29 hours).

[0269] Compounds were exposed as solids and dissolved in 0.1 M HCl / acetonitrile (75+25, v+v) at a target concentration of 0.3 mg / mL. Corresponding dark control samples were prepared and kept in UV light-tight vials in the irradiation chamber, equivalent to ambient conditions. Additionally, untreated solids were dissolved and analyzed as reference samples. All samples were prepared and irradiated at A&M Labor fur Analytik und Metabolismusforschung Service GmbH (A&M 15-034). After processing, samples were deep frozen and stored until shipment to AiCuris where the analysis was performed.

[0270] III.1-Materials Reference and test items Reference item: Priterivir free base MW free form: 402.5g / mol Purity: 99% Batch number: BX01AWL Micronized

[0271] Test item batch number Priterivir free base (Batch BXR2KVE) Priterivir mesylate free base (Batch Car-NE023932Batch05-2010) Priterivir free base sulfonate (Batch Carbogen-NE-021681-A-1-3 unpurified 1#1) Priterivir free base monoethanesulfonate salt (Batch Carbogen-NE-026323-A-1-1 crude 1#1) Priterivir free base maleate salt (Batch Carbogen-NE-026322-A-1-1 unpurified 1#1) Priterivir free base monobenzenesulfonate salt (Batch Carbogen-NE-026321-A-1-1 unpurified 1#1) Priterivir free base form hemiethane-1,2-disulfonate salt (Batch Carbogen-NE-026320-A-1-1 crude 1#1)

[0272] III.2-Method All samples were prepared and irradiated at A&M Labor fur Analytik und Metabolismusforschung Service GmbH (A&M 15-034). After processing, samples were deep frozen and stored until shipment to AiCuris where the analysis was performed.

[0273] Preparation of solid samples Two samples were prepared from each solid test article. Approximately 20 mg of each test article (corrected for free base) was weighed into a quartz glass vial. A second aliquot was weighed into a light-proof glass vial (dark control). Both samples were placed in the illumination chamber.

[0274] Preparation of solutions Approximately 20 mg of each test article (corrected for free base) was weighed and dissolved in 0.1 M hydrochloric acid / acetonitrile (75+25, v+v) to give a constant concentration of 300 μg / mL of pritelivir free base. Two aliquots were prepared (illuminated and dark control samples).

[0275] Dark control samples were stored in sealed and light-tight glass vials in the illumination chamber, while light stress solutions were stored in quartz flasks with only loose quartz glass covers. During illumination, samples partially evaporated due to heat generation in the illumination chamber. The degree of evaporation varied from sample to sample (the sulfate salt of pritelivir free base evaporated almost completely). Therefore, to ensure comparability between the different solutions and to the respective dark control samples, the illumination solutions were filled to the initial volume with 0.1 M hydrochloric acid / acetonitrile (75+25, v+v).

[0276] irradiation Samples (solution and solid) were subjected to 765Wh / m through a glass filter for 29 hours. 2 The sample was irradiated with a xenon lamp at 1000 Hz (total UV light application was approximately 2000 Wh / m 2 ). The instrument used was a Suntest CPS+ (Atlas). The use of a glass filter allowed only wavelengths >310 nm to be irradiated, simulating the ID65 standard (indoor indirect sunlight standard). The irradiated light also included the full VIS spectrum. The average chamber temperature recorded was 38°C. After irradiation, all samples were flash frozen and stored until analysis.

[0277] Sample preparation for chromatography The irradiated solids and dark controls were thawed and 2-3 mg were weighed and dissolved in 0.1 M hydrochloric acid / acetonitrile (75+25, v+v) at a concentration of 3 mg / mL. The solution was then diluted with 0.1 M hydrochloric acid / acetonitrile (75+25, v+v) to a final concentration of 0.3 mg / mL. The solution was thawed and transferred to a new glass vial for analysis.

[0278] Chromatography and detection The % peak area was determined for pritelivir free base in all test samples. Chromatographic separation was performed on a Phenomenex Luna C18(2), 5 μm column (150×2 mm) by gradient elution with 1% acetic acid and acetonitrile / methanol (1+1, v+v) containing 1% acetic acid. A diode array detector was used for detection. Absorbance was recorded at a wavelength of 280 nm. A detailed method description was filed in the source data folder.

[0279] Data Evaluation All samples (solids and solutions) were dissolved or diluted with 0.1 M hydrochloric acid / acetonitrile (75+25, v+v) to a final concentration of approximately 0.3 mg / mL prior to analysis. The extent of degradation was measured by chromatographic separation of the (UV-active) degradation products and by measuring their respective percentage of the total peak area per chromatogram (% total peak area). The peak area of ​​pritelivir free base was measured in all samples, since the salt dissociates in solution.

