Medical active substance

Abstract

The present invention relates to amines (AM) of general formula (I) for use in the treatment of Aspergillus fumigatus infections and influenza virus repeated infections with Aspergillus; a carbonic acid adduct (KA) and a pharmaceutical composition (PZ).

Description

Technical Field

[0001] The present invention relates to an amine (AM) of the general formula (I), a carbonic acid adduct (KA) and a pharmaceutical composition (PZ) for treating Aspergillus fumigatus infection and influenza virus and Aspergillus superinfection. Background Art

[0002] Influenza viruses are continuing to cause severe respiratory diseases, which result in considerable morbidity and mortality. Global seasonal epidemics cause 3-5 million severe cases each year, and an estimated 300,000-500,000 deaths (1). In addition, influenza A viruses have the potential to cause pandemics, which has caused millions of deaths in the past, as demonstrated by the outbreak of the Spanish flu in 1918 / 19 (2). Although most people recover from infection, others experience complications, such as lung inflammation, which is caused by the virus itself or other pathogens (including bacteria), among which Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae play a major role (3). In the case of influenza virus and bacterial repeated infection, the causes of severe progression have been well studied, and new treatment options have become the focus of attention. However, for influenza virus and fungal repeated infection, this is not the case (4,5).

[0003] However, it is clear that fungi such as Aspergillus spp. infections, especially Aspergillus fumigatus, occur in patients infected with influenza virus and cause increased morbidity and mortality (5-9). A common problem with secondary fungal infections is that they are usually identified too late (10,11). In addition to the pathogenicity increased in the case of repeated infection of influenza virus and Aspergillus fumigatus, the limited availability of effective anti-infective drugs for various pathogens is very important (5,6,12). The high variability of influenza virus and the continuous emergence of new strains, as well as the rapid development of influenza virus resistance to available drugs (13-16) and the combination of late identification of fungal infections (10,11) are the main reasons for poor treatment selection. So far, it is not feasible to treat repeated infection of influenza virus and fungi with a single active ingredient.

[0004] Despite the great progress in intensive research and possible treatments in the last century, influenza viruses still pose a serious threat to the population. Seasonal epidemics can be attributed to continuous point mutations (antigenic drift) in the genomes of influenza A and B viruses, which lead to changes in protein structure. In addition, influenza A viruses have the potential to cause pandemic outbreaks (2, 20-22). In the case where each individual is infected with more than one viral subtype, the exchange of gene segments (antigenic shift) can lead to viral subtypes that contain parental strain characteristics in new combinations (20, 21). As a result, the immune system of the infected host is naive and cannot effectively fight new pathogens. There have been several pandemics in the last century, among which the "Spanish flu" of 1918 / 19 had the most serious consequences (23). The influenza strain that caused the 2009 pandemic is still circulating in the population together with the 1968 H3N2 line and two different influenza B viruses (20).

[0005] Although viral and bacterial superinfections have been well studied in the past few years, little is known about viral and fungal superinfections. Bacterial superinfections usually occur within the first seven days after influenza virus infection, and these lead to more fulminant symptoms, accompanied by lung inflammation and elevated mortality (24, 25). However, in some cases, bacterial superinfections occur only when the viral infection seems to have been cured. There are many descriptions of the effect of influenza virus infection paving the way for bacterial superinfections. As a result of influenza virus infection, the cleaning function of cilia is destroyed, and the mucosal layer dissolves, thus exposing other bacterial receptors. In addition, immune response disorders lead to reduced defense and increased inflammatory processes (4, 26). In the past few years, it has also been reported that patients with severe influenza virus infection develop into invasive pulmonary aspergillosis, which is caused by influenza virus and fungi such as Aspergillus, especially repeated infection of Aspergillus fumigatus. This leads to even higher mortality (27, 28) compared with simple infection of influenza virus.

[0006] Aspergillus is a filamentous, saprophytic fungus found in the air and soil (11, 29). In healthy people, inhaled conidia are resisted by mucociliary clearance and early immune defense mechanisms (11). In patients with weakened immune systems or transplant patients, the risk of complications increases and mortality increases (5, 28). In patients with weakened immune systems, the likelihood of developing invasive pulmonary aspergillosis, characterized by penetration of lung tissue by hyphae of Aspergillus fumigatus, is further increased and associated with increased mortality (10). A relatively new and unresolved clinical entity is post-influenza aspergillosis, which is difficult to diagnose. It has recently become clear that influenza A and B virus infections are responsible for the development of fungal superinfections in patients with weakened and unweakened immune systems (6, 30, 31). It is speculated that, similar to the case of bacterial superinfections, the loss of mucociliary function means that patients are susceptible to fungal superinfections and invasive fungal infections (31).

[0007] To date, the most effective way to prevent the annual influenza virus epidemic is vaccination (1, 13). Even if new vaccines are produced every year, vaccination rates are low, efficiency is variable, and in the case of the emergence of new influenza A virus subtypes, adapted vaccines cannot be obtained in a timely manner. The transformation and production of new vaccines must be carried out for each new virus variant, which requires at least six months. Therefore, there is a period of unprotected populations between the emergence of pathogens and the introduction of new vaccines. Therefore, it is necessary to use antiviral alternatives for infection control.

[0008] For antiviral therapy, the European Medicines Agency (EMA) has approved three classes of compounds that target ion channel proteins (M2), neuraminidase, or CAP-dependent endonucleases. Although neuraminidase inhibitors are effective against influenza A and B viruses, M2 inhibitors are ineffective against influenza B virus (13). Unfortunately, influenza viruses can rapidly develop resistance to therapeutic drugs. Some reports involve resistant variants of influenza B virus to oseltamivir, H5N1, and pandemic H1N1v influenza A virus. The frequent emergence of resistant variants in clinical isolates of adamantanes has led to recommendations not to use M2 inhibitors for treatment and prevention until susceptibility to these drugs has been reestablished in circulating influenza A viruses (16). Another weakness in existing antiviral treatment approaches is that antiviral treatment must be started as soon as possible after symptoms have begun.

[0009] New antiviral strategies include (a) inhibiting virus-supporting cell function, (b) promoting antiviral defense, or (c) reducing inflammation (32).

[0010] The most promising antiviral strategies to combat influenza infection are based on the fact that influenza virus, as an intracellular pathogen, is greatly dependent on cellular signaling mechanisms. Influenza virus is able to manipulate cytokines for its own purposes to ensure its replication and spread. In addition, influenza virus can resist the innate immune response of its host. In view of these dependencies, cellular viral support functions are targets for antiviral intervention (32). In the past few years, various cytokines have been identified as suitable targets for antiviral intervention (33), including the Raf / MEK / ERK mitogen kinase cascade (32, 34-39), the IKK / NFκB module (40-42), and the PI3K signaling pathway (33, 43-48). It was found that attacking most of these factors was effective against influenza virus infection in vitro and in vivo in mouse models. The first clinical study of LASAG suggested its antiviral effect on influenza virus infection in hospitalized patients (61). Attacking cellular rather than viral factors reduces the possibility of resistance development because it is more difficult for pathogens to compensate for the lack of cellular functions.

[0011] Among antifungal drugs, triazoles are the first choice for the treatment of aspergillosis, but echinocandins and polyene amphotericin B are also used (29). Recent developments in resistance in Aspergillus spp., especially in Aspergillus fumigatus variants, are worrisome. Azole resistance has increased worldwide, and therefore, new guidelines recommend the voriconazole-eninocandin combination or amphotericin B (5). Typically, prophylactic treatment for aspergillosis is not initiated. Antifungal therapy is initiated empirically only when a fungal infection is evident or has been detected. This is a combination of immunomodulatory therapy and antifungal therapy (29).

[0012] There are only limited options for the treatment of viral / fungal superinfections. In fact, corticosteroid therapy, which is often used in ER, is contraindicated due to prolonged viral shedding, increased mortality, and increased invasive pulmonary aspergillosis (5). As recent studies have shown significant interference of A. fumigatus and its host in the course of invasive aspergillosis, specific fungal accessory cytokines and fungal-induced deleterious inflammatory processes are alternative attack options (29, 49, 50).

[0013] Due to the phylogenetic relationship between fungi and humans, there are a variety of very conserved factors (51). For example, these homologs may be simultaneously attacked by chemical inhibitors of cellular functions that subsequently act on host cell Aspergillus or pathogen-induced cellular functions. Among them, mitogen-activated protein kinase (MAPK) cascades have been identified (49, 52-54), which regulate fungal processes such as biofilm formation (55), stress tolerance (52, 53), toxicity (49) and host cell functions such as inflammatory processes (50). Interestingly, antifungal drugs such as itraconazole have recently been shown to have inhibitory effects on influenza virus replication (56, 57) and SARS-CoV-2 infection (58). Although the effects may be attributed to the different mechanisms of action of the compounds during different viral replication, in the case of influenza virus infection, there has been discussion on blocking the export of cholesterol from the endolysosomal compartment and thus reducing replication (56).

[0014] Notably, MAPKs have also been identified as potential targets for influenza virus intervention, as they are involved in viral replication and virus-induced excessive inflammation (59, 60).

