Pralsetinib free base hemihydrate, methods of making and uses thereof

Abstract

The present invention relates to N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate, processes for its manufacture and uses. In particular, the present invention relates to the use of the above-mentioned compound for the treatment of human herpes virus infections and for the preparation of a medicinal product comprising said compound. The present invention is in the field of antiviral active agents.

Description

[0001] This application is a divisional application of the application with international application date 28 November 2017, international application number PCT / EP2017 / 080653, entered into the Chinese national phase on 27 May 2019, application number 201780073223.2, entitled "N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate, processes for its manufacture and uses thereof". TECHNICAL FIELD

[0002] The present invention relates to the field of antiviral active agents, in particular to a free base hemihydrate form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide (hereinafter also referred to as "Pritelivir" and / or "free base hemihydrate") and processes for its manufacture. The present invention further relates to the use of the above-mentioned compound for the treatment of human herpes virus infections and for the manufacture of a pharmaceutical product comprising said compound. BACKGROUND

[0003] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]-acetamide is a known antiviral compound for the treatment of herpes simplex viruses (herpes simplex virus 1 and herpes simplex virus 2, respectively) as disclosed in WO2006103011A1. HSV-1 and / or HSV-2 infections are the cause of diseases such as cold sores (mainly due to infection with HSV-1), genital herpes (mainly due to HSV-2 infection), but can also rarely cause severe diseases such as keratitis and encephalitis. The viruses are widely distributed throughout the world. A well-known drug for the treatment of herpes simplex infections is acyclovir (2-amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one), which is a specific inhibitor of the viral DNA polymerase.

[0004] Antiviral drugs against herpes viruses can be administered to patients in various ways, for example systemically, topically and parenterally. As with all drugs, the stability upon storage and in or to the patient upon or in the patient is of utmost importance. Although the stability of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide is already good, it is an aim to provide even more stable, such as more storage- and light-stable, compounds which provide pharmaceutical compositions with an extremely high purity. SUMMARY

[0005] The stability of the compounds of the present application ensures that pharmaceutical compositions formulated to contain N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate have a significantly reduced amount of decomposition / degradation products. In other words, the active ingredient is present in a higher purity (i.e. a lower amount of degradation products) or the dosage of active compound per unit volume is higher. This feature permits to reduce the initial amount of active N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide when formulating the pharmaceutical composition, since the effective concentration per unit volume of a given drug product is achieved at a correspondingly lower amount and can be maintained for a longer period of time compared to formulations not based on the hemihydrate form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide.

[0006] Furthermore, the inventive manufacturing process of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate described herein ensures that impurities resulting from the production process, e.g. impurities from solvents, or degradation products of the active compound or other compounds used in the manufacturing process are essentially absent or not detectable by analytical methods. In contrast, known examples of mesylate salts of the active compound are essentially stable forms, but they contain potentially harmful impurities resulting from the conventional production of the compounds carrying a potential risk of genotoxic impurities or degradation products formed, e.g. during the manufacturing process or during storage.

[0007] Thus, the present application provides the unexpected stable form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide in the form of the free base hemihydrate which is of high purity as such after manufacturing and can be stored for an extended period of time due to the stability. Furthermore, after formulation as a drug product and storage, the active ingredient N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide is present in a high concentration essentially without or with very low decomposition, which ensures that the therapeutically effective concentration per unit volume of the drug product remains high without any significant reduction of the active substance content due to the degradation process. BRIEF DESCRIPTION OF DRAWINGS

[0008] Figure 1X-ray powder diffraction (XRPD) analysis of N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate.

[0009] Figure 2 Microscopy images show that N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]- N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate consists of rod-like crystals exhibiting birefringence under microscopy.

[0010] Figure 3 DSC of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate. 1 H-NMR spectrum of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate.

[0011] Figure 4 C-NMR spectrum of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate. 13 C-NMR spectrum of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2- [4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate.

[0012] Figure 5 DSC of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate.

[0013] Figure 6 - DVS cycle of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate shows no significant weight loss / gain and indicates Form C to be a stable hemihydrate. A): Weight vs. relative humidity, B): measured values over time.

[0014] Figure 7 TGA of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate indicates solvent loss. 2.1 wt% corresponds to the hemihydrate form.

[0015] Figure 8 A) and B) show Ortep plots of Form C of N-[5-(aminosulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate from different angles.

[0016] Figure 9 IR spectral data of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl]-acetamide free base hemihydrate. DETAILED DESCRIPTION

[0017] Before describing the present application in detail, it is considered advantageous to provide definitions of certain technical terms used throughout this description. While the application will be described in connection with particular embodiments, it is not intended to be limited to the

[0018] Definitions

[0019] As used throughout this description and the accompanying claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The term "comprising" encompasses the terms "consisting of" and "consisting essentially of."

[0020] In the context of the present application, the terms "about" and "approximately" denote an interval around the value to which they refer that will be understood by those of ordinary skill in the art to ensure the accuracy of the technical effect of the feature under discussion. The terms typically indicate a deviation of ± 20 %, preferably ± 15 %, more preferably ± 10 % and even more preferably ± 5 % from the indicated numerical value.

[0021] It is to be understood that the term "comprising" is not to be construed as being restricted to the recited means only. For the purposes of the present application, the term "consisting of" is to be considered as a preferred embodiment of the term "comprising". If a group is defined to comprise at least an amount of embodiments, and this group is later defined to consist of at least that amount of embodiments, it is then understood that the group cannot include only embodiments falling under the terms of the at least amount of embodiments. In other words, if a group is defined to comprise at least an amount of embodiments, and this group is later defined to consist of at least that amount of embodiments, it is then understood that the group cannot include only embodiments falling under the terms of the at least amount of embodiments.

[0022] Furthermore, the terms first, second, third or (a), (b), (c), (d) etc. and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the application described herein are capable of operating in other sequences than described or illustrated herein.

[0023] In case the terms first, second, third or (a), (b), (c), (d) etc. relate to steps of a method or use, unless otherwise indicated herein above or below in the application as interpreted by the application, no time or time interval consistency is to be inferred between the steps, i.e. a step can be carried out simultaneously with another step or there can be time intervals of seconds, minutes, hours, days, weeks, months or even years between the steps.

[0024] According to the present application, the term "antivirally effective amount" means the total amount of the individual active ingredients that is sufficient to exhibit a meaningful patient benefit, i.e. the cure of a condition characterized by the inhibition of a herpes virus infection. When applied to individual active ingredients administered separately, the term refers to that ingredient alone. When applied to a combination, whether given in sequence or simultaneously in combination, the term refers to the combined amounts of the active ingredients that produce the therapeutic effect.

[0025] The term "treatment" as used herein and in the claims means prevention or alleviation of a disease associated with a herpes virus infection. The term "prevention" or "preventing" as used herein and in the claims means administering or using a compound or composition disclosed herein so as to protect a non-infected organism or non-infected cells of an organism from infection, i.e. the organism can be infected with a virus, but the spread of the virus within the organism (from cell to cell) or within the social environment of the organism is prevented. The organism can be a human being or other mammal. In one aspect of the application, the organism to which the compound or pharmaceutical composition is administered is a human being infected with a herpes virus such as HSV-1 and / or HSV-2 or a human being at risk of being infected with such a virus.

[0026] The physical characterization of the free base hemihydrate referred to herein is performed using pharmacopoeial methods according to the European Pharmacopoeia (Ph. Eur.) and / or the United States Pharmacopeia Convention (USP).

[0027] In the following, various embodiments of the present application are explained in more detail. Anyway, respective alternatives with respect to the ingredients in the composition, the type of pharmaceutical composition, the concentration of the ingredients, the period of administration, the frequency of administration, the medical condition to be treated are mentioned, but the person of ordinary skill in the art will immediately understand that individual combinations can be made as long as these individual combinations are technically possible or if not explicitly indicated otherwise.

[0028] In one embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide free base hemihydrate having the molecular formula C 18 H 18 N4O3S2x 0.5 H2O. The Ortep plot of the compound is shown in Figure 8 A and Figure 8 B.

[0029] The free base hemihydrate comprises two molecules of formula (I):

[0030]

[0031] The two molecules of formula (I) are bound to each other by one water molecule, which is surprisingly located between the two aromatic rings present at the terminal ends of the compound, respectively. This surprising conformation provides the hemihydrate with an exceptionally high stability, which is not found in any other polymorph, salt, polymorph of a salt and solvate / hydrate identified in the polymorph screening of the monohydrate form of the compound of formula (I) as described in the Examples section. In one embodiment, the solid comprising or consisting of the hemihydrate is highly storage stable and also exhibits surprising light stability.