[0280] Due to chromatographic problems, dark control samples of the irradiated solutions of sulfate and hemiethane-1,2-disulfonate were reanalyzed in separate batches including dark controls of pritelivir free base and its mesylate salt as reference samples. Thus, the % peak areas of pritelivir free base and its mesylate salt were reported as the average of n=2. All calculations were performed in Microsoft Excel 2010.

[0281] III.4 Results and Discussion Unprocessed solid forms of pritelivir free base and its salts were found to be very stable when stored flash frozen at % total peak area of ​​pritelivir free base ranging from 99.7 to 100%. Individual degradation products were observed at % total peak area ≤ 0.5%. The solid free base and solid salts exhibited a % total peak area of ​​≤ 2000 Wh / m 2The drug showed good stability upon irradiation with UV light at a total dose of 100 mg / kg / day. No significant degradation was observed in the solutions of the irradiated solids and the corresponding dark control samples. A single degradation product was observed in small amounts with a %total peak area of ​​≤0.5%. The measured %total peak area of ​​pritelivir free base ranged from 97.4% to 100%.

[0282] Dark control samples of acidic solutions demonstrated good photostability of pritelivir free base with % total peak areas ranging from 97.4 to 98.3% for solutions of pritelivir free base, its mesylate salt, its monoethanesulfonate salt, its maleate salt and its monobenzenesulfonate salt. Slight degradation was observed for the sulfate salt and hemiethane-1,2-disulfonate salt where 95.7 and 94.7% of the total peak areas were observed to be associated with pritelivir free base. A single impurity was observed with % peak area ≤ 1.58%.

[0283] The irradiated solution is 2000Wh / m 2 showed a high degree of degradation after 29 hours at a total dose of 100 mg / kg. The free base of pritelivir was found to have a % total peak area of ​​6.67-11.9% in solutions of pritelivir free base, its mesylate, its sulfate, its monoethanesulfonate, its monobenzenesulfonate and its hemiethane-1,2-disulfonate. The main degradation product (relative retention time 0.85) was observed in solutions of pritelivir free base and all salts (except maleate) with a % total peak area of ​​27.8-36.2%. Three other degradation products (RRT 0.64, 0.67 and 0.87) were detected reaching a total peak area of ​​more than 10% in the same solutions. The dissolved maleate salt of pritelivir free base showed significantly less degradation. After 29 hours of irradiation with UV light, pritelivir free base represented 71.5% of the total peak area. The major degradation product with RRT 0.85, which was also seen for the other test articles, was observed at 14.7% total peak area. All other degradation products were found to be ≦3.3% total peak area.

[0284] For further details: The solid free base and solid salts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide tested have a maximum energy density of 2000 Wh / m 2 The solid showed sufficient stability against irradiation with UV light at a total dose of 100 mg / kg / day. No significant degradation was observed in the solutions of the irradiated solids and the corresponding dark control samples. Individual degradation products were found in small amounts with a % total peak area of ​​≦0.5%. The measured peak areas of the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide ranged from 97.4% to 100%, as shown in Figures 45-46 and 52-53.

[0285] The irradiated solution is 2000Wh / m 2 The free base showed a high degree of degradation after 29 h at a total dose of 0.67%. The free base was found to have a % total peak area of ​​6.67-11.9% in test solutions containing the free base, mesylate, sulfate, monoethanesulfonate, monobenzenesulfonate and hemiethane-1,2-disulfonate salts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide. The main degradation product (exhibiting a relative retention time of 0.85 (RRT)) was observed in solutions of the free base and all tested salts (except the maleate) with a % total peak area of ​​27.8-36.2%. Three other degradation products (RRTs of 0.64, 0.67 and 0.87) were detected reaching a total peak area of ​​more than 10% in the same solutions.

[0286] Surprisingly and unexpectedly, the dissolved maleate salt showed little decomposition. After 29 hours of irradiation with UV light, the residual free base content corresponded to 71.5% of the total peak area. The main decomposition product with RRT 0.85, which was also seen for the other tested salts, was observed at 14.7% of the total peak area. All other decomposition products were found to be ≦3.3% total peak area.

[0287] The % total peak area with respect to the content of the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in the tested illuminated solutions and in the respective dark controls are shown in Figures 45-46 and 52-53.