[0015] Therefore, there is a continuing need for new therapeutics for treating influenza virus, Aspergillus spp., and particularly for treating repeated infections caused by influenza virus and Aspergillus spp. Summary of the invention

[0016] The present invention relates to amines (AM) of the general formula (I) for use in treating Aspergillus fumigatus infections and influenza virus and Aspergillus superinfections,

[0017]

[0018] Wherein, in formula (I),

[0019] R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0020] R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0021] R3 is -(CH2)nNR8R9;

[0022] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0023] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0024] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl;

[0025] R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0026] R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0027] R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0028] R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O-(C 1-10 )alkyl;

[0029] The amines of the formula (I) can optionally also be used in the form of salts.

[0030] In another aspect, the present invention relates to a carbonic acid adduct (KA) comprising at least one structural unit of the general formula (II), (III) and / or (IV) for use in the treatment of Aspergillus fumigatus infections and superinfections with influenza virus and Aspergillus.

[0031]

[0032]

[0033] Wherein, in formula (II), (III) and (IV),

[0034] R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0035] R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0036] R3 is -(CH2) n NR8R9;

[0037] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0038] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0039] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl;

[0040] R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0041] R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10)alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0042] R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0043] R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or –-05O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0044] x is 0.5-30;

[0045] (S) is salt.

[0046] In another aspect, the present invention relates to a carbonic acid adduct (KA) for use in treating Aspergillus fumigatus infections and influenza virus and Aspergillus superinfections, comprising carbonic acid, at least one amine (AM) of the general formula (I) and at least one salt (S),

[0047]

[0048] Wherein, in formula (I),

[0049] R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0050] R2 is H, (C 1-10 ) alkyl, (C2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0051] R3 is -(CH2)nNR8R9;

[0052] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0053] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0054] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl;

[0055] R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0056] R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0057] R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0058] R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0059] wherein the at least one amine of formula (I) may optionally also be used in the form of a salt;

[0060] It can be prepared by a method comprising the following steps:

[0061] a) providing a solution (A) comprising at least one solvent and CO2 dissolved in the at least one solvent,

[0062] Optionally b) dissolving a base (BA) which does not correspond to the amine (AM) in the solution (A) to obtain a solution (A1),

[0063] c) dissolving the at least one amine (AM) in solution (A) or (A1) to obtain solution (B),

[0064] d) freezing the solution obtained at the end of step c),

[0065] e) storing the solution frozen in step d) at -100 to 0°C for no more than 4 days.

[0066] The present invention also relates to a pharmaceutical composition comprising the amine or the carbonic acid adduct for use in treating Aspergillus fumigatus infection and repeated infection with influenza virus and Aspergillus spp.

[0067] The disclosed substances can produce influenza virus infection and influenza virus-induced cytokine expression, and can block hyphae formation of Aspergillus fumigatus. Therefore, the present invention provides a novel method for antipathogenic treatment of two pathogens with a single active ingredient. In addition, the potential impact of pathogen-induced cytokines enables regulation of excessive immune responses in repeated infection situations. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 : Procaine-containing active ingredients (eg, procaine hydrochloride (HCl)) reduce hyphae formation of Aspergillus fumigatus.

[0069] (A) The steps of the treatment method are as follows: conidia [5*10 6conidia / well] were inoculated on coverslips in 24-well plates in 300 μl of DMEM / BA medium (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2) and supplemented in each case with solvent (H2O), procaine HCl [0.31 (B) or 1.25 (C) -10 mM] or voriconazole [0.2 μg ml -1 ], incubated at 37 ° C, 5% CO2 for 10 hours. Subsequently, the fungi were fixed (3.7% formaldehyde in PBS, 30 minutes, room temperature) and applied to a microscope slide with the help of a fluorescent dye solution (Agilent, Santa Clara, CA, USA). Mycelial size was analyzed with (B) Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and Fiji V 1.52b software (Github.com / fiji / fiji). (C) Fungal size was calculated using particle counter software (github.com / chko90 / particle counter). Data represent four experiments (B) or the mean ± SD of four experiments with two technical samples in each case (C). Statistical significance was calculated using a one-way ANOVA Dunnett multiple comparison test with GraphPad Prism 9.2 (GraphPadSoftware, Boston, USA). P values ​​are indicated with asterisks *p<0.05.

[0070] Figure 2 : In the presence of an active ingredient containing procaine (e.g., procaine hydrochloride), the pathogenic load of influenza virus and Aspergillus fumigatus is reduced in an in vitro test. (A) Treatment method steps: Human lung epithelial cells (A549) [0.5*10 5 Cells / well] were seeded in DMEM (10% FCS) on coverslips in 24-well plates and incubated at 37°C, 5% CO2 for 23.5 hours. 30 minutes before infection, cells were pretreated with specific concentrations of procaine hydrochloride or voriconazole in DMEM / BA (0.2% BSA, 1mM MgCl2 and 0.9mM CaCl2) and then infected with influenza virus A / Puerto Rico / 8 / 34 [0.5 multiplicity of infection (MOI)] in PBS / BA (0.2% BSA, 1mM MgCl2 and 0.9mM CaCl2) for 30 minutes. Then, the inoculum was removed, the cells were washed with PBS, and the cells were incubated in DMEM / BA / trypsin (0.2% BSA, 1mM MgCl2 and 0.9mM CaCl2, 167ng ml -1(B) The supernatant of infected cells was collected and the virus titer (plaque forming unit (PFU) / ml) was detected by standard plaque titration. (C) The expression of viral nucleoprotein (NP), GFP (GFP) of Aspergillus fumigatus strains and cellular protein extracellular signal-regulated kinase 2 (ERK2) was visualized in Western Blot analyses (D I-IV). Cells were fixed (3.7% formaldehyde in PBS, 30 minutes, room temperature) and prepared for immunofluorescence studies. Influenza virus nucleoprotein was visualized by anti-influenza virus nucleoprotein antibody (BioRad) and AlexaFluor647 (Invitrogen). Cell nuclei were stained with bisbenzimide H-33342 trihydrochloride (Hoechst-33342; Merck) diluted 1:1000 in PBS (3% normal goat serum). The presence of A. fumigatus was observed by internal GFP expression (GFP). Samples were applied to microscope slides together with a fluorescent dye solution (Agilent, Santa Clara, CA, USA). Imaging and image processing were performed with an Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and Fiji V 1.52b software (Github.com / fiji / fiji). Shown are images of individual channels and their overlays (combinations). Data are means ± SD of four independent experiments including two technical samples.

[0071] (B), and schematic diagrams from four experiments (C, D I-IV). Statistical significance was verified using GraphPad Prism 9.2 (GraphPad Software, Boston, USA) using a one-way ANOVA with Tukey's multiple comparison test (p < 0.05 was considered the level of statistical significance).

[0072] Figure 3 : Treatment of A549 cells infected with influenza A virus and / or Aspergillus fumigatus with ProcCluster or procaine hydrochloride resulted in reduced viral load and hyphae formation at 10 h post infection (pi). (A) Steps of the treatment method: Human lung epithelial cells (A549) [0.25*10 5 cells / 24 wells (BI-IV-C) or 0.5*10 5Cells / 12 well (DF)] were seeded in DMEM (10% FCS) and incubated at 37°C, 5% CO2 for 24 hours. The cells were infected with influenza virus A / Puerto Rico / 8 / 34 (IAV) [0.5 MOI] in PBS / BA (0.2% BSA, 1mM MgCl2 and 0.9mM CaCl2) for 30 minutes. Then, the inoculum was removed and the cells were inoculated in DMEM / BA / trypsin (0.2% BSA, 1mM MgCl2 and 0.9mM CaCl2, 167ng ml -1 Trypsin-TPCK Conidia of Aspergillus fumigatus (A.fu.) [10MOI] were added in the presence of procaine hydrochloride or solvent control (H2O). Subsequently, the cells were incubated at 37°C, 5% CO2 for 10 hours (BI-IV). The cells were fixed (3.7% formaldehyde in PBS, 1 hour, room temperature) and prepared for immunofluorescence studies. The influenza virus nucleoprotein was visualized by anti-influenza virus nucleoprotein antibodies (BioRad) and AlexaFluor647 (Invitrogen). The nuclei were stained with bisbenzamide H-33342 trihydrochloride (Hoechst-33342, Merck). The presence of Aspergillus fumigatus was observed by internal GFP expression. The samples were applied to a microscope slide together with a fluorescent dye solution (Agilent, Santa Clara, CA, USA). The scale of the immunofluorescence image corresponds to 100 μm. Immunofluorescence detection and imaging and image processing (C) were performed using an Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and Fiji V 1.52b software (Github.com / fiji / fiji). Fungal size was calculated using particle counter software (GitHub.com / Chko90 / Particle Counter). Five immunofluorescence images were recorded for each sample. The determined fungal size was standardized, and the control of uninfected virus, untreated, and Aspergillus fumigatus infection was set to 100%. (D) Supernatants of IAV or co-infected A549 cells were collected 10 hours after infection. Viral titers were detected by standard plaque titration and expressed in PFU / ml. (E) Expression of viral polymerase basic protein 1 (PB1), hemagglutinin (HA), nucleoprotein (NP) and matrix protein 1 (M1) and GFP and housekeeping protein ERK2 of Aspergillus fumigatus (GFP) were observed by Western blot analysis. (F) Individual signals from proteins were quantified relative to ERK2 using Fiji V 1.52b software (Gitchub.com / fiji / fiji) and are described as the relative amount of protein based on H2O IAV or H2O Aspergillus fumigatus (A.fu). Data are mean ± SD of three (CE, F) independent experiments with technical replicates. Immunofluorescence images (B) and Western blot images (E) are representative experiments of three experiments (B, E) with technical replicates (B). Statistical significance was determined by one-way (C, D) or two-way (F) ANOVA multiple comparison test and Tukey analysis using GraphPad Prism 9.2 (GraphPad Software, Boston, USA) (p < 0.05 was considered to be the level of statistical significance).