[0032] As used herein, the term "storage stable" or "light stable" and corresponding terms indicate that the hemihydrate does not decompose or degrade over an extended period of time. This means that the concentration of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate remains extremely high constantly, as using standard measurement methods allowing the identification of the compound and / or its decomposition products such as HPLC, XRPD, and standard curves showing N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide do not show any decomposition products of the compound. 13 C- and 1 H-NMR-spectroscopic methods. As mentioned above, the physical characterisation of the free base hemihydrate mentioned herein is performed using pharmacopoeia methods according to the European Pharmacopoeia (Ph. Eur.) and / or the United States Pharmacopeia Convention (USP).

[0033] Since generally no impurities (from the manufacturing process or due to decomposition of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base or N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate) are present, the purity of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is extremely high when manufacturing the product and formulating compositions or medicaments which initially comprise N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate, 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 unit volume is achieved. This is extremely advantageous when the compounds of the present application are used for formulating pharmaceuticals and medicaments, since the effective concentration of the active compound per unit volume is extremely high. This allows to reduce the amount of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate of the present application when formulating while maintaining a suitably high effective dose of the active compound. This is particularly required for pharmaceuticals used as topical compositions (in contrast to single unit dosage forms, e.g. essentially solid pharmaceuticals in the form of tablets etc. or as another example, dosage forms for immediate use as understood by the person of ordinary skill in the art, e.g. for systemic or parenteral use, reconstituted in a pharmaceutically acceptable medium or carrier), since the active ingredients in pharmaceuticals applied topically are subjected to harsh environmental conditions with regard to temperature changes, exposure to light such as UV radiation, humidity, mechanical stress after application to the affected area of the skin or mucosa and the like. Under these harsh conditions, it is important to reach a sufficiently high and therapeutically effective concentration of the active compound as quickly as possible on the treated surface and in the cells forming said surface (e.g. the epidermal layer of the skin, in which the herpes viruses impair affected cells). When the effective antiviral concentration in the treated area (cells, organs, e.g. the skin or parts thereof) is reached quickly, the number of herpes viruses in the treated area is reduced. This also reduces the number of viruses, especially of the herpes simplex virus, in the affected area which can infect nerve cells, in which these viruses can remain in a latent state, reactivated only by physical-chemical stimuli, e.g. changes in the cell due to psychological stress, UV stress or any other factor which shifts the balance of the affected cells from herpes virus latency (and the corresponding expression of virus-encoded polypeptides and / or polynucleotides) to herpes virus reactivation.Reactivation allows the herpes virus to exit latency and leave the cell that formed the latent reservoir only to infect and multiply productively within the cell subsequently, either by the virus itself or by host defense mechanisms such as by immune cells destroying the cell.

[0034] Another embodiment of the present application is a method of treating or inhibiting the incidence 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 an individual in need thereof an effective amount of a composition of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate.

[0035] The term "prevention and / or prophylaxis" or similar terms in the art relating to the present application clearly means to the person of ordinary skill in the art to inhibit or reduce the recurrence of infection or to inhibit or reduce the transmission of herpes simplex virus subtype 1 or 2 infection. In the context of the present application, the term "prevention and / or prophylaxis" does not mean that the patient is completely free and totally free of any infectious viral particles or infected cells, even under the broadest reasonable interpretation. This view is reasonable in the art relating to the disclosed subject matter in the context of the present application. To support the definition of the term "prevention and / or prophylaxis", the following publications are incorporated herein by reference:

[0036] Abdool Karim, S. S. et al. (2015) Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection. N Engl. J Med 373, 530-539.

[0037] Andrei, G. et al. (2011) Topical tenofovir, a microbicide effective against HIV, inhibits herpes simplex virus-2 replication. Cell Host. Microbe 10, 379-389.

[0038] Corey, L. et al. (2004) Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N. Engl. J. Med. 350, 11-20.

[0039] Kleymann, G. et al. (2002) New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nat. Med. 8, 392-398.

[0040] Mertz, G. J. et al. (1985) Frequency of acquisition of first-episode genital infection with herpes simplex virus from symptomatic and asymptomatic source contacts. Sex Transm. Dis. 12, 33-39.

[0041] Reitano, M. et al. (1998) Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J. Infect. Dis. 178, 603-610.

[0042] Schiffer, J. T. et al. (1997) Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J. Clin Invest 99, 1092-1097.

[0043] Wald, A. et al. (2014) Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl. J Med 370, 201-210.

[0044] Wald, A. et al. (2000) Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 342, 844-850.

[0045] Zhu, J. et al. (2007) Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595-603.

[0046] Gold, D. and Corey, L. MINIREVIEW Acyclovir Prophylaxis for Herpes Simplex Virus Infection. Antimicrobial Agents and Chemotherapy, March 1987, pp. 361-367.

[0047] Tyring, S., Baker, D., Snowden, W., Valacyclovir for Herpes Simplex Virus Infection: Long-Term Safety and Sustained Efficacy after 20 Years' Experience with Acyclovir. The Journal of Infectious Diseases 2002; 186 (Suppl 1): S40-6.

[0048] These documents support the correlation between helicase-primase inhibition and the prevention of herpes simplex virus infection or the prevention of its transmission as has been shown in the art. Furthermore, the above referenced Kleymann, 2002, teaches on page 396, bottom of left column, that recurrent disease and asymptomatic viral shedding are almost completely suppressed by helicase-primase inhibitors, which would reduce the transmission from person to person, i.e., effectively prevent the transmission of HSV. The above referenced disclosure in Corey, 2004, teaches on page 11, bottom and page 17, first column, that once-daily suppressive therapy with valacyclovir significantly reduced the risk of transmission, i.e., prevented the transmission of genital herpes between heterosexual couples, HSV-2 discordant couples. This study achieved these results by using a drug that has been shown to suppress the shedding of type 2 HSV (HSV-2) from the genital mucosa. See page 11, top. Furthermore, the frequency and amount of subclinical shedding of HSV from the genital mucosa has been found to be a major source of transmitted infection. See citations 20 through 22, tracing back to 1997, 1998, and 1997, respectively. Thus, a method of reducing the frequency and amount of subclinical shedding of HSV from the genital mucosa is a way to achieve the prevention of herpes transmission.

[0049] Karim, 2015 teaches on page 530 bottom, based on the study therein, that pericoital application of tenofovir gel reduced female acquisition of HSV-2, i.e., avoided contracting HSV. The effectiveness was a 51% reduction. See page 534, second column. In an earlier study by the same team, which goes back to 2010 (see citation 6 in this reference), pericoital application of a topical vaginal gel formulation of tenofovir was shown to reduce HIV acquisition. Although HIV is a different virus, given the above, one of ordinary skill in the art would not be unreasonable to believe that a drug could prevent acquisition of a viral infection. Moreover, such a case is explicitly acknowledged by Karim in the case of HSV. Gold and Corey in 1987 supported the well-known efficacy of acyclovir (i.e., a viral DNA polymerase inhibitor) prophylaxis. Moreover, Tyring et al. in 2000 supported the efficacy of the prodrug valacyclovir (i.e., a viral DNA polymerase inhibitor).

[0050] Those of ordinary skill in the art know that in the case of HSV-1 and HSV-2 infections, although the virus is present in the body due to the infection, there is no symptomatic onset because N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide effectively prevents viral shedding and onset, which is the "prevention" or "suppression" of symptoms produced by HSV-1 and HSV-2 infections. In further support of the prevention = suppression aspect of the present application, the references mentioned above for valacyclovir (i.e., Tyring et al., 2002) and acyclovir (i.e., Gold et al., 1987) are reiterated, which also demonstrate what is meant in the art by the acceptance of HSV infections being asymptomatic in normal individuals and the prevention / suppression therapy. In addition, HSV-prevention has been shown to be effective in clinical human trials, etc. In this regard, the announcement from ICAAC 2014 on HSV-2 genital herpes indications is incorporated herein by reference (Wald et al., 2014, supra). Finally, those of ordinary skill in the art know that by analogy to tenofovir, N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, known as a helicase-primase inhibitor, has even higher antiviral efficacy than tenofovir in the case of HIV, and therefore, for those of ordinary skill in the art, N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide would also be expected to have more pronounced prevention efficacy. In this regard, of particular relevance are the publications of Andrei et al. and Kleymann et al. mentioned above. When compared to N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, the IC50 values indicated for tenofovir are significantly higher.

[0051] In another embodiment, the present application relates to a N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate having a relative molecular mass of 411.50 as defined in the preceding embodiments. r 411.50 of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in the preceding embodiments.

[0052] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in the preceding embodiments having XRPD peaks at 5.940, 11.880 and 17.8402Q. An example of the analysis of the above free base hemihydrate is provided in the experimental section.

