Active substances for medical use

Abstract

The present invention relates to an amine (AM) according to general formula (I); a carbonic acid adduct (KA) and a pharmaceutical composition (PZ) for use in the treatment of Aspergillus fumigatus infections and superinfections with influenza viruses and Aspergillus spp..

Description

x active ingredients for medical use TECHNICAL AREA

[0001] The subject matter of the present invention relates to an amine (AM) according to the general formula (I); a carbonic acid adduct (KA) and a pharmaceutical composition (PZ) for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp. TECHNICAL BACKGROUND

[0002] Influenza viruses continue to cause severe respiratory illness, contributing significantly to morbidity and mortality. Seasonal epidemics are responsible for 3–5 million severe cases and an estimated 300,000–500,000 deaths worldwide each year (1). Furthermore, influenza A viruses have the potential to cause pandemics, which have historically resulted in millions of deaths, as demonstrated by the 1918–19 Spanish flu outbreak (2). While most people recover from infection, others experience complications such as pneumonia, caused either by the virus itself or by additional pathogens, including bacteria, among which Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae play a significant role (3).In cases of superinfection with influenza viruses and bacteria, the reasons for severe cases are well understood and novel treatment options have become a focus of interest. However, this is not the case for superinfections with influenza viruses and fungi (4, 5).

[0003] Nevertheless, it has become clear that infections caused by fungi such as Aspergillus spp., especially Aspergillus fumigatus, occur in influenza virus-infected patients and cause increased morbidity and mortality (5-9). A common problem with secondary fungal infections is that they are often diagnosed too late (10, 11). In addition to the increased pathogenicity of superinfections with influenza viruses and Aspergillus fumigatus, the limited availability of potent anti-infectives against the various pathogens is of great importance (5, 6, 12). The high variability of influenza viruses and the constant emergence of new strains, as well as the rapid development of influenza virus resistance to available drugs (13-16), combined with the late detection of fungal infections (10, 11), are the main reasons for the poor treatment options. To date, treatment has been Treatment of superinfections of influenza viruses and fungi with a single active ingredient is not yet possible.

[0004] Even though intensive research and enormous progress in treatment options have taken place in the last century, influenza viruses still pose a serious threat to the population. Seasonal epidemics are due to continuous point mutations in the genome of influenza A and B viruses (antigenic drift), which lead to changes in protein structures. Furthermore, influenza A viruses have the potential to cause pandemic outbreaks (2, 20-22). When an individual is infected with more than one viral subtype, the exchange of gene segments (antigenic shift) can lead to viral subtypes that contain the properties of the parent strains in a new combination (20, 21). As a result, the immune system of infected hosts is naive and unable to effectively combat the new pathogens.The last century saw several pandemics, the most devastating of which was the "Spanish flu" of 1918 / 19 (23). The influenza virus strain responsible for the 2009 pandemic outbreak still circulates in the population today, along with the 1968 H3N2 lineage and two different lineages of the influenza B virus (20).

[0005] While viral and bacterial superinfections have been well studied in recent years, little is known about viral and fungal superinfections. Bacterial superinfections typically occur within the first seven days after influenza virus infection, leading to even more fulminant illness, accompanied by pneumonia and increased mortality (24, 25). In some cases, however, bacterial superinfection only occurs after the viral infection appears to have cleared. It has been described several times that influenza virus infection paves the way for bacterial superinfection. As a result of influenza virus infection, the cleaning function of the cilia is disrupted, the mucosal layer is broken down, and thus additional receptors for bacteria are exposed. In addition, the immune response is dysregulated, leading to reduced defense and increased inflammatory processes (4, 26).

[0006] In recent years, it has also been reported that patients with severe influenza virus infection developed invasive pulmonary aspergillosis caused by superinfection of influenza viruses and fungi such as Aspergillus spp., particularly Aspergillus fumigatus. This resulted in an even higher mortality rate compared to simple influenza virus infection (27, 28).