[0073] Figure 4: Treatment of A. fumigatus with ProcCluster or procaine hydrochloride in a human cell-free system resulted in reduced hyphae formation. (A) Steps of the treatment method: Conidia [5*10 6 Conidia / well] were inoculated on coverslips of 24-well plates and incubated for 10 hours at 37°C, 5% CO2 in DMEM containing 10% FCS with solvent (HO) or with specific concentrations of voriconazole, ProcCluster (BC) or procaine hydrochloride (DE). Subsequently, the fungus was fixed (3.7% formaldehyde in PBS, 1 hour, room temperature) and applied to a microscope slide together with a fluorescent dye solution (Agilent, Santa Clara, CA, USA). (B, D) The growth of Aspergillus fumigatus was observed by internal GFP expression. The scale of the immunofluorescence image corresponds to 100 μm. Immunofluorescence detection and imaging and image processing were performed using an Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and Fiji V 1.52b software (Github.com / fiji / fiji). (C, E) Fungal size was determined by particle counter software (Github.com / chko90 / Particle Counter). Five immunofluorescence images were taken for each sample. The determined fungal size was normalized and the solvent control was set to 100%. Statistical significance was determined by one-way ANOVA test with Dunnett's multiple comparison test using GraphPad Prism 9.2 (GraphPad Software, Boston, USA) (p < 0.05 was considered as the level of statistical significance).

[0074] Figure 5 : Treatment of Aspergillus fumigatus with ProcCluster in a human cell-free system during germination resulted in a reduction in further hyphal growth. (A) Steps of the treatment method: Conidia of an Aspergillus fumigatus strain expressing GFP [5*1 06Conidia / well] were inoculated on coverslips of 24-well plates and incubated for 10 hours at 37°C, 5% CO2 in DMEM containing 10% FCS (added at time 0) with 2.5 mM ProcCluster or with solvent (H2O). Subsequently, the fungus was fixed (3.7% formaldehyde in PBS, 1 hour, room temperature) and applied to a microscope slide with a fluorescent dye solution (Agilent, Santa Clara, CA, USA). (B) The growth of Aspergillus fumigatus was observed by internal GFP expression. The scale of the immunofluorescence image corresponds to 100 μm. Immunofluorescence detection and imaging and image processing were performed using an Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and Fiji V 1.52b software (Github.com / fiji / fiji). (C) Fungal size was measured using a particle counter software (Gitohub.com / chko90 / particle counter). Five immunofluorescence images were taken for each sample. The determined fungal size was normalized and the untreated control (medium) was set to 100%. Statistical significance was determined by one-way ANOVA test with Dunnett's multiple comparison test using GraphPad Prism 9.2 (GraphPad Software, Boston, USA) (p < 0.05 was considered as the level of statistical significance).

[0075] Figure 6 : Treatment of A. fumigatus with ProcCluster results in inhibition of IAV-induced hyphae formation in a human cell-free system. (A) Steps of the treatment method: conidia [5*10 6Conidia / well] were inoculated on coverslips of 24-well plates and incubated with purified influenza virus A / Puerto Rico / 8 / 34 virus particles [10IAV particles / fungus] and solvent (H2O) or 2.5mM ProcCluster in DMEM containing 10% FCS at 37°C, 5% CO2 for 10 hours. Subsequently, the fungus was fixed (3.7% formaldehyde in PBS, 1 hour, room temperature) and applied to a microscope slide with a fluorescent dye solution (Agilent, Santa Clara, CA, USA). (B) The growth of Aspergillus fumigatus was observed by internal GFP expression. The scale of the immunofluorescence image corresponds to 100 μm. Immunofluorescence detection and imaging and image processing were performed using an Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and Fiji V 1.52b software (Github.com / fiji / fiji). (C) Fungal size was determined using particle counter software (Gitohub.com / chko90 / Particle Counter). Five immunofluorescence images were taken for each sample. The determined fungal size was normalized and the unstimulated solvent control was set to 100%. Statistical significance was determined by one-way ANOVA test with Dunnett's multiple comparison test using GraphPad Prism 9.2 (GraphPad Software, Boston, USA) (p < 0.05 was considered a level of statistical significance). DETAILED DESCRIPTION OF THE INVENTION

[0077] The present invention relates to amines (AM) of the general formula (I)

[0078]

[0079] Wherein, in formula (I),

[0080] R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0081] R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0082] R3 is -(CH2)nNR8R9;

[0083] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0084] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0085] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl;

[0086] R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0087] R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0088] R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0089] R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O-(C 1-10 )alkyl;

[0090] The amine of formula (I) can also be used in the form of a salt,

[0091] It is used for treating Aspergillus fumigatus infection and superinfection with influenza virus and Aspergillus, preferably superinfection with influenza virus and Aspergillus.

[0092] The influenza virus is preferably selected from influenza A virus, influenza B virus and influenza C virus, preferably influenza A virus.

[0093] The Aspergillus genus is preferably Aspergillus fumigatus.

[0094] In the context of the present invention, treating an infection with Aspergillus fumigatus preferably refers to treating aspergillosis caused by infection with Aspergillus fumigatus.

[0095] In the context of the present invention, repeated infection refers to that first the subject (e.g., patient) is infected by a pathogen, and then, before the first pathogen infection is overcome, a delay of a period of time is infected by at least one second pathogen, so that the result is at least temporarily infecting the first and second pathogens simultaneously. Therefore, in this article, first infect influenza virus, preferably influenza A virus, then infect Aspergillus, preferably Aspergillus fumigatus or first infect Aspergillus, then infect influenza virus, preferably other infection of influenza A virus, preferably first infect influenza virus, preferably influenza A virus, then infect other infection of Aspergillus. Preferably, in the case of repeated infection, Aspergillus, preferably infection of Aspergillus fumigatus causes aspergillosis in the infected subject. Preferably, in the repeated infection process, influenza virus infection causes influenza in the infected subject.

[0096] Application in the treatment of viral diseases, especially influenza, involves the use of antiviral effects. Typically, active antiviral ingredients inhibit the development and reproduction cycle rather than attacking the virus directly.

[0097] Without being bound by any particular theoretical explanation, it is currently hypothesized that the observed antiviral effects of the compounds of the present invention may be mediated preferentially indirectly through interactions with metabolic pathways of the infected organism responsible for viral multiplication.

[0098] Use in the treatment of fungal infections involves the use of antifungal effects. In general, antifungal substances have a damaging effect on the cell walls of fungi.

[0099] Without being bound by any particular theoretical explanation, it is currently believed that the observed antifungal effects of the compounds of the present invention may be mediated indirectly, preferably through interactions with fungal metabolic pathways responsible for viability.

[0100] In one embodiment, in formula (I), R1, R2, R3, R4, R5, R6 are H;

[0101] R3 is -(CH2) n NR8R9;

[0102] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0103] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0104] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl.

[0105] In the present invention, for example (C 1-10 )alkyl, as defined for the R1 group of formula (I), means that the substituent (group) is a saturated alkyl group having 1 to 10 carbon atoms. The alkyl group may be straight-chain or branched, and optionally cyclic. Alkyl groups having cyclic and linear parts are also covered by this definition. The same applies to other alkyl groups, such as C 1-2 Alkyl. The alkyl group may also be optionally mono- or polysubstituted by functional groups such as amino, hydroxyl, halogen, aryl or heteroaryl. Unless otherwise indicated, the alkyl group preferably has no functional groups as substituents. Examples of alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, isopropyl (also known as 2-propyl or 1-methylethyl), isobutyl, tert-butyl, sec-pentyl, neopentyl, 1,2-dimethylpropyl, isopentyl, isohexyl, isoheptyl.

[0106] In the present invention, for example, C 2-10 The definition of alkenyl, such as that for the R1 group of formula (I), means that the substituent (group) is an alkenyl group having 2 to 10 carbon atoms and having at least one unsaturated carbon-carbon bond. The alkenyl group may be straight-chain or branched and optionally cyclic. Alkenyl groups having cyclic and linear components are also covered by this definition. The same applies to other alkenyl groups, such as C 2-4 Alkenyl. The alkenyl group can also be optionally monosubstituted or polysubstituted by functional groups such as amino, hydroxyl, halogen, aryl or heteroaryl. The alkenyl preferably does not have any other functional groups as substituents. The example of alkenyl is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 5-octenyl, 1-nonenyl, 2-nonenyl.

[0107] In the present invention, the definition aryl refers to an aromatic or heteroaromatic group. An aromatic group is an aromatic cyclic hydrocarbon, which may consist of a ring or a ring system consisting of two or more condensed rings. An aromatic group may be, for example, monocyclic, bicyclic or tricyclic. A monocyclic aromatic group preferably forms a 5- or 6-membered ring. A bicyclic aromatic ring preferably forms a 9- or 10-membered ring. A tricyclic aromatic ring preferably forms a 13- or 14-membered ring. For example, (C5-C 14 ) The definition of aryl means that the aryl group contains 5-14 carbon atoms. The aryl group preferably contains 3 to 14, more preferably 4 to 6 carbon atoms. The aryl group may also be optionally mono- or polysubstituted by functional groups such as alkyl, alkenyl, amino, cyano, -CF3, hydroxyl, halogen, aryl or heteroaryl; the aryl group preferably does not have any other substituents. Examples of aromatic groups are phenyl and naphthyl.