[0053] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in the preceding embodiments having a melting point of about 204 °C to 212 °C, in particular 205 °C to 21 1 °C, especially 206 °C to 210 °C, especially 207 °C to 209 °C, for example about 208.2 °C. The person of ordinary skill in the art knows that the determination of the melting point can depend on various other environmental parameters such as humidity etc.

[0054] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in the preceding embodiments having a calculated pKa value of 4.53.

[0055] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of the preceding embodiments having an octanol / water partition coefficient of 0.911 ± 0.891 at 25 °C.

[0056] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of the preceding embodiments having a stability of 90% to 100% at a pH in the range of 4.5 to 7.0.

[0057] In another embodiment, the present application relates to a pharmaceutical composition comprising or formulated to initially comprise N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of the preceding embodiments, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

[0058] In another embodiment, the present application relates to a pharmaceutical composition obtainable by formulating N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any of the preceding embodiments together with at least one pharmaceutically acceptable excipient. The pharmaceutical composition obtainable according to the preceding embodiment can further comprise other active compounds, for example active compounds selected from the group consisting of anti-inflammatory agents, antiviral agents, centrally and peripherally acting analgesics, (local) anesthetics, etc.

[0059] As used herein, the term "anti-inflammatory agent" generally refers to any compound or combination of compounds, such as steroids and non-steroidal anti-inflammatory drugs (NSAIDs), that tend to reduce inflammation upon administration to an individual experiencing such inflammation, as also defined in the Background section above.

[0060] As used herein, "centrally- and peripherally-acting analgesics" include opioid analgesics including, for example, buprenorphine or a physiologically acceptable salt or ester thereof, suitable opioid analgesics include alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, bezitramide, butorphanol, clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, dipipanone, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmoφhine, etonitazene, fentanyl, hydromoφhone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, moφhine, myrophine, nalbuphine, papaverine, nicomorphine, norlevorphanol, normethadone, nalbuphine, nalorphine, naloxone, naltrexone, normoφhine, norpipanone, oxycodone, oxymoφhone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, raubasine, salmoφhan, thebaicne, tildipirosine, and trioxazocine.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.

[0061] As used herein, a non-opioid analgesic includes, for example, an NSAID, a tricyclic antidepressant (e.g., amitryptyline), an anticonvulsant (e.g., gabapentin), or an anti-migraine compound (e.g., sumatriptan or naratriptan). The NSAID can be a cyclooxygenase (COX) COX-1 or COX-2 inhibitor. Particular examples of NSAIDs include ibuprofen, flurbiprofen, diclofenac, indomethacin, piroxicam, ketoprofen, etodolac, diflusinal, meloxicam, aceclofenac, fenoprofen, naproxen, tiaprofenic acid, tolmetin, celecoxib, and rofecoxib, and physiologically acceptable salts and esters thereof. Suitable salts are base addition salts such as potassium or sodium salts.

[0062] In the compositions of the present application, long-acting and short-acting local and volatile anesthetics selected from the group consisting of Bupivacaine, Lidocaine, xyclocaine, TTX, STX, and the like can be used.

[0063] In one embodiment, the pharmaceutical composition obtainable by formulating N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate comprises a local anesthetic.

[0064] In one embodiment, the pharmaceutical composition obtainable by formulating N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate comprises a local anesthetic agent, wherein the local anesthetic agent is lidocaine.

[0065] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, further comprising or formulated to initially comprise an active selected from the group consisting of anti-inflammatory agents, antiviral agents, centrally and peripherally acting analgesics, (local) anesthetics.

[0066] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, further comprising a sun- or UV-blocker. In one embodiment, the sun- or UV-blocker is Octisalate. In one embodiment, the sun- or UV-blocker is titanium dioxide. In one embodiment, the sun- or UV-blocker is zinc oxide. In one embodiment, the sun- or UV-blocker is PABA. In one embodiment, the sun- or UV-blocker is homosalate. In one embodiment, the sun- or UV-blocker is Trolamine salicylate. In one embodiment, the sun- or UV-blocker is dioxybenzone. In one embodiment, the sun- or UV-blocker is sulisobenzone. In one embodiment, the sun- or UV-blocker is oxybenzone. In one embodiment, the sun- or UV-blocker is avobenzone. In one embodiment, the sun- or UV-blocker is ecamsule. In one embodiment, the sun- or UV-blocker is meradimate. In one embodiment, the sun- or UV-blocker is cinoxate. In one embodiment, the sun- or UV-blocker is octocrylene.

[0067] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the composition is selected from the group consisting of a topical formulation for patch administration, a cream, an ointment, a salve, a gel, a skin lotion, a wax formulation, a lip balm, tonics and / or a mousse, a spray, a topical oil, a solution, a film, and the like.

[0068] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate has a photostability of about 102% to 105% (103.61 to 105.11 ) in terms of mean percent recovery as measured according to ICH guideline Q1 B.

[0069] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate has a photostability of about 102% to 105% (103.61 to 105.11 ) in terms of mean percent recovery as measured according to ICH guideline Q1 B.

[0070] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate has a photostability of about 102% to 105% (103.61 to 105.11 ) in terms of mean percent recovery as measured according to ICH guideline Q1 B.

[0071] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is initially formulated in an amount of about 0.1 % w / w to about 10% w / w. The amount of free base in the drug product can be determined using the above mentioned methods such as HPLC, NMR spectroscopy, XRPD method etc.

[0072] In another embodiment, the present application is directed to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is initially contained in an amount of about 1.0% w / w to about 7.5% w / w.

[0073] In another embodiment, the present application is directed to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is initially contained in an amount of about 2.5% w / w to about 6.0% w / w.

[0074] In another embodiment, the present application is directed to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is initially contained in an amount of about 5.0% w / w.

[0075] In another embodiment, the present application is directed to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is initially contained in an amount of about 5.0% w / w.

[0076] In another embodiment, the present application is directed to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is initially contained in an amount of about 1.0% w / w to about 7.5% w / w, in particular about 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day. It will be apparent that each concentration can be administered according to any of the above-mentioned frequencies. Each combination represents an embodiment of the present application, as will be appreciated by a person of ordinary skill in the art.

[0077] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 1.0 to 7.5 % w / w, in particular 5.0 % w / w after formulation, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day, and wherein the ointment is administered over a period of 2 to 14 days, 3 to 10 days, 3 to 7 days, 4 to 5 days, or over 5 days, or over 4 days. It is obvious that each concentration can be administered according to any of the above mentioned frequencies and each of the corresponding time periods. Thus, each possible combination of concentration / amount, frequency of administration and time period is indicative of a corresponding embodiment of the present application, as will be understood by the person of ordinary skill in the art.

[0078] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 5.0 % w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 5 times a day, and wherein the ointment is administered over a period of 4 days.

[0079] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 5.0 % w / w, wherein the pharmaceutical composition is a gel, and wherein the gel is administered 5 times a day, and wherein the ointment is administered over a period of 4 days.

[0080] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 5.0 % w / w, wherein the pharmaceutical composition is a cream, and wherein the cream is administered 5 times a day, and wherein the ointment is administered over a period of 4 days.

[0081] In another embodiment, the present application relates to a pharmaceutical composition as defined in any of the preceding embodiments, wherein N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount sufficient to achieve a concentration of > 10 nM in the epidermis or dermis of an individual being treated with said composition.

[0082] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in the preceding embodiments for use as a medicament.

[0083] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment and / or prevention of a herpes virus infection.

[0084] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment and / or prevention of a herpes virus infection, wherein the herpes virus is selected from the order Herpesvirales.

[0085] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in the preceding embodiments for use in the treatment and / or prevention of a herpes virus infection, wherein the herpes virus is selected from the order Herpesvirales.

[0086] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment and / or prevention of a herpes virus infection, in particular a herpes simplex infection, in an individual in need thereof in the form of an oral pharmaceutical formulation.

[0087] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment and / or prevention of a herpes virus infection, in particular a herpes simplex infection, in an individual in need thereof in the form of a topical pharmaceutical formulation.

[0088] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of recurrent herpes labialis.

[0089] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in systemic administration to a subject in need thereof.

[0090] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of recurrent herpes labialis.

[0091] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of recurrent herpes labialis, said recurrent herpes labialis being selected from the group consisting of patients showing signs of prodromal phase of herpes labialis, patients with erythema, patients showing papules on the lips, patients with vesicles on the lips, patients with erosions and / or soft scabs on the lips, patients with hard scabs on the lips, patients with residual erythema on the lips.

[0092] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of genital herpes.

[0093] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of herpes keratitis.

[0094] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of herpes keratitis.