[0007] Aspergillus spp. are filamentous, saprotrophic fungi found in soil and air (11, 29). In healthy individuals, inhaled conidia are cleared by mucociliary clearance and early immune mechanisms (11). Immunocompromised or transplanted patients are at increased risk of complications and mortality (5, 28). The likelihood of developing invasive pulmonary aspergillosis, characterized by the invasion of lung tissue by Aspergillus fumigatus hyphae, is further increased in immunocompromised patients and associated with higher mortality (10). Post-influenza aspergillosis is a relatively new and under-researched clinical entity that is difficult to diagnose. Recently it has become clear that influenza A and B virus infections are responsible for the development of fungal superinfections in immunocompromised and non-immunocompromised patients (6, 30, 31).It is assumed that, similar to bacterial superinfections, the loss of ciliary function of the mucosa predisposes the patient to fungal superinfection and promotes the development of an invasive fungal infection (31).

[0008] The most efficient way to protect against annual influenza virus epidemics to date is vaccination (1, 13). Although new vaccines are produced every year, vaccination rates are low, efficacy is variable, and in the case of entirely new influenza A virus subtypes, adapted vaccines are not available in time. New vaccines must be adapted and produced for each new virus variant, which takes at least six months. Thus, there is a period between the emergence of a pathogen and the introduction of the new vaccine during which the population is unprotected. Consequently, antiviral alternatives must be used to control the infection.

[0009] For antiviral therapy, the European Medicines Agency (EMA) has approved three classes of compounds that target either the ion channel protein (M2), neuraminidase, or CAP-dependent endonuclease. While neuraminidase inhibitors are effective against influenza A and B viruses, M2 inhibitors are ineffective against influenza B viruses (13). Unfortunately, influenza viruses rapidly develop resistance to therapeutics. Several reports indicate resistant variants of influenza B viruses to oseltamivir, as well as resistant influenza A viruses of the H5N1 and pandemic H1N1v types. The frequent occurrence of resistant variants in clinical isolates against adamantanes has led to the recommendation not to use M2 inhibitors for treatment and prophylaxis until susceptibility to these drugs is restored in circulating influenza A viruses (16). Another weakness of existing antiviral treatment approaches is that antiviral treatment must be initiated as soon as possible after the onset of symptoms.

[0010] Novel antiviral strategies include (a) inhibiting virus-supporting cell functions, (b) promoting antiviral defense, or (c) resolving inflammation (32).

[0011] The most promising antiviral strategies for combating influenza infections are based on the fact that influenza viruses, as intracellular pathogens, are highly dependent on cellular signaling machinery. Influenza viruses have the ability to manipulate cellular factors for their own purposes to ensure their replication and spread. Furthermore, influenza viruses can counteract the innate immune response of their hosts. Given these dependencies, cellular virus-supporting functions represent targets for antiviral interventions (32). In recent years, several cellular factors have been identified as suitable targets for antiviral intervention (33), including the Raf / MEK / ERK mitogen kinase cascade (32, 34-39) and the IKK / NF KB-module (40-42) and the PI3K signaling pathway (33, 43-48). Targeting most of these factors proved effective against influenza virus infection in vitro, as well as in in vivo mouse models. Initial clinical studies of LASAG suggest its antiviral activity against influenza virus infection in hospitalized patients (61). Targeting cellular rather than viral factors reduces the likelihood of resistance development, as the pathogen has more difficulty compensating for the lack of cellular function.

[0012] Among antifungal agents, triazoles are the first-line treatment for aspergillosis, but echinocandins and the polyene amphotericin B are also used (29). The recent development of resistance in Aspergillus spp., particularly in Aspergillus fumigatus variants, is concerning. Azole resistance has increased worldwide, and consequently, new guidelines recommend a voriconazole-eninocandin combination or amphotericin B (5). As a rule, prophylactic treatment for aspergillosis is not initiated. Empirical antifungal therapy is only started when a fungal infection is suspected or confirmed. This involves a combination of immunomodulatory treatment and antifungal therapy (29).

[0013] Treatment options for viral / fungal superinfections are limited. Corticosteroid treatment, frequently used in intensive care units, is contraindicated due to prolonged viral shedding with increased mortality and a higher risk of invasive pulmonary aspergillosis (5). Recent studies have shown strong interference between Aspergillus fumigatus and its host during invasive Aspergillosis may indicate, targeted fungi-supporting cellular factors and fungus-induced harmful inflammatory processes represent alternative attack options (29, 49, 50).