[0108] In the present invention, the definition of heteroaryl refers to heteroaryl. "Heteroaromatic ring" means an aromatic group as defined above, whose ring system is formed by carbon atoms, one or more of which are replaced by heteroatoms such as O, N or S. For example, (C5-C 10 The definition of heteroaryl is based on the corresponding definition of aryl and means that heteroaryl has 5 to 10 atoms in the ring. However, as defined above, one or more carbon atoms are replaced by heteroatoms. This means that (C5-C 10 ) Heteroaryl has 5 to 10 atoms in the ring, not all of which are carbon atoms. Thus, for example, furanyl is a C5-heteroaryl. Heteroaryl groups may also optionally be mono- or polysubstituted by functional groups such as alkyl, alkenyl, amino, cyano, -CF3, hydroxyl, halogen, aryl or heteroaryl; preferably, heteroaryl does not have any other substituents. Examples of heteroaromatic groups encompassed by the definition of aryl according to the present invention are furanyl, thienyl, oxazolyl, pyrazolyl, pyridyl and indolyl.

[0109] In the present invention, halogen as defined above, for example, for the R4 group of formula (I), is defined as a chlorine, bromine, iodine or fluorine substituent. It is preferably a chlorine or fluorine substituent.

[0110] The amine (AM) of general formula (I) is preferably selected from 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine), ethyl 4-aminobenzoate (benzocaine), 2-(diethylamino)ethyl 4-amino-2-chlorobenzoate (chloroprocaine), 2-diethylaminoethyl 4-amino-3-butoxybenzoate (oxybuprocaine), 2-(dimethylamino)ethyl 4-(butylamino)benzoate (butylcaine), more preferably 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine).

[0111] The amines (AM) of the general formula (I) and the amines (AM) mentioned specifically above are used in medicine as local anesthetics and are correspondingly commercially available.

[0112] The present invention also relates to a carbonic acid adduct (KA) comprising at least one structural unit of the general formula (II), (III) and / or (IV)

[0113]

[0114]

[0115] Wherein, in formula (II), (III) and (IV),

[0116] R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0117] R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0118] R3 is -(CH2) n NR8R9;

[0119] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0120] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0121] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl;

[0122] R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0123] R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0124] R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0125] R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0126] x is 0.5-30;

[0127] (S) is salt;

[0128] It is used for treating Aspergillus fumigatus infection and superinfection with influenza virus and Aspergillus, preferably superinfection with influenza virus and Aspergillus.

[0129] In one embodiment, in formula (I), R1, R2, R3, R4, R5, R6 are H;

[0130] R3 is -(CH2) n NR8R9;

[0131] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0132] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0133] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl.

[0134] The salt (S) comprises at least one selected from Na+ , K + , Li + 、M g2+ 、Zn 2+ , Fe 2+ , Fe 3+ and Mn 2+ The cation is preferably Na + The salt (S) further comprises at least one selected from Cl - Br - ,I - 、F - 、SO4 2- 、SO3 2- 、HSO4 - 、HSO3 - 、-HCO3 - 、CO3 2- PO4 3- 、HPO4 2- 、H2PO4 - 、SiO4 4- 、AlO2 - 、SiO3 - and / or [AlO2) 12 (SiO2)2] 2- The anion is preferably Cl - and Br - , more preferably Cl - .

[0135] The preparation of the carbonic acid adduct (KA) is also disclosed in WO2006 / 007835, DE102013015035A1 and WO2019 / 048590, which are incorporated herein by reference.

[0136] The invention also relates to a carbonic acid adduct (KA) comprising carbonic acid, at least one amine (AM) of the general formula (I) and at least one salt (S),

[0137]

[0138] Wherein, in formula (I),

[0139] R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0140] R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H;

[0141] R3 is -(CH2) n NR8R9;

[0142] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0143] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0144] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl;

[0145] R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0146] R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen;

[0147] R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0148] R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl;

[0149] wherein the at least one amine of formula (I) may optionally also be used in the form of a salt;

[0150] It is used to treat Aspergillus fumigatus infections and superinfections with influenza virus and Aspergillus spp.

[0151] In one embodiment, in formula (I), R1, R2, R4, R5, R6 are H;

[0152] R3 is -(CH2) n NR8R9;

[0153] n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,

[0154] R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl,

[0155] R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl.

[0156] If an acid addition salt of the amine (AM) is used, the salt (S) can be formed, for example, by an acid-base reaction of the base (BA) with the acid added to the amine (AM) when step b) is carried out. The salt (S) can also be added directly in one of steps a), b) and / or c). If the amine (AM) is not used in the form of a salt and / or step b) is not carried out, the salt (S) is preferably added directly.

[0157] The carbonic acid adduct (KA) is preferably stable when stored at a temperature of 2-10° C. for at least 12 months, more preferably at least 13 months, even more preferably at least 20 months, particularly preferably at least 23 months, most preferably at least 27 months.

[0158] The carbonic acid adduct (KA) is no longer considered to be stable when specific bands of the at least one amine (AM), in particular in the solid carbonic acid adduct (KA), can be detected by IR spectroscopy. The specific IR bands of the amines are those which are also detected in the IR spectral analysis of the pure amines (AM). If the amine (AM) is bound in a stable carbonic acid adduct (KA), the specific IR bands of the amine (AM) cannot be detected.

[0159] In various embodiments, the loss of stability may also be associated with an increase in pH or with the measurement of two melting / decomposition ranges, one corresponding to the amine (KA) and one corresponding to the carbonic acid adduct (KA). In the case of a carbonic acid adduct that has become unstable due to at least partial decomposition into the amine (AM) and CO2 and / or water, the solubility characteristics may also change. It can be found that the carbonic acid adduct (KA) that has become unstable is sparingly soluble or at least partially insoluble.

[0160] The carbonic acid adduct (KA) can be prepared by a process comprising steps a), optionally b), c), d) and e).

[0161] In step a), a solution (A) is provided comprising at least one solvent and CO2 dissolved in the at least one solvent.

[0162] Solution (A) comprises at least one solvent and dissolved CO2. In the context of the present invention, CO2 means carbon dioxide. In the context of the present invention, dissolved CO2 means all forms of CO2 into which it enters when dissolved. For example, in the case of aqueous solutions, it is known that the CO2 dissolved in the solution can be present in equilibrium in the form of CO2, carbonic acid, mono- or di-deprotonated carbonic acid (i.e. as bicarbonate or carbonate).

[0163] Solution (A) is obtained by introducing CO2 into at least one solvent. CO2 can be introduced into the solvent in all suitable forms known to the person skilled in the art. Preferably, gaseous or frozen CO2, more preferably gaseous CO2, in the form of dry ice is introduced into the solvent. The gaseous CO2 or frozen CO2 preferably has at least food quality, more preferably a quality suitable for pharmaceutical purposes. The gaseous and / or frozen CO2 used preferably has a purity of at least 99.5%, even more preferably 99.9%.

[0164] In the context of the present invention, "food quality" preferably means meeting the relevant provisions of German and European food law. These preferably include Regulation (EC) No 852 / 2004 and Regulation (EC) No 178 / 2002, as well as Regulation (EC) No 1333 / 2008 and Regulation (EU) 231 / 2012.

[0165] "Pharmaceutical quality" preferably means meeting the relevant provisions of the European Pharmacopoeia (Ph. Eur.).

[0166] CO2 can also be introduced under pressure, especially when gaseous CO2 is introduced into the solution. In this regard, "introduced under pressure" means using a pressure greater than atmospheric pressure, preferably greater than 1.01325 bar. For this purpose, the introduction of CO2 into the solvent can be carried out in a container that isolates the solvent from the environment, so that a pressure can be generated in the container, especially by introducing CO2 above atmospheric pressure, preferably above 1.01325 bar. The introduction of CO2 into the solution, especially in gaseous form, can be carried out in one step or at intervals.

[0167] A person skilled in the art will be able to use any suitable solvent in step a). The solvent used is preferably a polar protic solvent; the solvent is more preferably water. Depending on the intended end use of the carbonic acid adduct (KA), solvents of various purities can be used. For example, if the carbonic acid adduct (KA) is used for pharmaceutical and medical purposes, water of "water for injection (Aqua adiniectabilia)" purity can be used.

[0168] Step a) may comprise a constituent step a1), wherein the solvent is preferably cooled to 3 to 8° C., preferably to 5° C., before the introduction of CO 2. Cooling may be performed by any method known to those skilled in the art that has been determined to be suitable. For example, cooling may be achieved by keeping the solvent in a refrigerator for a sufficient period of time so that the solvent has the target temperature. External cooling may also be used, for example.

[0169] Step a) may include a component step a2), wherein CO2 is introduced into the solvent, preferably until a saturation concentration of 3 to 10 g / l based on the total volume of the solution is reached, more preferably a saturation concentration of up to 4.5 to 7.5 g / l. The pH value of the solution after CO2 saturation is preferably ≤3.0≤6.0, more preferably ≤4.3 to ≤4.8. In the component step a2), CO2 is preferably dissolved under pressure, wherein the pressure is 1.5-10 bar, more preferably 1.9-7 bar, even more preferably 2-5 bar.