[0095] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of a herpes infection in a neonate.

[0096] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of a herpes infection in an immunocompetent and / or immunocompromised individual.

[0097] In another embodiment, the present application relates to N-[5-(amino-sulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate for use in the treatment of a herpes infection in an immunocompromised individual, wherein said immunocompromised individual is selected from the group consisting of a recipient of an organ transplant, an individual suffering from an infection caused by another virus or bacteria, in particular an infection with HIV and / or another herpes virus, and an individual infected with a herpes simplex virus that is resistant to at least one antiviral agent.

[0098] In another embodiment, the present application relates to a method of treating and / or preventing a herpes virus infection, comprising administering to an individual in need thereof N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate.

[0099] In another embodiment, the present application relates to a method of manufacturing N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in any of the preceding embodiments, wherein said method comprises the following steps:

[0100] a) mixing (4-pyridin-2-yl-phenyl)-acetic acid with amino thiazole sulfonic acid amide in N-methyl pyrrolidone (NMP);

[0101] b) cooling the mixture obtained in step a);

[0102] c) adding N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCI) to the mixture obtained in b);

[0103] d) stirring the solution obtained in c) and adding to purified H20;

[0104] e) filtering the solution obtained in d);

[0105] f) washing the product cake obtained in e) with H2O;

[0106] g) drying the product obtained in f);

[0107] h) adding purified H2O to the solution obtained in g);

[0108] i) stirring the suspension obtained in h);

[0109] j) cooling the suspension obtained in i);

[0110] k) stirring the suspension obtained in j);

[0111] l) isolating the product by filtration of the suspension obtained in n);

[0112] m) washing the product obtained in o) with water;

[0113] n) drying the product obtained in p).

[0114] In another embodiment, the process of manufacturing N-[5-(amino-sulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide free base hemihydrate as defined in any of the preceding embodiments, wherein the process comprises the following steps:

[0115] a) mixing (4-pyridin-2-yl-phenyl)-acetic acid (5.5 to 6.3 kg, e.g. 5.905 kg) and aminothiazole sulfonic acid amide (5.855 kg) in N-methyl pyrrolidone (NMP) (6.5 to 7.5 L, e.g. 7 L) and THF (34 to 39 L, e.g. 36.5 L) at a temperature of (about 15 to 25 °C, e.g. 20 °C);

[0116] b) cooling the mixture obtained in step a) to about -2 to 2 °C, e.g. 0 °C; c) adding N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCI) in an amount of 6.2 to 6.8 kg (e.g. 6.538 kg) - (stepwise addition, e.g. about 4 portions of about 1.6 kg each) to the mixture obtained in step b);

[0117] d) slowly stirring the solution obtained in step c) over about 1.5 to 2.5 h (e.g. 2 h) and adding to purified H2O (70 to 76 L, e.g. 73 l);

[0118] e) filtering the solution obtained in step d) under a pressure of 1000 to 1400 mbar, e.g. 1200 mbar;

[0119] the solution obtained in step e);

[0120] f) washing the product cake obtained in step e) (using purified H2O, for example using 3 washings of 2.5 to 3.5 L, such as 3 L each (8.5 to 9.5 L, such as 9 L));

[0121] g) drying the product obtained in step f) under a stream of nitrogen (at 20 to 25 °C, such as 22 °C under vacuum), drying at higher temperatures, such as 35 to 40 °C, is also possible;

[0122] h) adding purified H2O (73 + 7 L)

[0123] to the product obtained in step g);

[0124] i) stirring the suspension obtained in step h) for at least 2 to 6 hours, such as 4 hours; j) cooling the suspension obtained in step i) to 0 to 10 °C, such as 5 °C;

[0125] k) stirring the suspension obtained in step j) for at least 15 to 45 minutes, such as 30 minutes;

[0126] l) isolating the product obtained in step k) by filtration at a pressure of, for example, 1200 to 6000 mbar;

[0127] m) washing the product obtained in step l) with 15 to 20 L, such as 18 L, of purified H2O about 3 times at a pressure of about 6000 mbar;

[0128] n) drying the product obtained in step m) (at 60 to 70 °C, such as 65 °C, for example under vacuum).

[0129] In another embodiment, the present application relates to a pharmaceutical composition comprising N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate obtainable in the process according to the previous embodiment.

[0130] In another embodiment, the present application relates to a pharmaceutical composition obtainable by formulating N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate obtainable in the process according to the previous embodiment together with at least one pharmaceutically acceptable excipient.

[0131] In another embodiment, the present application relates to the use of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate obtainable in the process according to the previous embodiment as a medicament.

[0132] N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate according to the present application is a useful compound for the treatment and / or prophylaxis of infectious diseases and / or for the prevention of the transmission of infectious diseases.

[0133] N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate is highly active against herpes viruses and infections caused by herpes viruses and / or the transmission of one or more herpes viruses. Therefore, N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate is especially suitable for the manufacture of a pharmaceutical composition for the treatment and / or prophylaxis of diseases caused by herpes viruses or caused by the transmission of one or more herpes viruses.

[0134] N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate is especially suitable for the treatment and / or prophylaxis of infections caused by herpes simplex viruses or for the prevention of the transmission of one or more herpes viruses.

[0135] Infections with herpes simplex viruses (HSV subtypes 1 and 2) are classified into one of several different conditions depending on the site of infection. Oral-facial herpes infections, colloquially known as cold sores or visible symptoms of fever blisters, affect the face and mouth. Oral-facial herpes is the most common form of infection. Genital herpes is the second most common form of herpes simplex infection. While genital herpes is largely considered to be caused by HSV-2 only, genital HSV-1 infections are increasing. Other conditions such as herpetic whitlow, traumatic herpes, ocular herpes (keratitis), cerebral herpes encephalitis, Mollaret's meningitis, neonatal herpes and possibly Bell's palsy are also caused by herpes simplex viruses.

[0136] N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate is therefore suitable for the treatment and / or prophylaxis of infections caused by herpes simplex viruses and / or for the prevention of the transmission of herpes viruses.

[0137] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate of the present application can be administered in combination with other active agents or (local) anesthetics, other antiviral agents, etc. such as antiinflammatory agents such as acetylsalicylic acid and acetaminophen.

[0138] The combination of the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate of the present application with an anesthetic agent and pharmaceutical compositions containing this combination are an embodiment of the present application.

[0139] Furthermore, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate of the present application can be combined with and used in combination with antiviral agents.

[0140] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate of the present application and a further active agent such as an antiinflammatory agent, an immunomodulator or an antiviral agent such as a therapeutic vaccine, an siRNA, an antisense oligonucleotide, a nanoparticle or a viral entry inhibitor such as docosanol can be administered simultaneously as one single pharmaceutical composition or in more than one pharmaceutical composition, wherein each composition comprises at least one active agent.

[0141] The pharmaceutical compositions of the present application can be prepared in known manner in conventional solid and in conventional pharmaceutically produced adjuvants at suitable dosage levels. Preferred preparations can be suitable for oral administration. These administration forms include, for example, pills, tablets, film tablets, coated tablets, sustained release formulations and capsules.

[0142] The pharmaceutical compositions according to the present application can comprise from 1 to 70 % by weight, more preferably from 1 to 30 % by weight, for example from 1 to 10 % by weight of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate (all percentage data are percentages by weight based on the weight of the pharmaceutical preparation).

[0143] The pharmaceutical compositions according to the present application can be suitably formulated for systemic, oral, topical or parenteral administration.