[0014] Due to the phylogenetic relationship between fungi and humans, several factors are highly conserved (51). Thus, these homologs could be simultaneously targeted by a chemical inhibitor, which subsequently acts on the host cell, Aspergillus spp., or pathogen-induced cell functions. Among these, the mitogen-active fourth protein kinase (MAPK) cascades have been identified (49, 52-54), which regulate fungal processes such as biofilm formation (55), stress tolerance (52, 53), and virulence (49), as well as host cell functions such as inflammatory processes (50). Interestingly, it has recently been shown that antifungals such as itraconazole have an inhibitory effect on influenza virus replication (56, 57) and SARS-CoV-2 infection (58).Although the effects are probably due to different mechanisms of action of the compound during the replication of the different viruses, in the case of influenza virus infection the blockage of cholesterol export from the endolysosomal compartment and the resulting reduced replication is discussed (56). Remarkably, MAPKs have also been identified as potential targets for influenza virus intervention, as they are involved in viral replication and virus-induced hyperinflammation (59, 60).

[0015] Therefore, there is a further need for new therapeutics for the treatment of influenza viruses, Aspergillus spp., and especially superinfection of influenza viruses and Aspergillus spp. SUMMARY OF THE INVENTION

[0016] The invention relates to an amine (AM) according to the general formula (I) where in formula (I) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 amine according to formula (I) can optionally also be used in the form of a salt, for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp..

[0017] In another aspect, the invention relates to a carbonic acid adduct (KA) comprising at least one structural element according to the general formula (II), (III) and / or (IV) where in formulas (II), (III), and (IV) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 to 30; (S) is a salt; 8 For use in the treatment of infections with Aspergillus fumigatus and superinfections with influenza viruses and Aspergillus spp.

[0018] In another aspect, the invention relates to a carbonic acid adduct (KA) comprising carbonic acid, at least one amine (AM) according to the general formula (I) and at least one salt (S), where in formula (I) R1ist 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; R2ist 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; R3ist -(CH2) nNR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 according to formula (I) may optionally also be used in the form of a salt; prepareable by a process comprising the steps of: 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) not corresponding to the amine (AM) in the solution (A) to obtain solution (A1), c) dissolving the at least one amine (AM) in the solution (A) or (A1) to obtain solution (B), d) freezing the solution obtained after completion of step c), e) storing the solution frozen in step d) at -100 to 0 °C for no longer than 4 days; for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp.

[0019] The invention further relates to a pharmaceutical composition comprising the amine, or the carbonic acid adduct for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp.

[0020] The substances described in this invention disclosure are capable of reducing influenza virus infections and influenza virus-induced cytokine expression, as well as blocking hyphal formation in Aspergillus fumigatus. Thus, the present invention offers a novel approach to the anti-pathogenic therapy of both pathogens with a single active ingredient. Furthermore, the potential modulation of pathogen-induced cellular factors enables the regulation of excessive immune responses in superinfection scenarios. BRIEF DESCRIPTION OF THE FIGURES

[0021] Figure 1: Procaine-containing agents (e.g., procaine hydrochloride (HCl)) reduce hyphal formation in A. fumigatus. (A) Treatment procedure: Conidia of a green-fluorescence protein (GFP)-expressing A. fumigatus strain [5*10 6 Conidia / Well] were seeded onto coverslips in 24 corrugated plates in 300 μl medium DMEM / BA (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2) and each supplemented with solvent (H2O), procaine HCl [0.31 (B) or 1.25 (C) - 10 mM] or voriconazole [0.2 μg ml -1The fungi were incubated for 10 h at 37 °C with 5% CO2. Subsequently, they were fixed (3.7% formaldehyde in PBS, 30 min, room temperature) and mounted on microscope slides using fluorescent staining solution (Agilent, Santa Clara, CA, USA). Hyphae size was analyzed using (B) an Axio Observer.ZI microscope (Zeiss, Jena, Germany) and the Fiji V 1.52b software (github.com / fiji / fiji). (C) Fungal size was calculated using the particle counter software (github.com / chko90 / particle counter). The data represent either four experiments (B) or the mean + SD of four experiments, each with two technical samples (C). Statistical significance was calculated using GraphPad Prism 9.2 (Graphpad Software, Boston, USA) with the one-way Dunnett multiple comparison test for ANOVA. P-values ​​are marked with an asterisk *p < 0.05.