[0170] Step a) may comprise a constituent step a3), wherein the solution (A) obtained in constituent step a2) is preferably stored at 1 to 10°C for preferably at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; up to 5 days (120 hours). Preferably, the solution (A) preferably obtained in constituent step a2) is stored at 3-8°C for at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; up to 5 days (120 hours).

[0171] Step a) preferably comprises all constituent steps a1), a2) and a3).

[0172] Preferably, the constituent steps a1), a2) and a3) are performed in the order of a2) after a1), and a3) after a2).

[0173] Optionally, step b) can be performed, wherein a base (BA) which does not correspond to the amine (AM) is dissolved in solution (A) to obtain solution (A1). The base (BA) is preferably a bicarbonate or a carbonate, more preferably a bicarbonate, even more preferably sodium bicarbonate.

[0174] In step c) or c1), at least one amine (AM) is dissolved in solution (A) or (A1) to obtain solution (B).

[0175] At least one amine (AM) as defined above can be used in step c) in neutral form or in salt form. Optionally, the at least one amine (AM) can also be used in the form of a mixture of an amine (AM) in neutral form and an amine (AM) in salt form. Therefore, the at least one amine (AM) can include a neutral amine (AM) and / or a salt form of the at least one amine (AM). The salt form of the at least one amine (AM) is preferably an acid addition salt; the acid addition salt is preferably a hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydrogen methanesulfonate, hydrogen toluenesulfonate, hydrogen acetate, hydrogen format, hydrogen propionate, hydrogen malonate, hydrogen succinate, hydrogen fumarate, hydrogen oxalate, hydrogen tartrate, hydrogen citrate, hydrogen maleate, more preferably a hydrochloride or hydrobromide, even more preferably a hydrochloride.

[0176] Preferably, the concentration of amine (AM) in solution (B) is 0.01-0.25 g / ml, preferably 0.03-0.20 g / ml, more preferably 0.08-0.15 g / ml.

[0177] Step c) may comprise a constituent step c2) in which the at least one amine (AM) is dissolved in solution (A) or, in case step b) is carried out, in solution (A1 ), to obtain solution (B).

[0178] In one possible embodiment, when performing step b), the ratio of amine (AM) to base (BA) in solution (B) is 2:1 to 5:1, more preferably 3:1 to 4:1, even more preferably 3.23:1 to 3.26:1 [g / g].

[0179] In another possible embodiment, in the case of carrying out step b), the molar ratio of the base equivalents of the amine (AM) to the base (BA) in the solution (B) is 0.8: 1-1.5: 1, preferably 1.2: 1, more preferably 1: 1. In this regard, the base equivalent means that when a monobasic base, such as NaHCO3, is used, the molar ratio of the base (BA) to the amine (AM) complies with the ratio specified above. When a diacid base (BA) is used, such as Na2CO3, based on the molar amount of the base (BA) relative to the monobasic base used, only half the amount of base is required to introduce the same amount of base equivalents. For example, in the case of a ratio of 1: 1, when 10 mmol of amine (AM) is used, 10 mmol of NaHCO3 is required, but only 5 mmol of Na2CO3 is required.

[0180] In another embodiment, step b) is performed, in which, constituting step c1), the amine (AM) is added in the form of an acid addition salt, wherein the amount of amine (AM) added is such that the acid combined with the amine (AM) is able to neutralize the base (BA) to such an extent that the solution (B) exhibits a pH of 6-8.

[0181] Step c) may comprise a constituent step c2) wherein solution (A) is added to solution (B) to obtain solution (B1).

[0182] Preferably, the concentration of amine (AM) in solution (B1) is 0.01-0.25 g / ml, preferably 0.03-0.20 g / ml, more preferably 0.08-0.15 g / ml.

[0183] Step c) may comprise a composition step c3), wherein solution (B) or, in the case of carrying out composition step c2), solution (B1) is enriched with CO2. Preferably, solution (B) is enriched with 2.5 g / l to 9 g / l, more preferably 5 to 7.5 g / l CO2.

[0184] Step c) may comprise a constituent step c4) wherein solution (B) or, in the case of constituent step c2), solution (B1) is stored at 1 to 10°C, preferably 3 to 8°C, for at least 1 hour, preferably 24 to 120 hours, even more preferably 24 to 72 hours.

[0185] Step c) may comprise a composition step c5), wherein solution (B) or, in the case of carrying out composition step b2), solution (B1) is enriched with CO2, preferably to a total concentration of at least 6 g / l, more preferably at least 10 g / l, even more preferably at least 12 g / l, very particularly preferably at least 14 g / l and most preferably at least 15 g / l. Preferably, in composition step c5), a further 0.4 to 4.7 g / l, more preferably 1 to 3.5 g / l of CO2 is introduced or dissolved in solution (B) or (B1) until the desired total concentration is reached.

[0186] The expression "total concentration" refers here to the total concentration of dissolved CO2 in solution (B) or (B1), including the CO2 bound in the carbonic acid adduct (KA). The total concentration is the sum of the increase in the weight of the solution due to the addition of CO2 in all the aforementioned enrichment steps a2) and / or c3) (carried out here) and c5), without taking into account the CO2 optionally added to the solution in the form of bicarbonate or carbonate as base (BA).

[0187] Solution (B) or solution (B1) in step c5) can be enriched with CO2 to the desired total concentration at a pressure of 2.5 to 10 bar, preferably 4 to 10 bar, more preferably 5 to 10 bar, even more preferably 6 to 10 bar, most preferably 6.5 to 10 bar.

[0188] After enrichment with CO2 in composition step c5), the temperature of solution (B) or (B1) is between 3 and 8°C, more preferably 5°C.

[0189] In constituent steps c3) and c5), the enrichment of solution (B) or (B1) can be carried out in the same way as described in step a).

[0190] After carrying out step c5), the pH of solution (B) or, in case of carrying out constituent step c2), solution (B1) is ≤ 7.0.

[0191] Step c) preferably comprises all constituent steps c1), c2), c3), c4) and c5).

[0192] The constituent steps c1), c2), c3), c4) and c5) are preferably carried out in the order of c2) after c1), c3) after c2), c4) after c3), and c5) after c4).

[0193] In step d), the solution obtained at the end of step c) is frozen. Preferably, in step d), solution (B), or, after having been subjected to constituent step c2), solution (B1) is frozen.

[0194] The solution subjected to step d), preferably solution (B) or (B1), has a CO2 content of at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l.

[0195] Preferably, the solution obtained at the end of step c), preferably solution (B) or (B1), is frozen at -100°C to -20°C, more preferably at -90°C to 30°C, even more preferably at -80°C to 40°C, most preferably at -70°C to 50°C.

[0196] The solution obtained at the end of freezing step c), preferably solution (B) or (B1), can in principle be carried out by any method known to those skilled in the art that has been determined to be suitable. For example, freezing can be carried out by transferring the solution obtained in step c) to a suitable container immersed in a cooling medium. The container is preferably spherical. The container containing the solution obtained in step c) is preferably immersed in the cooling medium at an angle of 40 °. The cooling medium can be composed of, for example, a solvent such as methanol, ethanol or acetone, which is heated to the desired temperature by adding dry ice or a suitable cooling device such as a cryostat.

[0197] Freezing is preferably carried out at atmospheric pressure, more preferably at 1.01325 bar.

[0198] Preferably, the solution obtained at the end of step c), preferably solution (B) or (B1), is frozen within 0.3 to 60 minutes, more preferably within 1 to 30 minutes, even more preferably within 1.1 to 10 minutes, particularly preferably within 1.5 to 5 minutes.

[0199] The solution obtained at the end of step c), preferably solution (B) or (B1), is preferably frozen at a cooling rate of 10-100 K / min, more preferably 20-80 K / min, even more preferably 30-70 K / min, particularly preferably 40-60 K / min.

[0200] During the freezing operation, the container in which the solution obtained at the end of step c), preferably solution (B) or (B1), is present, is preferably rotated in the cooling medium at 10-1000 rpm, more preferably 50-600 rpm, even more preferably 100-400 rpm, particularly preferably 200-300 rpm.

[0201] Freezing can be achieved by the shell freezing method.

[0202] In step e), the solution frozen in step d), preferably solution (B) or (B1), is stored at -100 to 0°C for not more than 4 days.

[0203] The solution frozen in step d), preferably solution (B) or (B1), is preferably stored in step e) for 1.5 to 4 days, more preferably 2.5 to 4 days.

[0204] The solution frozen in step d), preferably solution (B) or (B1), is stored in step e) at -50 to 0°C, more preferably -30 to -5°C, even more preferably -25 to -10°C, especially preferably -20 to -15°C.

[0205] In principle, the storage can be carried out at a defined temperature in any cooling device known to the person skilled in the art. For example, the storage can be carried out in an upright refrigerator or a freezer.

[0206] The method for preparing a carbonic acid adduct (KA) may include a further step f) performed after step e). In step f), the solution stored in step e), preferably solution (B) or (B1), is dried to obtain a dried carbonic acid adduct (KA).

[0207] Preferably, in step f), water is removed from the solution stored in step e), preferably solution (B) or (B1), until a residual content of <0.8 wt.-%, based on the total weight of the dry carbonic acid adduct (KA), more preferably until a residual content of <0.1 wt.-%.

[0208] Preferably, in step f), CO2 not bound to the carbonic acid adduct (KA) is removed from the solution stored in step e), preferably (B) or (B1), until a residual content of <0.8 wt.-%, based on the total weight of the dry carbonic acid adduct (KA), more preferably until a residual content of <0.1 wt.-%.