[0144] As pharmaceutically acceptable carriers, excipients and / or diluents, carriers such as, preferably, inert carriers, like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethanol (liquid-filled capsules); suitable binding agents include starch, gelatin, natural sugars such as dextrose, corn sweeteners, natural and synthetic gum such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, sugars such as sucrose, starches derived from corn, maize rice and potato, natural gum such as acacia, gelatin and tragacanth, alginic acid derivatives such as alginic acid, sodium alginate and calcium ammonium alginate, cellulose materials such as methyl cellulose, sodium carboxymethylcellulose and

[0145] The compounds and compositions of the present application can also be administered using a patch applied to a site on the body of an organism, such as a human, infected with a herpes virus, such as HSV-1 and / or HSV-2. More particularly, such a patch invention comprises a skin-adhesive layer, a backing layer and a drug-releasing liner, the adhesive layer comprising a hemihydrate of the present application and / or other active compounds dissolved in a low volatile solvent and a polymeric adhesive that is soluble in a highly volatile solvent. The antiviral agent can be present in a therapeutically and / or prophylactically effective amount, such as 0.1 to 10% by weight of the dried adhesive layer, dissolved in a low volatile solvent, incorporated in the adhesive layer. Solvents can be functionally classified according to their physico-chemical properties. Major properties include, among others, density, viscosity, dielectric constant, dipole moment, melting point and boiling point. Solvents can be broadly classified according to the boiling point temperature at 1 bar as low, medium or high boiling: low boiling: boiling point in the range below 100°C; medium boiling: boiling point in the range between 100°C and 150°C; high boiling: boiling point in the range above 150°C. Low boiling solvents are highly volatile solvents, while high boiling solvents are solvents with a weak tendency to evaporate so that they can be defined as low volatile solvents. An example of a low volatile solvent according to the present invention is dimethyl sulfoxide which can be present in an amount of 10 to 50% by weight of the dried adhesive layer. The adhesive polymer is selected from pectin, agar gum, gum arabic, xanthan gum, polyvinyl alcohol, polymethacrylic acid, polymethacrylate, acrylate / methacrylate alkyl copolymer, any acrylate copolymer, methacrylic amino alkyl ester copolymer, polyvinyl pyrrolidone, cellulose or cellulose derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose or blends thereof. The adhesive layer can be formed from a solution of the adhesive polymer in a highly volatile solvent, i.e. with a low boiling point (in the range 40°C to 100°C) and a high vapor pressure. The solvent is then typically evaporated during the manufacturing process, although an amount of up to 15% by weight can remain in the adhesive layer after drying. The adhesive polymer or adhesive polymer blend can be present in an amount of 20 to 50% by weight of the dried adhesive layer. The patch can further contain citric acid, succinic acid, lactic acid and esters thereof as non-polymeric crystallization inhibitors in an amount of, for example, 0.5 to 15% by weight of the dried adhesive layer. The patch can also contain other excipients such as cross-linking agents, penetration enhancers, plasticizers, preservatives, antioxidants, fragrances, softeners. The backing layer can be transparent, semi-occlusive or occlusive, permeable to oxygen, for example consisting of a polyurethane ether or ester film, polyethylene, ethylene vinyl acetate or polyolefin film, with an MVTR (moisture vapor transmission rate) of 50 to 3500 g / m2 / day and a thickness of 20 to 150 pm. The backing layer should be very flexible and soft, transparent or colored, and can be occlusive or permeable to sweat, providing a masking effect for cold sores.Additionally, it protects the damaged skin and viral lesions from external contact, thus reducing the pain of the patient and possible other contaminations or infections, and improving the process of epidermal regeneration. The adhesive layer is protected from the external environment by a release membrane, which must be removed before the patch is applied to the body part associated with the viral lesion. Once applied, the patch remains in place for 6 to 24 hours, delivering the active ingredients to and through the skin, by the adhesive layer. The patch is prepared by a process comprising the incorporation of a solution of adhesive polymer in a highly volatile solvent, together with the other components, and then casting the mixture on a release membrane coated with silicone before drying and final lamination. The highly volatile solvent evaporates, leaving the adhesive film on the release membrane, while the low volatile solvent remains in the adhesive layer, preventing the crystallization of the drug. The polymer used according to the present invention is the one usually used to create pressure sensitive adhesives (PSA) or bioadhesive films in organic or aqueous solutions, in a range from 20% to 80%, preferably from 20% to 50% of the composition of the adhesive mixture, while the concentration of the highly volatile solvent is from 10% to 50%. The other components of the adhesive or reservoir layer include thickening agents, chemical penetration enhancers, non-polymeric crystallization inhibitors, flavoring agents, surfactants, cross-linking agents, buffers, plasticizers, preservatives, antioxidants, pigments. The chosen solvent and polymer must be of course compatible and form a homogeneous solution that can be uniformly cast. The low boiling point solvent, i.e. the highly volatile solvent with a boiling point not higher than 100°C, is preferably water, ethanol, methanol, isopropyl alcohol, ethyl acetate, more preferably water. It is thus possible to prepare an antiherpetic patch with an effective amount of the active semihydrate drug that can be continuously delivered to the application site. The low volatile solvent helps to avoid crystallization by keeping the active substance dissolved in the matrix, and influences the diffusion of the drug through the matrix to reach the skin and the site of action. The matrix must be chosen according to the physical-chemical properties of the low volatile solvent or solvent blend. The polymer must provide good cohesion to the final product. The quantitative composition of the adhesive blend is chosen so as to have a film that is acceptable in terms of thickness, tack properties, mechanical resistance, skin adhesion, peel properties and handling. The polymer blend in the dry matrix dissolved in the low boiling point solvent or solvent mixture ranges from 5% of 50%, most preferably from 20% to 35%. The percentage of solvent in the mixture that must be cast to create the adhesive or reservoir layer ranges from 20% to 70%, preferably from 35% to 55%. The amount of low boiling point solvent in the dry matrix must not exceed 15% by weight. The low volatile solvent is actually included in the dry matrix, entangled in the polymer and dissolving the active ingredient. The amount of these solvents in the dry state ranges from 10% to 50%, but preferably from 30% to 55%.

[0146] The following examples are included to demonstrate preferred embodiments of the application. It should be appreciated by those of ordinary skill in the art that the techniques disclosed in the examples which follow are exemplary and are not intended to limit the scope of the application, which is defined in the claims. The following examples further illustrate the use of the application but, of course, should not be construed as limiting its scope.

[0147] Further modifications and alternatives to the various aspects of the application will be apparent to one of ordinary skill in the art in view of the present description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those of ordinary skill in the art the general manner of carrying out the application. It is to be understood that the forms of the application shown and described herein are to be taken as embodiments exemplifying the principles of the application. Elements and materials can be substituted for those illustrated and described herein, parts and processes can be reversed, and certain features of the application can be utilized independently, all as would be apparent to one of ordinary skill in the art after inspection of the description. Changes can be made to the elements described herein without departing from the spirit and scope of the application as described in the following claims.

[0148] Experiments

[0149] Example 1 - Identification of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N- methyl-2-[4-(2-pyridinyl)-phenyl]acetamide free base hemihydrate

[0150] N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide free base hemihydrate was identified by conducting a broad polymorphic hydrate screen of the monohydrate form of the above compound according to Formula (I) starting with N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide in order to identify a suitable or most stable form of the Formula I compound (the free base of the mesylate salt of N-[5-(aminosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide):

[0151]

[0152] Several polymorphs / solvates were identified and characterized by single XRPD and DSC, Karl Fischer water content. Surprisingly, the free base hemihydrate was the only stable polymorph. The polymorph screening was performed using a method to find the kinetically preferred polymorph as well as the thermodynamically preferred or in other words more stable polymorph. The kinetically preferred polymorph was checked using evaporation and cooling crystallization, the thermodynamically preferred polymorph was checked using slurry experiments. The nomenclature for the classification of the different forms is as follows: forms are usually assigned to capital letters in chronological order. The first material isolated and analyzed by X-ray powder diffraction was named form A. For the screening, two different batches of starting material were used, both with the same form according to XRPD: form B which is a monohydrate.

[0153] Evaporation screening method

[0154] For the evaporation experiments, about 100 mg of monohydrate form B were suspended / dissolved in each solvent listed in table 1 below (max. 4 mL). The solvents were chosen with high diversity, e.g. polarity, protic / aprotic, acceptability according to ICH guidelines, and assumed solubility of the mesylate free base. Experiments which did not dissolve at room temperature were heated up to 60 °C and in case of still no dissolution, filtered at elevated temperature to obtain a more concentrated starting solution. The solutions were started to evaporate in a drying cabinet at 25 °C and 850 mbar, where the constant nitrogen flow was reduced to vacuum 750 mbar after 3 days; the remaining solution was concentrated using a nitrogen flow after 5 days. The obtained solids were checked by eye and X-ray powder diffraction was performed in case of sufficient amount of solid was obtained. In total 15 different polymorphic forms were identified (including the initial form B).

[0155] Cooling and precipitation screening method:

[0156] For the cooling experiments, about 100 mg of monohydrate polymorph form B were slurried in each solvent listed below (max. 4 mL) and the obtained suspensions were heated up to 65 °C. In case of still no dissolution, the suspensions were filtered or decanted and the mother liquor was then shock cooled in an ice bath (approximately -10 °C) until a suspension was obtained. After about 15 minutes at low temperature, the solutions which did not spontaneously nucleate were treated with an antisolvent as indicated in table 2 below. The obtained suspensions were filtered, the solids were slightly dried and tested by XRPD.

[0157] Table 1 : Evaporation screening results. Form X indicates additional reflections which do not correspond to any other observed form.