[0288] Surprisingly and unexpectedly, the maleate salt showed significantly higher photostability; i.e. 71.5% of the total peak area of ​​the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide compared to 11.9% of the total peak area of ​​the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide with the salt and the free base tested simultaneously.

[0289] Example IV - Further characterization of the maleate salt of the free base form of pritelivir The maleate salt of the free base form of pritelivir according to the present invention is 1 H-NMR and 13 It was further characterized by C-NMR, FT-IR, UV-Vis and Mass Spectrometry.

[0290] IV.1 Apparatus and methods used 1 H and 13 C nuclear magnetic resonance Proton and carbon nuclear magnetic resonance analyses were recorded in deuterated dimethyl sulfoxide (DMSO-d6) on a Bruker-AV500Mhz NMR spectrometer. Spectra were obtained by dissolving 10-20 mg of sample in 0.6 mL of deuterated solvent. Number of scans: 128 ( 1 H-NMR), 2048( 13 C-NMR).

[0291] Fourier transform infrared spectroscopy FTIR spectra were recorded using an Agilent Cary 630 spectrometer equipped with a Diamond single reflection ATR system. A background was obtained before each measurement and the spectra were recorded from 4000 to 600 cm. -1 Within 4cm -1 The images were acquired with 128 scans at a resolution of .

[0292] UV visible spectroscopy UV-Vis measurements were carried out at room temperature in 1 cm quartz cuvettes on a Shimadzu UV-2401PC spectrophotometer equipped with a photomultiplier tube detector, dual beam light, and D2 and W light sources. For sample preparation, the samples were dissolved in acetonitrile (25 g / mL) and then analyzed by UV-visible spectroscopy in the wavelength range of 200-900 nm.

[0293] mass spectrometry Mass spectra were acquired on a Bruker Daltonics HLPC MS TOF MicroTOF II with a mass range of 50-20000 m / z, a resolution of 16500 FWHM (full width at half maximum) at m / z 1220 and a mass accuracy of ≦5 ppm. Ionization mode used: ESI Negative.

[0294] IV.2 Results: 1 H-NMR and 13 C-NMR analysis The proton and carbon NMR spectra of the free base form of pritelivir maleate salt in deuterated DMSO (see Figures 12 and 14 and the tables in Figures 13 and 15) showed no significant impurities.

[0295] FTIR analysis The FTIR spectrum of the maleate salt of the free base form of pritelivir is shown in FIG. 16 and the corresponding peak list is available in the table of FIG.

[0296] UV-Vis analysis The UV-Vis spectra (ranging from 200-900 nm) of the free base form of the maleate salt of pritelivir in acetonitrile (4 g / mL solution) are shown in Figures 18-19.

[0297] mass spectrometry The mass spectrum of the maleate salt of the free base form of pritelivir is shown in Figures 20-21.

[0298] Example V - Preparation V.1 Representative process for the preparation of the free base form of the maleate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide

[0299] In this example relating to a process for the preparation of the maleate salt according to the invention, all equivalents, volumes (specified in L / kg) and weights (specified in kg / kg) refer to the weight of the starting material, pritelivir free base.

[0300] In a 5 L flask equipped with overhead stirring, the free base of Pritelivir (1 equivalent, 1 wt, 475.4 g) was suspended in water (4.0 vol.) and ethanol (4.0 vol.). The suspension was heated to 51°C. Maleic acid (2.0 equivalents, 0.576 wt) was added as a solid over a period of 1 hour. Towards the end of the acid addition, the suspension was almost completely dissolved and turned into a solution after the addition was complete. The solution was cooled to 48°C and introduced (an aliquot of the solution was introduced along with the crude maleate salt of the free base form of Pritelivir). The suspension was allowed to cool to 21°C (within approximately 2 hours) and stirred overnight.

[0301] The suspension was filtered and the resulting filter cake was washed with a mixture of water (0.8 vol.) and ethanol (0.8 vol.). After desolvation of the filter cake on the filter, the solid was transferred to a flask and dried to constant weight by a rotary evaporation device (Rotavapor®) (at a temperature of 35° C. and <20 mbar for 28 hours). The resulting maleate material was homogenized with a mortar and pestle.