[0022] Figure 2: The viral load of influenza viruses and A. fumigatus is reduced in in vitro assays in the presence of procaine-containing agents (e.g., procaine HCl). (A) Procedure of the treatment process: The human lung epithelial cells (A549) [0.5*10 5 Cells / well were seeded in DMEM (10% FBS) onto coverslips in 24 well plates and incubated for 23.5 h at 37 °C, 5% CO2. The cells were pretreated 30 min prior to infection with the specified concentrations of procaine HCl or voriconazole in DMEM / BA (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2) and subsequently infected for 30 min with the influenza A / Puerto Rico / 8 / 34 virus [0.5 multiplicity of infection (MOI)] in PBS / BA (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2). The inoculum was then removed, cells were washed with PBS, and conidia of A. fumigatus [10 MOI] were collected in the presence of the specified substances in DMEM / BA / trypsin (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2, 167 ng ml). -1Trypsin-TPCK). The cells were then incubated for 10 h at 37 °C, 5% CO2. (B) Supernatants of infected cells were collected and viral titers (plaque-forming units (PFU) / ml) were determined by standard plaque titration. (C) The expression of viral nucleoprotein (NP), GFP of the A. fumigatus strain (GFP), and the cellular protein extracellular signal-regulated kinase 2 (ERK2) was visualized by Western blot analysis. (D) I - IVThe cells were fixed (3.7% formaldehyde in PBS, 30 min, room temperature) and prepared for immunofluorescence analysis. The influenza virus nucleoprotein was visualized using an anti-influenza virus nucleoprotein antibody (BioRad) and AlexaFluor647 (Invitrogen). The 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 visualized by internal GFP expression. The samples were mounted on slides using a fluorescent staining solution (Agilent, Santa Clara, CA, USA). The images were acquired and processed using an Axio Observer.ZI microscope (Zeiss, Jena, Germany) and the Fiji V 1.52b software (github.com / fiji / fiji). Shown are the images of the individual channels as well as their superimposed (merged) images.The data represent the mean + SD of four independent experiments, including two technical ones. Samples (B) or an exemplary representation from four experiments (C, D) I - IV ). Statistical significance was calculated using GraphPad Prism 9.2 (Graphpad Software, Boston, USA) using the multiple comparison test of one-way ANOVA with a Tukey analysis (p < 0.05 was considered the statistical significance level).

[0023] Figure 3: Treatment of influenza A virus and / or A. fumigatus-infected A549 cells with ProcCluster® or procaine HCl leads to a reduced viral load and hyphal formation 10 h post-infection (pi). (A) Treatment procedure: The human lung epithelial cells (A549) [0.25*10 5 Cells / 24 Well (B I- IV -C ) on coverslips or 0.5*10 5Cells (12-well, DF) were seeded in DMEM (10% FBS) and incubated for 24 h at 37 °C, 5% CO2. The cells were infected for 30 min with influenza A / Puerto Rico / 8 / 34 (IAV) [0.5 MOI] in PBS / BA (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2). The inoculum was then removed, and conidia of A. fumigatus (A.fu.) [10 MOI] were inoculated in the presence of ProcCluster®, procaine HCl, or the solvent control (H2O) in DMEM / BA / trypsin (0.2% BSA, 1 mM MgCl2 and 0.9 mM CaCl2, 167 ng / ml). -1 Trypsin-TPCK) was added. The cells were then incubated for 10 h at 37 °C, 5% CO2. (B I - IVThe cells were fixed (3.7% formaldehyde in PBS, 1 h, room temperature) and prepared for immunofluorescence studies. The influenza virus nucleoprotein was visualized using an anti-influenza virus nucleoprotein antibody (BioRad) and AlexaFluor647 (Invitrogen). The nuclei were stained with bisbenzimide H-33342 trihydrochloride (Hoechst-33342, Merck). The presence of A. fumigatus was visualized by internal GFP expression. The samples were mounted on slides using a fluorescent staining solution (Agilent, Santa Clara, CA, USA). The scale of the immunofluorescence images corresponds to 100 μm. Immunofluorescence detection, image acquisition, and processing were performed using an Axio Observer.ZI microscope (Zeiss, Jena, Germany) and the Fiji V 1.52b software (github.com / fiji / fiji). (C) Mushroom size was calculated using the particle counter software (github.com / chko90 / particle counter). Five immunofluorescence images were acquired for each sample.The determined fungal sizes were normalized, and the virus-uninfected, untreated, A. fumigatus-infected control was set to 100%. (D) Supernatants from IAV- or co-infected A549 cells were collected 10 h post-infection. Viral titers were determined by standard plaque titration and are shown as PFU / ml. (E) The expression of viral polymerase basic protein 1 (PB1), hemagglutinin (HA), nucleoprotein (NP), and matrix protein 1 (M1), as well as A. fumigatus GFP (GFP) and the housekeeping protein ERK2, was visualized by Western blot analysis. (F) The individual protein signals were quantified with respect to ERK2 using Fiji V1.52b software (github.com / fiji / fiji) and plotted as relative protein amounts based on H₂O IAV or H₂O A. fumigatus. The data represent the mean + SD of three (CE, F) independent experiments using technical duplicates.The immunofluorescence images (B) and the Western blot images (E) represent one experiment for three. Experiments (B, E) with technical duplicates (B) were presented. Statistical significance was determined by a one-way (C, D) or two-way (F) ANOVA multiple comparison test with a Tukey analysis using GraphPad Prism 9.2 (Graphpad Software, Boston, USA) (p < 0.05 was considered the statistical significance level).