[0209] Drying can be carried out by any method known to those skilled in the art that has been determined to be suitable. Drying is preferably carried out by freeze drying, also known as lyophilization. In the case of freeze drying, step d) constitutes a freezing step and step e) constitutes a maturation step.

[0210] Preferably, the pressure during the drying process is 0.01-30 mbar, preferably 0.02-20 mbar, more preferably 0.03-10 mbar, even more preferably 0.03-0.5 mbar, most preferably 0.05-0.1 mbar. The pressure is preferably maintained throughout the drying operation. During the drying process, the above pressure is preferably reached within 7 hours, more preferably within 5 hours, and particularly preferably within 4 hours from the start of vacuuming.

[0211] The drying end point can be determined by a person skilled in the art from the temperature change record. The total drying time in step f) is preferably 10-60 hours, more preferably 30-55 hours, and particularly preferably 41-52 hours. The total drying time is defined as the time interval between the end of storage in step e) and the end of drying in step f).

[0212] Preferably, the temperature of the entire drying process in step f) is 0 to 20°C, preferably 4 to 18°C, more preferably 8 to 16°C.

[0213] The present invention also comprises a pharmaceutical composition (PZ) for treating atypical pneumonia, comprising an amine (AM) or a carbonic acid adduct (KA) as described above.

[0214] WO2019 / 048590 describes pharmaceutical compositions which also contain carbonic acid adducts (KA).

[0215] In principle, a pharmaceutical preparation (PZ) in the context of the present invention is a composition comprising an amine (AM) or a carbonic acid adduct (KA), which may additionally comprise further auxiliaries or additives which are suitable for pharmaceutical-medical use.

[0216] Furthermore, the pharmaceutical preparation (PZ) may contain other bases which do not correspond to the amine (AM) and which may be different from the base (BA). In principle, a person skilled in the art will be able to select additives according to the desired end use. In doing so, they will take into account the desired form of administration.

[0217] In principle, the pharmaceutical preparation (PZ) may be in any suitable dosage form. For example, the pharmaceutical preparation (PZ) may be in the form of a capsule, or in the form of a tablet, solution, ointment, cream, gel, paste, compress or patch containing the active ingredient.

[0218] In principle, the pharmaceutical preparation (PZ) can be used in any suitable form of administration. A person skilled in the art will select a suitable dosage form according to the intended form of administration. For example, the pharmaceutical preparation (PZ) can be taken orally, inhaled, injected, as a patch, administered to the skin, including at least to the skin, to the eye, to the nose, to the rectum and to the vagina.

[0219] In the formulation of the pharmaceutical preparations (PZ), the person skilled in the art can basically use methods known in the art.

[0220] Preferably, during formulation of the pharmaceutical preparation (PZ), the temperature of the mixture of the carbonic acid adduct (KA) and the auxiliary agents used and any further base is below 60°C, preferably below 50°C, more preferably 0-50°C.

[0221] In the formulation of the pharmaceutical preparation (PZ), preferably in the form of an ointment, dispersion can also be used, preferably by means of an ointment mixer. Speeds of <2000 rpm are preferably used here.

[0222] Before being processed into oral dosage forms such as tablets, capsules or semisolid dosage forms described below, the carbonic acid adduct (KA) can be ground into a powder alone or in the presence of other auxiliaries or a base. The person skilled in the art can in principle use known technical means suitable for the corresponding purpose. For the grinding step, for example, a mortar or a similar suitable tool can be used. In the grinding step, preferably a technical auxiliary agent is used that minimizes the mechanical stress on the carbonic acid adduct. Grinding is preferably carried out with a mortar.

[0223] The powder thus obtained can then, for example, be compressed into tablets or dispensed into customary capsules or mixed with suitable auxiliaries and processed into semisolid dosage forms.

[0224] One embodiment of the pharmaceutical preparation (PZ) relates to a pharmaceutical preparation (PZ) comprising a carbonic acid adduct (KA) and which is administered orally. In this embodiment, the pharmaceutical preparation (PZ) is preferably administered in the form of a capsule, more preferably in the form of a hard gelatin or cellulose capsule, more preferably in the form of a hard gelatin capsule. In this embodiment, the pharmaceutical preparation (PZ) can also be administered in the form of a tablet.

[0225] The pharmaceutical preparation (PZ) in this embodiment preferably comprises at least one auxiliary (H), preferably selected from starch, in particular corn starch and / or rice starch, dextran, cellulose esters and SiO2.

[0226] Furthermore, the pharmaceutical preparation (PZ) in this embodiment may comprise at least one base (BA1) which does not correspond to the amine (AM) and is identical or different from the base (BA). The base (BA1) is preferably selected from NaHCO3 and KHCO3, more preferably NaHCO3.

[0227] The above general description of the pharmaceutical preparation (PZ) preferably also applies to this embodiment, in particular also to the preparation of the pharmaceutical preparation (PZ), which technically applies to this embodiment.

[0228] The pharmaceutical preparation (PZ) in this embodiment preferably comprises:

[0229] a) 1 to 99% by weight, more preferably 15 to 95% by weight, of a carbonate adduct (KA),

[0230] b) 0 to 60% by weight, more preferably 3 to 50% by weight, of a base (BA1) and 1 to 90% by weight, more preferably 2 to 75% by weight, of an auxiliary (H), based on the total weight of the pharmaceutical preparation.

[0231] Another embodiment of the pharmaceutical preparation (PZ) relates to a semisolid pharmaceutical preparation (PZ) comprising a carbonic acid adduct (KA) and is for skin administration. The pharmaceutical preparation (PZ) in this embodiment can be applied, for example, in the form of an ointment, or in the form of a cream, gel, paste, compress or patch containing the active ingredient.

[0232] The above general description of the pharmaceutical preparation (PZ) preferably also applies to this embodiment, in particular also to the production of the pharmaceutical preparation (PZ), which technically applies to this embodiment.

[0233] In this embodiment, the pharmaceutical preparation (PZ) preferably comprises at least one auxiliary (H1) which is selected from paraffins, especially viscous and fluid paraffins, wool waxes, wool wax alcohols, hydrophobic base gels, vegetable oils, animal fats, synthetic glycerides, liquid polyalkylsiloxanes, waxes, petrolatum and starch, especially corn starch, preferably petrolatum.

[0234] Viscous paraffin (sub-liquid paraffin) refers to paraffin with a viscosity of 110-230 mPas, while liquid paraffin (full liquid paraffin) has a viscosity of 25-80 mPas.

[0235] The pharmaceutical preparation (PZ) in this embodiment preferably comprises:

[0236] a) 0.1 to 40% by weight, preferably 0.4 to 10% by weight, of a carbonic acid adduct (KA), and

[0237] b) 60% to 99.9% by weight, preferably 80% to 96% by weight, of auxiliary agent (H1), based on the total amount of the pharmaceutical preparation (PZ).

[0238] Another embodiment of the pharmaceutical preparation (PZ) comprising the carbonic acid adduct (KA) relates to a pharmaceutical preparation for administration by the parenteral, nasal and / or inhalation route.

[0239] The above general description of the pharmaceutical preparation (PZ) preferably also applies to this embodiment, in particular also to the preparation of the pharmaceutical preparation (PZ), which technically applies to this embodiment.

[0240] The pharmaceutical preparation (PZ) in this embodiment is preferably in the form of a solution (A2) comprising a carbonic acid adduct (KA), dissolved CO2 and at least one auxiliary (H2).

[0241] The auxiliary (H2) is preferably selected from alkali metal halides or alkaline earth metal halides, more preferably NaCl and MgCl2, even more preferably NaCl. The auxiliary (H2) may be identical to the salt (S). In the context of the present invention, the amount based on the auxiliary (H2) (wherein in various embodiments it is identical to the salt (S)) relates to an additional amount of auxiliary (H2), which is not introduced into the pharmaceutical preparation (PZ) in the form of the salt (S) as part of the carbonic acid adduct (KA).

[0242] Solution (A2) is preferably obtained by introducing CO2 into a solvent. The solvent is preferably water. For the preparation of solution (A2), CO2 is preferably introduced into the solvent at a temperature of 0-8°C, more preferably CO2 is introduced into the solvent in the form of gas or solid, such as dry ice, at 0-5°C. CO2 is preferably introduced into the solvent in gaseous form. CO2 can also be introduced into the solution under pressure until the desired concentration is reached, such as described above for the composition step a2).

[0243] For preparing solution (A2), CO2 is preferably introduced into the solvent to a concentration of at least 3 g / l, more preferably to 4 g / l, even more preferably 4 g / l to 8 g / l.

[0244] The CO2 used for preparing solution (A2) has a purity of at least 99.9%, more preferably also of a quality suitable for pharmaceutical applications, as defined above.