[0158] Experiment: NE-023931-Z-0-3 (series A)

[0159] BXR2KVE / 001123 by evaporation crystallization

[0160] Approximately 100 mg was dissolved in 3 mL solvent. In cases where a solution was not obtained, heating to 50 °C and filtration of the solid, and evaporation of the mother liquor for up to one week.

[0161]

[0162]

[0163] Table 2: Cooling / precipitation screening results. Maximum temperature in °C

[0164]

[0165] Slurry screening method

[0166] Slurry experiments were performed by taking approximately 100 mg of monohydrate Form B and slurring in each of the solvent mixtures using a magnetic stir bar as detailed in the table below. Since the focus was on hydrate forms, most of the aqueous solvent mixtures were used as shown in Table 3.

[0167] Table 3: Slurry screening results

[0168]

[0169] The identified forms were then further characterized by several methods: XRPD, optical microscopy, 1 The physical characterization of the free base hemihydrate mentioned herein was performed using pharmacopoeial methods according to the European Pharmacopoeia (Ph. Eur.) and / or the United States Pharmacopeia Convention (USP).

[0170] Melting point measured by DSC

[0171] Principle: Differential Scanning Calorimetry with power compensation

[0172] Equipment: DSC-system (DSC 822e - Mettler Toledo) / analytical microbalance

[0173] Procedure: An accurately weighed sample (typically 1 to 5 mg) was placed in a clean and dry aluminum crucible and closed with an aluminum lid with a hole. The second crucible was a reference crucible.

[0174] Conditions:

[0175] Starting temperature: 20 °C

[0176] Heating rate: 10 °C / min

[0177] Final temperature: 300 °C

[0178] Atmosphere: N2(flow 20 mL / min)

[0179] TGA Volatile Components

[0180] Principle: Thermogravimetric analysis.

[0181] Equipment: TGA 851 e instrument with oven, oven temperature sensor and sample temperature sensor / Alumina pan / Analytical microbalance.

[0182] Procedure: Empty alumina pan was used to collect the background curve. Then, an accurately weighed sample (typically 10 mg) was placed in a clean and dry pan. The measurement was done as described in the analysis instructions.

[0183] Conditions:

[0184] Starting temperature: 25 °C

[0185] Heating rate: 5 °C / min

[0186] Final temperature: 300 °C

[0187] Atmosphere: N2(flow 50 mL / min)

[0188] 1 H NMR

[0189] Equipment: Bruker AVANCE 400 MHz

[0190] Solvent: DMSO-D6 or CDCl3

[0191] Internal standard: Tetramethylsilane (TMS) or solvent peak

[0192] Decoupling: Reverse gate decoupling

[0193] Analysis: Analysis was determined using the macro of ACD / Spec Manager 9 by comparing the integrated area of the compound to the integrated area of the internal standard (typically hydroquinone dimethyl ether).

[0194] Light microscopy using a hot stage apparatus:

[0195] Olympus BX41 with Di-Li 5MP camera and QCapture software

[0196] Hot stage Mettler Toledo FP90 with FP 82 heating stage

[0197] Method: Samples were prepared by brushing onto object holders. Observations were done using either non-polarized light or polarized light using two polarizing filters at 40x, lOOx, 200x or 400x magnification. Images were taken by software and exported as JPEG, scale only similar and not verified.

[0198] X-ray powder diffraction (XRPD)

[0199] Equipment: MiniFlex by Rigaku Corporation using a silicon low background sample holder (24 mm diameter, 0.2 mm recess); sleeve: 15 kV

[0200] Method: Angle: 2 theta = 2° to 2 theta = 40°; sampling width 0.02 [2 theta]; measurement time: 75 minutes.

[0201] Preparation: The sample was ground with a mortar and pestle when sufficient amount was isolated; this resulted in more consistent results, less preferred orientation and better handling of material with large particle size. Solids positioned on the sample holder were prepared with grease and flattened with a glass plate.

[0202] HPLC

[0203] The following method is a quick determination of concentration laboratory method and is different from the method used to follow the synthesis of C-019998.

[0204] Chromatographic column: Phenomenex Luna 3 μιη C18 (50 X 4.6 mm), detection: DAD detector, recorded at 240 nm; diluent: 0.2 mg / mL in ACN / H20 1 :9 + 1% TFA; eluent: A = "H20 + 0.05% CF3COOH"; B = "CH3CN + 0.05% CF3COOH"; method: injection: 5 μί; flow rate: 1.0 mL / min

[0205]

[0206] A total of 14 different forms were identified from the screen; additional forms were found during the scale-up phase. In most of the forms identified by XRPD, sufficient amount for additional analysis was still available from the screen phase. First microscopy (habit, aspect) and NMR (structure confirmation, residual solvent) were performed and if more material was available, also DSC and TGA to get an idea how residual solvent and which type of form transformation would occur. The following table shows an overview of the analytical data collected after the screen phase as well as during the scale-up phase.

[0207] Table 4: Summary of forms identified during screening / scale-up phase, sample used for reference XRPD pattern, number of occurrences (sampling) during screening, and solvent used to prepare the sample characterized.

[0208]

[0209] Table 5: Summary of 1H NMR results for different forms of monohydrate Form B.

[0210]

[0211]

[0212] DMSO-D6 was used as solvent and can contain significant amounts of water making it impossible to estimate the amount of water.

[0213] Table 6: Summary of thermal analysis for different forms of monohydrate Form B.

[0214]

[0215]

[0216] For TGA weight loss, a temperature range is given. DSC data show endothermic and exothermic phenomena as well as melting points; the given temperatures represent the peak temperatures. Data collected on solvent content were used together with TGA data to exclude a series of forms from further characterization work as these forms were assumed to be solvates or at least forms including significant amounts of solvent. The following forms were excluded:

[0217] Form B: monohydrate that has released water at slightly above ambient temperature.

[0218] Form F: methanol solvate.

[0219] Form G: ethanol solvate.

[0220] Form H: form including significant amounts of methanol and dichloromethane.

[0221] Form K: possibly a methanol solvate.

[0222] Form L: dihydrate that releases water from 40°C to 160°C.

[0223] Form M: isopropanol solvate.

[0224] Form N: acetonitrile solvate.

[0225] Form O: methanol solvate.

[0226] Form P: TBME solvate.

[0227] Of the remaining forms, only form C, namely N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]-acetamide hemihydrate, proceeds to the next stage as the sole hydrated form. Form E cannot be definitively designated as a solvate or non-solvate form, but is assumed to be a channel solvate. In the case where form E is assumed to be a non-solvate form including the solvent currently present in the crystallization experiment, it must be considered as a very stable form occurring simultaneously with form A, which is the most stable non-solvate. In this case, it is highly dependent on the composition of the crystallization system; those skilled in the art can infer that form A is unlikely to convert to form A in the absence of a solvent. Some forms contain 0.5 to 1 equivalent of solvent and are designated as solvates. According to DSC / TGA, hydrates appear to have a clear order of stability: C > L > B, but experiments producing form L (dihydrate) indicate that form L is very unstable. Most forms provide sufficient space in the crystal lattice to include water or solvent. Including water in any possible gaps and reducing the risk of high levels of residual solvent is preferred.

[0228] Advantageously, the hemihydrate form C provides sufficient stability with a low risk of dehydration when stored in a closed container at ambient temperature.

[0229] Example 2

[0230] XRPD analysis of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]-acetamide free base hemihydrate

[0231] Sample preparation: To obtain the powder diffraction pattern of the obtained solid, approximately 20 mg of white powder sample was prepared in a standard sample holder using two polyacetate foils and then analyzed as described below.

[0232] Data collection: using CuKα1-radiation in transmission geometry Powder diffraction patterns were acquired on a Bruker D8 Advanced Series 2θ / θ Powder Diffraction System. The system is equipped with... The equipment included a single-photon counting PSD, a germanium monochromator, a 90-bit automatic converter sample stage, a fixed divergence slit, and a radiotherm. The procedures used were: data collection using DIFFRAC with XRD command tool V.2.4.1, and evaluation using EVA V.12.0 and Microsoft Excel. Samples were measured in 2θ (step size: 0.016°) within a 20-minute scan range from 4° to 40°.

[0233] Powder X-ray diffraction pattern

[0234] The powder X-ray diffraction pattern of the free base hemihydrate Figure 1 ) is that of a highly crystalline solid. Characteristic peaks are labeled. Table 7 below shows a peak list for the PXRD pattern of the free base hemihydrate presented in the text below. Figure 1 The peak list for the PXRD pattern of the free base hemihydrate presented in the text below. Characteristic peaks have been highlighted with bold font.

[0235] Table 7

[0236]

[0237] Solubility and relative stability of the Form.

[0238] For the analysis of the stability of the Form, both the hydrate and the solvent-free Form were investigated separately.