[0024] Figure 4: Treatment of A. fumigatus with ProcCluster® or procaine HCl in a human cell-free system leads to reduced hyphae formation. (A) Treatment procedure: Conidia of a GFP-expressing A. fumigatus Siamese [5*10 6Conidia / well were seeded onto coverslips in 24 well plates and incubated with solvent (H₂O) or with the specified concentrations of voriconazole, ProcCluster® (BC), or procaine HCl (DE) in DMEM with 10% FBS for 10 h at 37 °C, 5% CO₂. The fungi were then fixed (3.7% formaldehyde in PBS, 1 h, room temperature) and mounted on microscope slides using fluorescent staining solution (Agilent, Santa Clara, CA, USA). (B, D) The growth of A. fumigatus could be visualized by internal GFP expression. The scale of the immunofluorescence images corresponds to 100 μm. Immunofluorescence detection, image acquisition, and processing were performed using an Axio Observer.Z1 microscope (Zeiss, Jena, Germany) and the Fiji V 1.52b software (github.com / fiji / fiji). (C, E) Mushroom size was determined using the particle counter software (github.com / chko90 / particle counter). Five immunofluorescence images were acquired for each sample.The determined mushroom sizes were normalized and the solvent control was set to 100%. Statistical significance was determined by a one-way Dunnett multiple comparison ANOVA using GraphPad Prism 9.2 (Graphpad Software, Boston, USA) (p < 0.05 was considered the statistical significance level).

[0025] Figure 5: Treatment of A. fumigatus with ProcCluster® in a human cell-free system leads to a reduction in further hyphal growth during germination. (A) Treatment procedure: Conidia of a GFP-expressing A. fumigatus strain [5*10 6Conidia / well were seeded onto coverslips in 24 well plates and incubated at the specified time points with 2.5 mM ProcCluster® or with solvent (H₂O) in DMEM with 10% FBS (added at time point 0) for 10 h at 37 °C, 5% CO₂. The fungi were then fixed (3.7% formaldehyde in PBS, 1 h, room temperature) and mounted on slides using fluorescent staining solution (Agilent, Santa Clara, CA, USA). (B) The growth of A. fumigatus was visualized by internal GFP expression. The scale of the immunofluorescence images corresponds to 100 μm. Immunofluorescence detection, image acquisition, and processing were performed using an Axio Observer.ZI microscope (Zeiss, Jena, Germany) and the Fiji V 1.52b software (github.com / fiji / fiji). (C) Mushroom size was determined using the software particle counter (github.com / chko90 / particle counter). For each sample Five immunofluorescence images were acquired. The determined fungal sizes were normalized, and the untreated control (medium) was set to 100%. Statistical significance was determined by a one-way Dunnett multiple comparison ANOVA using GraphPad Prism 9.2 (Graphpad Software, Boston, USA) (p < 0.05 was considered the statistical significance level).