[0245] In this embodiment, if the pharmaceutical preparation (PZ) is obtained by dissolving the carbonic acid adduct (KA) in the solution (A2), it preferably comprises:

[0246] a) 0.05-100 mg / ml, more preferably 0.08-50 mg / ml of a carbonic acid adduct (KA), and

[0247] b) 0-20 mg / ml, more preferably 3-10 mg / ml of auxiliary agent (H2)

[0248] In each case based on the total volume of the pharmaceutical preparation (PZ). Specific implementation plan

[0249] Example

[0250] 1. Working Example 1, Preparation of Carbonic Acid Adduct (KA)

[0251] 1.1 Materials:

[0252] Amine (AM): 68.8-110.1 g procaine hydrochloride (e.g. ultrapure, for use as active pharmaceutical ingredient; Ph. Eur. or in a quality suitable for this purpose)

[0253] Base (BA): 22.2 to 33.9 g sodium bicarbonate (e.g. ultrapure, or in a quality suitable for the purpose),

[0254] Solvent: 630-900ml water (water for injection)

[0255] CO2: at least 12.0 g / l of carbon dioxide (suitable quality CO2)

[0256] · Dry ice for providing cold mix and cooling

[0257] Methanol, industrial grade, to provide cold mixture

[0258] 1.2 Step a)

[0259] Water (eg water for injection) is introduced into a clean plastic squeeze bottle up to the mark (about 800 to 900 ml) and precooled to 5° C. in a refrigerator (3 to 8° C.) or by external cooling for at least 1 hour.

[0260] Prepare a carbonic acid solution saturated with carbon dioxide. To this end, CO2 is intermittently introduced into pre-cooled water under pressure (1.6-8 bar). A hissing sound (gas escaping via a pressure reducing valve) indicates that the solution is saturated with CO2. The saturation is monitored by weight until 4.0 to 6.0 g CO2 (corresponding to 4.5 to 7.5 g / l) are dissolved. The pH value of the saturated solution is ≤4.3-4.8. Immediately seal the carbonated water and store in a refrigerator for at least 1 hour.

[0261] 1.3 Step b)

[0262] An initial charge of 21.2 g of sodium bicarbonate in a second plastic squeeze bottle was mixed with 320 ml of cooled carbonated water and dissolved by turning the bottle upside down.

[0263] 1.4 Step c)

[0264] At constant temperature, an equal amount of solid procaine hydrochloride was added to the solution to form a substantially neutral solution, and after adding 320 ml of cold carbonated water, a clear weakly acidic solution was obtained. The solution was rich in CO2. The solution thus prepared was stored in a refrigerator for at least 1 hour.

[0265] Subsequently, the solution was adjusted again with CO2 until a CO2 concentration of 12 g / l was reached in the solution. The pH was monitored by a pH indicator stick. pH ≤ 6.6.

[0266] 1.5 Step d)

[0267] Precool the round bottom flask. When freezing, the reaction solution was measured in a precooled measuring cylinder, transferred to the round bottom flask in batches, and frozen by shell freezing in 1.5 to 3.5 minutes by immersing each flask (~200 rpm) in a cold dry ice / methanol mixture (<-60°C). The angle of immersion of the flask in the rotary evaporator was set to about 40°.

[0268] 1.6 Step e)

[0269] The flask containing the thus frozen substance was closed with a ground glass stopper and temporarily stored in a freezer at -15 to -20°C for 2 to 4 days.

[0270] 1.7 Step f)

[0271] The flasks that have been subjected to this temperature are wrapped with pre-cooled Styropor containers and immediately connected individually to an evacuated (0.060 ± 0.01 mbar, about -46 ° C, leak test) freeze drying system through flexible rubber cones. Carefully open the valve tap and place the individual flasks under vacuum. All flasks must be evacuated in the end.

[0272] To monitor the process, a temperature sensor is located at the bottom of the Styropor housing, which records the entire temperature profile during the entire drying operation. Before the freeze drying starts, the temperature sensor indicates a temperature of < -5°C.

[0273] During freeze drying, the pressure is 0.07 ± 0.02 mbar. This sublimation pressure is reached within 4 hours and maintained throughout the freeze drying time. During the entire drying operation, the temperature of the cooling chamber is adjusted to 9 to 15 ° C. The end point of freeze drying is determined by a graph recorded by temperature progression. The total drying time does not exceed 52 hours. The dry freeze dried product is transferred to a brown glass container with a screw cap, equipped with a desiccant bag, and stored in a refrigerator at 0-15 ° C.

[0274] 2. Examples of pharmaceutical preparations (PZ)

[0275] 2.1 Capsules and tablets

[0276] The composition of the pharmaceutical preparation (PZ) according to the invention is described below by way of example, in this embodiment, a capsule or tablet of procainamide (AM). For the production of capsules, commercial two-piece capsules of commercial size (5-000) can be used, which are filled with a powder containing a carbonic acid adduct (KA), the carbonic acid adduct (KA) comprising procaine as an amine (AM) (powdered carbonic acid adduct (KA) active ingredient, comprising procaine as an amine (AM), optionally comprising auxiliaries, fillers and flow regulators). The carbonic acid adduct (KA) is prepared according to Example 1. It has been found that hard gelatin capsules have better suitability than cellulose capsules in terms of stability. For example, filled hard gelatin capsules, such as hard gelatin capsules with 60 and 100 mg active ingredient according to Table 1, do not show any changes even after storage in a refrigerator for 12 months and are therefore stable. Stability is detected by IR spectroscopy. For example, in the case of hard gelatin capsules, no procaine was detected by IR spectroscopy within 12 months, while cellulose capsules detected procaine bands in the IR spectrum only after a few days. The content is determined by UV / VIS spectroscopy at room temperature. For drug products, a tolerance range of ±15% is specified according to point 2.9.6 of the European Pharmacopoeia, based on the total content including by-products.

[0277] The current and customary pharmaceutical regulations for the production (preparation) of pharmaceutical products apply (eg Pharmacopoea Europaea, Deutscher Arzneimittel-Codex [German Drug Code]).

[0278] Table 1: Exemplary composition of capsules produced according to Working Example 1 with added NaHCO3 and carbonic acid adduct (KA) as active ingredients.

[0279]

[0280] Table 2: Exemplary composition of tablets produced according to Working Example 1 with NaHCO3 and carbonic acid adduct (KA) as active ingredients.

[0281]

[0282] 2.2 Ointment

[0283] Taking procaine as the amine (AM) in the carbonic acid adduct (KA) as an example, the composition of the pharmaceutical preparation (PZ) of the present invention as an ointment in the embodiment is described below. When preparing the ointment, the current and generally conventional pharmaceutical rules for the production (formulation) of drugs (e.g. European Pharmacopoeia, Deutscher Azenemittel-Codex) are applied. Relatively high shear forces are avoided in the production of the ointment. In addition, the temperature during the preparation process is even locally kept below 60° C. Therefore, in a standard mortar or Fanta type mortar adjusted to 40-45° C. by a water bath, the mortar-ground carbonic acid adduct (KA) containing procaine as the amine (AM) is added to an ointment base, such as vaseline. Alternatively, the electric mixing system commonly used in pharmacy can also be used.

[0284] Table 3: Exemplary composition of an ointment prepared according to Working Example 1 and a carbonic acid adduct (KA) as an active ingredient.

[0285]

[0286] 2.3 Parenteral Solutions

[0287] To provide a parenteral solution containing a carbonic acid adduct (KA) comprising procaine as an amine (AM), the required amount of water (water for injection) is cooled to about 5±3° C. in a suitable container with a stirring bar or the like and allowed to stand at this temperature. The water is enriched with the required mass of gaseous carbon dioxide to about 3.2 g / l. An appropriate amount of a carbonic acid adduct (KA) comprising procainamide (AM) and an isotonic content of sodium chloride is dissolved in the carbonated water.

[0288] Alternatively, in a closed system, water at a temperature of about 5±3° C. is enriched with CO2 under pressure to a significant excess (4.5-7.5 g / l). A corresponding amount of a carbonic acid adduct (KA) containing procainamide (AM) and sodium chloride is likewise added to the carbonated water.

[0289] This cold solution containing procaine as amine (AM) and sodium chloride carbonate adduct (KA) is sterile filtered under suitable ambient conditions and dispensed into suitable vials. Current and generally customary pharmaceutical regulations for the production (formulation) of pharmaceuticals apply (eg European Pharmacopoeia).

[0290] Table 4: Exemplary composition of parenteral formulations produced according to Working Example 1 with added NaCl and carbonic acid adduct (KA) as active ingredients.

[0291]

[0292] 3. Solubility in octanol

[0293] Solubility tests were carried out in octanol, and the content in the organic phase was monitored by UV / VIS spectroscopy, as well as the pH value.

[0294] Table 5: Solubility of various dosage forms

[0295]

[0296] The determined pH values ​​show that the carbonic acid adduct of procaine is converted itself rather than into procaine and in this form is soluble in the organic phase and is therefore membrane permeable. Also, it is clear from the measurement of the content by UV / VIS spectroscopy that the carbonic acid adduct of procaine is more similar to procaine in terms of lipophilicity than procaine hydrochloride. It therefore behaves like an alkaline component - a fat-soluble base, the formation of which depends on the pH value. The carbonic acid adduct of procaine has this pH-independent property, which means that it does not need to be converted into the lipophilic form by changing the pH, as is the case with procaine hydrochloride. Procaine hydrochloride has a much lower value of 8%, which is of the same order of magnitude as the protein binding of 6%.

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Claims

1. Amines (AM) of formula (I) for use in treating Aspergillus fumigatus infections and influenza virus and Aspergillus superinfections in, In formula (I), R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H; R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl, R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl; R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl; R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O-(C 1-10 )alkyl; The amines of the formula (I) can optionally also be used in the form of salts.