[0239] Hydrate

[0240] The hemihydrate Form C was isolated to a greater extent. The starting material used for the screening (Form B) was a monohydrate. In addition, a possible dihydrate (Form L) was identified. DVS indicated that the monohydrate (Form B) appeared to release and adsorb water more rapidly than Form C (hemihydrate). During the DVS experiment time (for Form C < 600 min), almost no change was observed at 25 °C. To extend the exposure to different relative humidity (RH) values, vials with solid / saturated solution were loaded at the top with an open dish of Form C, and the sealed vials were kept for 5 days (see data below for different humidity levels). The resulting hemihydrate was checked by XRPD, and all samples were confirmed as Form C (free base hemihydrate).

[0241] Table 8 - Salts and solutions simulating different relative humidity values

[0242] Salt (solution) target relative humidity

[0243] KOH (solid) < 5% RH

[0244] KOH (saturated) 10% RH

[0245] KOAc (saturated) 20% RH

[0246] K2CO3 (saturated) 43% RH

[0247] NaCr2O7 (saturated) 58% RH

[0248] NH4CI (saturated) 80% RH

[0249] Water 100% RH

[0250] In combination with the results from TGA and DSC, where a difference of about 60°C between the dehydration temperatures can be observed for Form B and Form C, the stability of the hemihydrate is much higher than for the other hydrate forms.

[0251] Detailed characterization of the hemihydrate Form C:

[0252] General properties of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate in Table 9:

[0253] Table 9

[0254]

[0255]

[0256] The microscopy images shown in Figure 2 indicate that Form C consists of rod-like crystals showing birefringence under microscopy.

[0257] A crystallization screen was performed using 3 different solvents (ethanol / water 8:2, acetonitrile / water 8:2 and THF / water 9:1) in order to obtain crystals suitable for single crystal X-ray diffraction analysis. General procedure: Hemihydrate of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate (50 mg) was dissolved in the minimum amount of solvent at 60°C and the solution was cooled to room temperature and slowly evaporated. Results: Single crystals were obtained using ethanol / water and acetonitrile / water as solvents. However, only the crystals obtained in ethanol / water corresponded to Form C (P067-01-EOH-H2O-01). The samples were characterized by single crystal X-ray diffraction (SCXRD). The asymmetric unit contains two independent organic compound molecules and one water molecule. The measured crystal in Table 10 below corresponds to the hemihydrate as shown in Figure 1

[0258] Table 10 Characterization by single crystal X-ray diffraction (SCXRD)

[0259]

[0260]

[0261] Synthesis route - manufacturing of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate

[0262] ​Starting material (4-pyridin-2-yl-phenyl)-acetic acid (PP-acid; C-023930) and aminothiazole sulfonic acid amide (C-023936) were coupled using standard reaction conditions (N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCI), tetrahydrofuran (THF) / N-methylpyrrolidinone (NMP) to give N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate (C-023931). To obtain the hemihydrate, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate free base was recrystallized from THF / water. A flow diagram showing the synthesis of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide is provided below in the reaction scheme of Example 1 below.

[0263]

[0264] Description of the manufacturing process of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate

[0265] PP-acid and aminothiazole sulfonic acid amide were mixed in THF / NMP, the mixture was cooled and then EDC x HCI was added portionwise. The reaction mixture was stirred for several hours and then slowly added to purified water. The suspension was stirred and filtered; the product cake was washed with purified water and dried at room temperature under a stream of nitrogen and then under vacuum. Purified water was slowly added at elevated temperature, the suspension was stirred for several hours. The suspension was allowed to cool to 5°C and further stirred for several hours. The product was isolated by filtration and washed with purified water. The product was dried at 65°C under vacuum until the water content criteria were reached. The main advantage of the synthesis of the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate is the absence of impurities related to the presence of methanesulfonate which can be present in N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide methanesulfonate.

[0266] According to the free base hemihydrate form C of 1 H-NMR spectrum Figure 3 ), the solvent is not visible.

[0267] As indicated by assigning the band maxima to functional groups of the molecule, the obtained infrared spectral data are in agreement with the chemical structure Figure 9

[0268] Solubility comparison of free base and free base hemihydrate in individual excipients

[0269] The free base hemihydrate exhibits similar or slightly higher solubility in the primary solvents compared to the free base; therefore any physicochemical data of the free base can be extrapolated to the free base hemihydrate.

[0270] The saturated solubility (% w / w), mean (range, n=3) of Prexige® in PEG 400 and propylene glycol for both forms (batch: BXR2KVE for free base and M023862-CA15-033 for Prexige® hemihydrate) are shown in Table 11 below.

[0271] Table 11

[0272]

[0273] Light stability testing of current clinical formulation O1v3

[0274] Formulation O1v3 contains the following excipients and active ingredient (% w / w)

[0275]

[0276] Light stability testing of lead formulation O1v3 containing Prexige® hemihydrate was performed to confirm that the formulation prepared using this form of Prexige® is stable upon exposure to light. Samples of borosilicate vials filled with O1v3 were exposed to light according to ICH guideline Q1B and Prexige® recovery and purity levels have been outlined in Table 12 and Table 13 respectively.

[0277] The formulation was exposed to UV light (1,200,000 lux / hour per square meter and more than 200 watt / hour) under ICH conditions.

[0278] The data show that Prexige® in the formulation (O1v3) is stable upon exposure to UV light as there is little change in the percent recovery and purity of Prexige® compared to t=0.

[0279] Table 12: Mean percent recovery (%) of Prexige® hemihydrate mean (range n=3) at t=0 and after exposure to UV light according to ICH guideline Q1B

[0280]

[0281] ​* In this case, "T0": indicates the formulation before exposure to light stress conditions, while "light stability" indicates the sample after exposure to light stress conditions

[0282] Table 13: Average purity levels (% a / a) of Prasugrel hemi-hydrate at t=0 and after exposure to UV light according to ICH guidelines (mean (range n=3)

[0283]

[0284] * In this case, "T0": indicates the formulation before exposure to light stress conditions, while "light stability" indicates the sample after exposure to light stress conditions

[0285] SUMMARY OF SOME EMBODIMENTS:

[0286] 1. N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate having the molecular formula C 18 H 18 N4O3S2 x 0.5 H2O.

[0287] 2. N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate according to embodiment 1 having a relative molecular mass of M r 411.50.

[0288] 3. N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate according to any one of embodiments 1 and 2 comprising XRPD peaks at 5.9, 11.7, 15.5 and 18.7 2 theta.

[0289] 4. N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate according to any one of embodiments 1 to 3 having a melting point of 205 °C to 211 °C.

[0290] 5. N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate according to any one of embodiments 1 to 4 having a calculated pKa value of 4.53.

[0291] 6. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate according to any one of embodiments 1 to 5 having an octanol / water partition coefficient of 0.911 ± 0.891 at 25 °C.

[0292] 7. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate according to any one of embodiments 1 to 6 having a stability of 90% to 100% at a pH in the range of 4.5 to 7.0.

[0293] 8. A pharmaceutical composition comprising N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate according to any one of the preceding embodiments, wherein the composition further comprises at least one pharmaceutically acceptable excipient.

[0294] 9. A pharmaceutical composition obtainable by formulating N-[5-(amino- sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of the preceding embodiments 1 to 7 together with at least one pharmaceutically acceptable excipient.

[0295] 10. The pharmaceutical composition according to any one of embodiments 8 and 9, further comprising an active ingredient selected from the group consisting of antiinflammatory agents, antiviral agents, centrally and peripherally acting analgesics, anesthetics.

[0296] 11. The pharmaceutical composition according to any one of embodiments 8 to 10, further comprising a UV blocker.

[0297] 12. The pharmaceutical composition as defined in embodiments 8 to 11, wherein the composition is selected from the group consisting of topical formulations for patch administration, creams, ointments, salves, gels, skin emulsions, wax formulations, lipsticks, tonics, mousses, foams, sprays, films, emulsions, pastes, solutions, oils and lipogels and patches.

[0298] 13. The pharmaceutical composition as defined in any one of embodiments 8 to 12, wherein N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate has a photostability of about 95% to 107%, in particular of about 103.61 % to 105.11 % in terms of mean percent recovery as measured according to ICH guideline Q1 B.

[0299] 14. The pharmaceutical composition as defined in any one of embodiments 8 to 13, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate has a photostability of about 95% to 105% area / area, advantageously in the range of 98% to 102% area / area in terms of mean purity according to ICH guideline Q1 B.