[0026] Figure 6: Treatment of Aspergillus fumigatus with ProcCluster® in a human cell-free system leads to the inhibition of IAV-induced hyphae formation. (A) Treatment procedure: Conidia of a GFP-expressing A. fumigatus strain [5*10 6Conidia / well were seeded onto coverslips in 24 well plates and incubated with purified influenza A / Puerto Rico / 8 / 34 virus particles [10 IAV particles / fungus] and solvent (H₂O) or 2.5 mM ProcCluster® in DMEM with 10% FBS for 10 h at 37 °C, 5% CO₂. The fungi were then fixed (3.7% formaldehyde in PBS, 1 h, room temperature) and mounted on slides using fluorescent staining solution (Agilent, Santa Clara, CA, USA). (B) The growth of A. fumigatus was visualized by internal GFP expression. The scale of the immunofluorescence images corresponds to 100 μm. Immunofluorescence detection, image acquisition, and processing were performed using an Axio Observer.ZI microscope (Zeiss, Jena, Germany) and the Fiji V 1.52b software (github.com / fiji / fiji). (C) Mushroom size was determined using the particle counter software (github.com / chko90 / particle counter). Five immunofluorescence images were acquired for each sample.The determined mushroom sizes were normalized and the unstimulated solvent control was set to 100%. Statistical significance was determined by a one-way Dunnett multiple comparison ANOVA using GraphPad Prism 9.2 (Graphpad Software, Boston, USA). (p < 0.05 was considered the statistical significance level.) DETAILED DESCRIPTION OF THE INVENTION

[0027] The invention relates to an amine (AM) according to the general formula (I). where in formula (I) R1ist 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; R2ist 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; R3ist -(CH2) nNR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 amine according to formula (I) can optionally also be used in the form of a salt, for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp., preferably of superinfections with influenza viruses and Aspergillus spp.

[0028] Preferably, the influenza viruses are selected from the group consisting of influenza A viruses, influenza B viruses, and influenza C viruses, preferably influenza A viruses.

[0029] Aspergillus spp. is preferably Aspergillus fumigatus.

[0030] Treatment of infections with Aspergillus fumigatus involves, within the framework of The invention is preferably understood to be a treatment for aspergillosis caused by infection with Aspergillus fumigatus.

[0031] In the context of this invention, a superinfection is understood to mean an infection of a subject (e.g., a patient) initially with one pathogen, followed at a later time by an infection with at least one second pathogen before the infection with the first pathogen is overcome, so that, as a result, there is at least a temporary simultaneous infection with both the first and the second pathogen. Thus, in this sense, an infection with influenza viruses, preferably influenza A viruses, can occur first, followed by an additional infection with Aspergillus spp., preferably Aspergillus fumigatus, or first with Aspergillus spp., followed by an additional infection with influenza viruses, preferably influenza A viruses. Preferably, during the superinfection, the infection with Aspergillus spp.Preferably, Aspergillus fumugatus triggers aspergillosis in the infected subject. Preferably, influenza is triggered in the infected subject as part of a superinfection during infection with influenza viruses.

[0032] The use of antiviral drugs in the treatment of viral diseases, particularly influenza, involves exploiting their antiviral effects. Typically, antiviral agents inhibit the development and replication cycle of viruses rather than directly attacking them.

[0033] Without committing to a specific theoretical explanation, it is currently assumed that the observed antiviral effect of the compounds according to the invention is probably mediated preferably indirectly by interaction with metabolic pathways of the infected organism, which are necessary for the multiplication of the virus.

[0034] The use of antifungal agents in the treatment of fungal infections involves utilizing their antifungal effect. Typically, antifungal substances work by destroying the cell wall of the fungi.

[0035] Without committing to a specific theoretical explanation, it is currently assumed that the observed antifungal effect of the compounds according to the invention is probably mediated preferably indirectly by interaction with metabolic pathways of the fungus, which are responsible for its vitality.

[0036] In one embodiment in formula (I) R1R2, R3, R4, R5, R6ist H; R3ist -(CH2)nNR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl;

[0037] In the present invention, definitions such as (C) mean 1-10) Alkyl, as for example for the residue R1 of formula (I), is defined as a saturated alkyl group with a carbon number of 1 to 10. The alkyl group can be linear, branched, and optionally cyclic. Alkyl groups that have both a cyclic and a linear component also fall under this definition. The same applies to other alkyl groups, such as a C 1-2Alkyl group. Optionally, alkyl groups may also be singly or multiply substituted with functional groups such as amino, hydroxy, halogen, aryl, or heteroaryl. Unless otherwise specified, alkyl groups preferably do not have 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 called 2-propyl or 1-methylethyl), isobutyl, tert-butyl, sec-pentyl, neo-pentyl, 1,2-dimethylpropyl, iso-amyl, iso-hexyl, and iso-heptyl.