[0302] V.2 Characterization of the material obtained in Example V.1 IPC: 99.26% dry mass (Ta 160℃). 289.29 g of crude maleate salt of the free base form of pritelivir (89.6% yield not corrected for assay). Ethanol content measured by NMR: 1520 ppm Water content determined by Karl Fischer titration: 3.4% w / w (monohydrate 3.4% w / w) Assay as determined by NMR: 98.7% w / w as maleate salt / 76.6% w / w as free base

Claims

1. The maleate salt of the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.

2. The maleate salt has a wavelength ranging from 300 nm to 800 nm for at least 29 hours, a light exposure of at least 1.2 million Lux hours, and a light energy of at least 200 Wh / m 2 2. The maleate salt of claim 1, characterized by a photostability of at least 70% retention of the free base of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide after light exposure to a light exposure energy of 100 nm, wherein said photostability is measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

3. 3. The maleate salt of any one of claims 1 to 2, further characterized in that the maleate salt has characteristic XRPD peaks at 6.6, 15.9, 16.2, 18.1, 20.5, 22.5, 26.1, and 28.6 2θ, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

4. 4. The maleate salt according to any one of claims 1 to 3, wherein the maleate salt is physico-chemically stable, characterized by a recovery of at least 85% of the starting concentration of the maleate salt after storage for 2 weeks in aqueous solution at room temperature and a pH between 3.5 and 7.0, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

5. 5. The maleate salt of any one of claims 1 to 4, wherein the maleate salt is characterized by a solubility in water of about 0.48 mg / mL as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

6. 6. A pharmaceutical composition comprising the maleate salt of any one of claims 1 to 5, wherein the pharmaceutical composition further comprises at least one pharma- ceutically acceptable excipient.

7. A photostable pharmaceutical composition obtainable by formulating the maleate salt according to any one of claims 1 to 5 together with at least one pharma- ceutically acceptable excipient.

8. 8. The pharmaceutical composition according to claim 6 or 7, further comprising another medicamentously active ingredient selected from the group consisting of anti-inflammatory agents, antiviral agents, centrally or peripherally acting analgesics, (local) anesthetics.

9. 9. The pharmaceutical composition of any one of claims 6 to 8, further comprising an ultraviolet light blocking agent selected from the group including octisalate, titanium dioxide, zinc oxide, PABA, homosalate, trolamine salicylate, dioxybenzone, sulisobenzone, oxybenzone, avobenzone, ecamsule, melazimate, cinoxate, and octocrylene.

10. 6. A topical pharmaceutical formulation comprising the maleate salt of any one of claims 1 to 5, wherein the formulation further comprises formulations for patch administration, creams, ointments, salves, gels, skin lotions, wax formulations, lipsticks, tonics, mousses, foams, films, emulsions, pastes, solutions, oils, and lipogels.

11. 11. The topical pharmaceutical formulation of claim 10, wherein said maleate salt has an average recovery percentage of about 95-105% when measured according to ICH guideline Q1B.

12. 12. The pharmaceutical composition or topical pharmaceutical formulation according to any one of claims 6 to 11, wherein the maleate salt is present in dissolved form in an amount of 0.1 to 10% w / w as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

13. 13. The topical pharmaceutical formulation of any one of claims 10 to 12, wherein the maleate salt is present in an amount sufficient to reach a concentration of at least > 10 nM in the epidermis and dermis at least 1 hour after application to a subject individual in a topical treatment method with the composition, as measured using compendial methods according to "Ph. Eur" and / or "USP" methods.

14. A maleate salt according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 6 to 13 for use in a method for the treatment and / or prophylaxis of herpes infections.

15. A process for the preparation of the maleate salt of the free base form of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide according to any one of claims 1 to 5, comprising the steps of: i) providing a mixing means, preferably a mixing means equipped with an overhead stirrer; ii) charging 460-490 g of pritelivir free base into said mixing means of step i); iii) suspending the free base of pritelivir from step ii) in 3-5 volumes of water; iv) heating the suspension of step iii) to 45-55°C by suitable heating means; v) adding 225-240 g of maleic acid in solid form over a period of 40-90 minutes until a resulting solution is obtained; vi) cooling the solution obtained in step v) to 44-52° C.; vii) introducing an aliquot of the solution of step vi) together with the crude maleate salt of the free base form of pritelivir; viii) Cooling the resulting suspension of step vii) to 18-24° C. for 1.5-2.5 hours; ix) The suspension of step viii) is subsequently stirred overnight; x) filtering the suspension of step ix) to obtain a resulting filter cake; xi) transferring the solid filter cake obtained in step x) to a mixing means, preferably a flask; xii) Followed by rotary evaporation of the mixing means of step xi) for 25-32 hours to obtain a constant weight, applying the following conditions: a. Ambient temperature between 30 and 40°C; b. a pressure of 15 to 25 mbar; xiii) followed by homogenization, preferably using a mortar and pestle; xiv) obtaining the maleate salt of the free base form of pritelivir according to the present invention; The manufacturing process includes:

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