[0300] 15. The pharmaceutical composition as defined in any one of embodiments 8 to 14, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate has a percent recovery of about 90% to 118% (92.24 to 114.49) at t=0, about 102% to 105% (103.16 to 103.71%) at t=24 hours at 2°C to 8°C, and about 100 to 102 (101.47 to 101.70) at t=25 hours at 37°C, about 102 to 108 (103.57 to 106.24) at t=48 hours at 2°C to 8°C, and about 104 to 118 (105.42 to 116.70) at t=48 hours at 37°C; about 102 to 107 (103.78 to 105.69) at t=120 hours at 2°C to 8°C, and about 84 to 98 (85.85 to 96.40) at t=120 hours at 37°C, as measured by HPLC in a Franz diffusion cell using a 2% w / v Brij 98 in PBS solution as the receiving fluid.

[0301] 16. The pharmaceutical composition as defined in any one of embodiments 8 to 15, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of about 0.1% w / w to about 10% w / w.

[0302] 17. The pharmaceutical composition as defined in any one of embodiments 8 to 16, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of about 1.0% w / w to about 7.5% w / w.

[0303] 18. The pharmaceutical composition as defined in any one of embodiments 8 to 17, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of about 2.5% w / w to about 6.0% w / w.

[0304] 19. The pharmaceutical composition or topical pharmaceutical composition as defined in any one of embodiments 8 to 18, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of about 5.0% w / w.

[0305] 20. The pharmaceutical composition as defined in any one of embodiments 8 to 19, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is an ointment.

[0306] 21. The pharmaceutical composition as defined in any one of embodiments 8 to 20, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of about 1.0% to about 7.5% w / w, in particular about 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day or 5 times a day.

[0307] 22. The pharmaceutical composition as defined in any one of embodiments 8 to 21, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 1.0% to 7.5% w / w, in particular 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 1 to 10 times a day, or 2 to 10 times a day, or 3 to 8 times a day, or 3 to 7 times a day, or 4 to 6 times a day, or 5 times a day, and wherein the ointment is administered over a period of 2 to 14 days, 3 to 10 days, 3 to 7 days, 4 to 5 days, or over 5 days or over 4 days.

[0308] 23. The pharmaceutical composition as defined in any one of embodiments 8 to 22, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 5.0% w / w, wherein the pharmaceutical composition is an ointment, and wherein the ointment is administered 5 times a day, and wherein the ointment is administered over a period of 4 days.

[0309] 24. The pharmaceutical composition as defined in any one of embodiments 8 to 23, wherein the N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount sufficient to achieve a concentration of >10 nM in the epidermis and dermis of an individual being treated with the composition.

[0310] 25. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use as a medicament.

[0311] 26. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prevention of a herpes virus infection.

[0312] 27. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prevention of a herpes virus infection, wherein the herpes virus is selected from the order Herpesvirales.

[0313] 28. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prevention of a herpes virus infection as defined in embodiment 27, wherein the herpes virus is selected from the group consisting of herpes simplex virus 1 (HSV-1 ) and herpes simplex virus 2 (HSV-2).

[0314] 29. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in an oral pharmaceutical formulation for the treatment and / or prevention of a herpes virus infection in an individual in need thereof.

[0315] 30. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 in the form of a topical pharmaceutical formulation for use in the treatment and / or prophylaxis of a herpes virus infection in an individual in need thereof.

[0316] 31. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 in the form of a topical pharmaceutical formulation for use in the therapeutic and / or prophylactic treatment of an individual in need thereof, wherein the individual is suffering from a herpes virus infection or is suspected to suffer from a herpes virus infection.

[0317] 32. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for topical administration to an individual in need of therapeutic and / or prophylactic treatment, wherein the topical administration involves administration to the skin in general, facial administration and / or administration to the mouth, the genital area and / or the eyes.

[0318] 33. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for systemic administration to an individual in need of therapeutic and / or prophylactic treatment, wherein the individual is suspected to suffer from a herpes virus infection or is an individual suffering from a herpes virus infection.

[0319] 34. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of recurrent herpes labialis.

[0320] 35. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of recurrent herpes labialis, the recurrent herpes labialis being selected from the group consisting of a patient showing signs of prodromal stage of herpes labialis, a patient having an erythema, a patient showing lip papules, a patient having lip vesicles, a patient having lip ulcerations and / or soft scabs, a patient having hard scabs of the lips, a patient having residual lip erythema.

[0321] 36. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of genital herpes.

[0322] 37. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of herpes keratitis.

[0323] 38. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of herpes meningitis and / or encephalitis.

[0324] 39. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of herpes infections in neonates.

[0325] 40. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of herpes infections in individuals with normal immune capacity and / or immunocompromised individuals.

[0326] 41. N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7 for use in the treatment and / or prophylaxis of herpes infections in immunocompromised individuals, wherein the immunocompromised individuals are selected from the group consisting of recipients of organ transplants, individuals suffering from an infection caused by another virus or bacteria, in particular an infection with HIV and / or another herpes virus, and individuals infected with a herpes simplex virus that is resistant to at least one antiviral agent.

[0327] 42. A method of treating and / or preventing a herpes virus infection comprising administering to an individual in need thereof N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7.

[0328] 43. A process for the manufacture of N-[5-(amino-sulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate as defined in any one of embodiments 1 to 7, wherein the process comprises the following steps:

[0329] a) mixing (4-pyridin-2-yl-phenyl)-acetic acid with amino thiazole sulfonic acid amide in N-methyl pyrrolidone (NMP);

[0330] b) cooling the mixture obtained in step a);

[0331] c) adding N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCI) to the mixture obtained in step b);

[0332] d) stirring the solution obtained in step c) and adding to purified H20;

[0333] e) filtering the solution obtained in step d);

[0334] f) washing the product cake obtained in step e);

[0335] g) drying the product obtained in step f);

[0336] h) adding H20 to the solution obtained in step g);

[0337] i) stirring the suspension obtained in step h);

[0338] j) cooling the suspension obtained in step i);

[0339] k) stirring the suspension obtained in step j);

[0340] 1) isolating the product by filtering the suspension obtained in step k);

[0341] m) washing the product obtained in step 1) with H20;

[0342] n) drying the product obtained in step m).

[0343] 44. A pharmaceutical composition comprising N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate obtainable in the process of embodiment 43.

[0344] 45. A pharmaceutical composition obtainable by formulating the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide obtainable in the process of embodiment 43 together with at least one pharmaceutical excipient.

[0345] 46. Use of the free base hemihydrate of N-[5-(amino-sulfonyl)-4-methyl-l,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide obtainable in the process of embodiment 43 as a medicament.

Claims

1. Use of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridyl)phenyl]acetamide free base hemihydrate having the molecular formula C 18 H 18 N4O3S2x0.5H2O in the manufacture of a topical pharmaceutical formulation for the treatment and / or prevention of a herpes virus infection in an individual in need thereof, wherein the topical pharmaceutical formulation is suitable for administration to the eye.

2. A topical pharmaceutical composition comprising N-[5-(amino-sulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate having the molecular formula C 18 H 18 N4O3S2 x 0.5 H2O and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is polyethylene glycol.

3. A topical pharmaceutical composition comprising N-[5-(amino-sulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide free base hemihydrate having the molecular formula C 18 H 18 N4O3S2 x 0.5 H2O and at least one pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl methyl cellulose.

4. The topical pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable excipient is hydroxypropyl methylcellulose.

5. The topical pharmaceutical composition according to any one of claims 2 to 4, wherein the composition is selected from the group consisting of an ointment, a gel and a film.

6. The topical pharmaceutical composition according to any one of claims 2 to 4, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 0.1% w / w to 10% w / w.

7. The topical pharmaceutical composition according to any one of claims 2 to 4, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 1.0% w / w to 7.5% w / w.

8. The topical pharmaceutical composition according to any one of claims 2 to 4, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 2.5% w / w to 6.0% w / w.

9. The topical pharmaceutical composition according to any one of claims 2 to 4, wherein the N-[5-(amino-sulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)phenyl]acetamide free base hemihydrate is present in an amount of 5.0% w / w.

10. The topical pharmaceutical composition according to claim 9, wherein the topical pharmaceutical composition is an ointment.

11. The topical pharmaceutical composition according to claim 10, wherein the ointment is administered 1 to 10 times a day.

12. The topical pharmaceutical composition according to claim 10, wherein the ointment is administered 2 to 10 times a day.

13. The topical pharmaceutical composition according to claim 10, wherein the ointment is administered 3 to 8 times a day.

14. The topical pharmaceutical composition according to claim 10, wherein the ointment is administered 3 to 7 times a day.

15. The topical pharmaceutical composition according to claim 10, wherein the ointment is administered 4 to 6 times a day.

16. The topical pharmaceutical composition according to claim 10, wherein the ointment is administered 5 times a day.

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