2. A carbonate adduct (KA) comprising at least one structural unit of the general formula (II), (III) and / or (IV) for use in treating Aspergillus fumigatus infection and influenza virus and Aspergillus superinfection in, In formulae (II), (III) and (IV), R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H; R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl, R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl; R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl; R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl; x is 0.5-30; (S) is salt.

3. A carbonic acid adduct (KA) for use in treating Aspergillus fumigatus infections and influenza virus and Aspergillus superinfections, comprising carbonic acid, at least one amine (AM) of the general formula (I) and at least one salt (S), in, In formula (I), R1 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H; R2 is H, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 )aryl or (C5-C 10 ) heteroaryl, preferably H or (C 1-10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl, R9 is (C 1-10 ) alkyl, preferably (C 1-2 )alkyl; R4 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O-(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl; R7 is H, halogen, (C 1-10 ) alkyl, (C 2-10 )alkenyl, (C5-C 14 ) aryl, (C5-C 10 )heteroaryl or -O(C 1-10 ) alkyl, preferably H, halogen, (C 1-10 )alkyl or -O(C 1-10 ) alkyl, more preferably H or -O(C 1-10 )alkyl; wherein the at least one amine of formula (I) may optionally also be used in the form of a salt; It can be prepared by a method comprising the following steps: a) providing a solution (A) comprising at least one solvent and CO2 dissolved in the at least one solvent, Optionally b) dissolving a base (BA) which does not correspond to the amine (AM) in the solution (A) to obtain a solution (A1), c) dissolving the at least one amine (AM) in solution (A) or (A1) to obtain solution (B), d) freezing the solution obtained at the end of step c), e) storing the solution frozen in step d) at -100 to 0°C for no more than 4 days.

4. A pharmaceutical composition (PZ) comprising an amine (AM) as claimed in claim 1 or a carbonic acid adduct as claimed in any one of claims 2 and 3 for use in the treatment of Aspergillus fumigatus infections and superinfections with influenza virus and Aspergillus.

5. An amine for use according to claim 1, a carbonic acid adduct (KA) for use according to claim 2 or 3 and a pharmaceutical composition (PZ) for use according to claim 4, wherein i) The amines described in the general formula (I) and the general formulas (II), (III) and (IV) are selected from 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine), ethyl 4-aminobenzoate (benzocaine), 2-(diethylamino)ethyl 4-amino-2-chlorobenzoate (chloroprocaine), 2-diethylaminoethyl 4-amino-3-butoxybenzoate (oxybuprocaine), 2-(dimethylamino)ethyl 4-(butylamino)benzoate (butylcaine), preferably 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine), and / or ii) the salt (S) is at least one selected from Na + , K + , Li + 、M g2+ 、Zn 2+ , Fe 2+ , Fe 3+ and Mn 2+ The cation is preferably Na + , and at least one selected from Cl - Br - ,I - 、F - 、SO4 2- 、SO3 2- ,HSO4 - 、HSO3 - , - HCO3 - 、CO3 2- PO4 3- 、HPO4 2- 、H2PO4 - 、SiO4 4- 、AlO2 - 、SiO3 - and / or [AlO2) 12 (SiO2)2] 2- , preferably Cl - and Br - , more preferably Cl - A salt composed of anions.

6. Carbonate adduct (KA) for use according to claims 3 and 5, wherein step a) comprises at least one of the following steps: a1) cooling the solvent, preferably water, to 3-8°C, preferably 5°C and / or a2) introducing CO2 into the solvent, preferably at a saturation concentration of at most 3 to 10 g / l, more preferably at a saturation concentration of at most 4.5 to 7.5 g / l, wherein the pH of the solution after saturation with CO2 is preferably ≤ 3.0 to 6.0, even more preferably ≤ 4.3 to 4.8, and / or a3) storing the solution (A) at 1 to 10° C. for preferably at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; up to 5 days (120 hours); preferably storing at 3-8° C. for at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; up to 5 days (120 hours); Step a) preferably comprises all constituent steps a1), a2) and a3); Preferably, the constituent steps a1), a2) and a3) are performed in the order of a2) after a1), and a3) after a2).

7. The carbonic acid adduct (KA) for use according to any one of claims 3, 5 and 6, wherein i) the base (BA) in step b) is bicarbonate or carbonate, more preferably bicarbonate, even more preferably sodium bicarbonate, and / or ii) the CO2 content of the solution subjected to step d) is at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l, and the amine (AM) can also be used in the form of a salt.

8. Carbonate adduct (KA) for use according to any one of claims 3 and 5 to 7, wherein step c) comprises at least one of the following composition steps: c1) dissolving the at least one amine (AM) in solution (A) or (A1) to obtain solution (B) and / or c2) adding solution (A) to solution (B) to obtain solution (B1) and / or c3) enriching solution (B) or (B1) with CO2 and / or c4) storing the solution (B) or (B1) at 1-10°C, preferably 3-8°C, for at least 1 hour, preferably 24-120 hours, even more preferably 24-72 hours, and / or c5) enriching solution (B) or (B1) with CO2 to a concentration of at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l and most preferably at least 15 g / l; in, Optionally, i) the concentration of the amine (AM) in solution (B), or in solution (B1) in case of performing composition step c2), is 0.01-0.25 g / ml, preferably 0.03-0.20 g / ml, more preferably 0.08-0.15 g / ml, and / or ii) after step c5), the pH of solution (B) or (B1) is ≤ 7.0 and / or iii) in case of carrying out step b), the ratio of the amine (AM) to the base (BA) in the solution (B) is 2-5, more preferably 3-4, even more preferably 3.23-3.26 [g / g], and / or iv) in step c1), the at least one amine (AM) comprises at least one amine (AM) as an acid addition salt, preferably as a hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydrogen methanesulfonate, hydrogen toluenesulfonate, hydrogen acetate, hydrogen formates, hydrogen propionates, hydrogen malonates, hydrogen succinates, hydrogen fumarates, hydrogen oxalates, hydrogen tartrates, hydrogen citrates, hydrogen maleates, more preferably as a hydrochloride or hydrobromide salt; Step c) preferably comprises all constituent steps c1), c2), c3), c4) and c5); The constituent steps c1), c2), c3), c4) and c5) are preferably carried out in the order of c2) after c1), c3) after c2), c4) after c3), and c5) after c4).

9. The carbonic acid adduct (KA) for use according to any one of claims 3 and 5 to 8, wherein in step d): i) freezing the solution (B) or (B1) at -100°C to -20°C, preferably -90°C to -30°C, even more preferably -80°C to -40°C, most preferably -70°C to -50°C, and / or ii) solution (B) or (B1) is frozen within 0.3-60 minutes, preferably within 1-30 minutes, more preferably within 1.1-10 minutes, even more preferably within 1.5-5 minutes, and / or iii) during the freezing operation, the container containing the solution (B) or (B1) is preferably rotated in the cooling medium at 10-1000 rpm, preferably 50-600 rpm, more preferably 100-400 rpm and even more preferably 200-300 rpm, and / or iv) The solution (B) or (B1) is frozen at a cooling rate of 10 to 100 K / min, preferably 20 to 80 K / min, more preferably 30 to 70 K / min, particularly preferably 40 to 60 K / min.

10. The carbonic acid adduct (KA) for use according to any one of claims 3 and 5 to 8, wherein in step e): i) the frozen solution (B) or (B1) is stored for 1.5-4 days, preferably 2.5-4 days, and / or ii) The frozen solution (B) or (B1) is preferably stored at -50 to 0°C, more preferably at 30 to -5°C, even more preferably at -25 to -10°C, particularly preferably at -20 to -15°C.

11. Carbonate adduct (KA) for use according to any one of claims 3 and 5 to 10, wherein the method comprises a further step f) after step e): f) drying the solution stored in step e) to obtain a dry carbonic acid adduct (KA), wherein in step f), optionally, i) removing water from the solution (B) or (B1) until the residual content is <0.8% by weight, preferably <0.1% by weight, based on the total weight of the dry product (C), and / or ii) removing CO2 not bound to the carbonic acid adduct (KA) from the solution (B) or (B1) until the residual content is <0.8% by weight, preferably <0.1% by weight, based on the total weight of the dry product (C), and / or iii) drying by freeze drying and / or iv) during the drying process, the pressure is 0.01-30 mbar, preferably 0.02-20 mbar, more preferably 0.03-10 mbar, even more preferably 0.03-0.5 mbar, most preferably 0.05-0.1 mbar, and this pressure is preferably maintained throughout the drying operation, and / or v) during the drying process in iv), the pressure is reached within 10 hours, preferably within 7 hours, more preferably within 5 hours, particularly preferably within 4 hours from the start of the emptying, and / or vi) during the drying process in step f), the temperature is from 0 to 20°C, preferably from 4 to 18°C, more preferably from 8 to 16°C, and / or vii) The total drying time is from 10 to 60 hours, preferably from 30 to 55 hours, more preferably from 41 to 52 hours.

12. An amine (AM) according to claim 1, a carbonic acid adduct (KA) for use according to any one of claims 2, 3 and 5-11 and a pharmaceutical composition (PZ) for use according to claim 4 for the treatment of repeated infections with influenza virus and Aspergillus, preferably Aspergillus fumigatus.

13. The amine (AM) according to claim 1, and the carbonic acid adduct (KA) for use according to any one of claims 2, 3 and 5-12 and the pharmaceutical composition (PZ) for use according to claims 4 and 12, wherein administration is by oral, parenteral, nasal, inhalation or dermal route.

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