[0038] In the present invention, definitions such as C mean 2-10Alkenyl, as for example for the residue R1 of formula (I), is defined as follows: this substituent (residue) is an alkenyl group with a carbon number of 2 to 10, which has at least one unsaturated carbon-carbon bond. The alkenyl group can be linear, branched, and optionally cyclic. Alkenyl groups that have both a cyclic and a linear component also fall under this definition. The same applies to other alkenyl groups, such as a C 2-4Alkenyl residue. Optionally, alkenyl residues can also be singly or multiply substituted with functional groups such as amino, hydroxy, halogen, aryl, or heteroaryl. Preferably, alkenyl residues do not have any other functional groups as substituents. Examples of alkenyl residues are 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, and 2,-nonenyl.

[0039] In the present invention, the definition of aryl means that it is an aromatic or heteroaromatic residue. An aromatic residue is an aromatic cyclic hydrocarbon that may consist of a single ring or a ring system of several fused rings. The aromatic residue may, for example, be monocyclic, bicyclic, or tricyclic. Preferably, the monocyclic aromatic residue forms a 5- or 6-membered ring. Preferably, the bicyclic aromatic ring forms a 9- or 10-membered ring. Preferably, the tricyclic aromatic ring forms a 13- or 14-membered ring. A definition such as (C5-C 14 )Aryl means, that the aryl group comprises 5 to 14 carbon atoms. The aryl group preferably contains 3 to 14, more preferably 4 to 6 carbon atoms. Optionally, aryl groups can also be singly or polynomially substituted with functional groups such as alkyl, alkenyl, amino, cyano, -CF3, hydroxy, halogen, aryl, or heteroaryl; preferably, the aryl groups have no further substituents. Examples of aromatic groups are phenyl and naphthyl.

[0040] In the present invention, the definition of heteroaryl means that it is a heteroaromatic residue. Heteroaromatic ring means that in an aromatic residue, as defined above, whose ring system is formed by carbon atoms, one or more of these carbon atoms are replaced by heteroatoms such as O, N, or S. A definition such as (C5-C 10Heteroaryl is based on the corresponding definition for the aryl group and means that the heteroaryl group has 5 to 10 atoms in the ring. However, as defined above, one or more carbon atoms are replaced by heteroatoms. That is, the (C5-C 10 The heteroaryl group comprises 5 to 10 atoms in the ring, not all of which are carbon atoms. Therefore, furanyl, for example, would be a Cs heteroaryl group. Heteroaryl residues can optionally be singly or multiply substituted with functional groups such as alkyl, alkenyl, amino, cyano, -CF3, hydroxy, halogen, aryl, or heteroaryl; preferably, the heteroaryl residues have no further substituents. Examples of heteroaromatic residues that fall under the definition of aryl in the present invention are furanyl, thienyl, oxazolyl, pyrazolyl, pyridyl, and indolyl.

[0041] In the present invention, the definition of halogen, as defined above for the R4 group in formula (I), means that it is a chlorine, bromine, iodine, or fluorine substituent. Preferably, it is a chlorine or fluorine substituent.

[0042] Preferably, the amine (AM) according to general formula (I) is selected from the group consisting of 4-aminobenzoic acid 2-(N,N-diethylamino)ethyl ester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), 2-(diethylamino)ethyl-4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid 2-diethylaminoethyl ester (oxybuprocaine), (2-(dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), more preferably 4-aminobenzoic acid 2-(N,N-diethylamino)ethyl ester (procaine).

[0043] The amines (AM) according to the general formula (I) and the amines (AM) specifically named above are used as local anesthetics in medical use and are accordingly commercially available.

[0044] Furthermore, the invention relates to a carbonic acid adduct (KA) comprising at least one structural element according to the general formula (II), (III) and / or (IV) where in formulas (II), (III), and (IV) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 to 30; (S) is a salt; for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp., preferably of superinfections with influenza viruses and Aspergillus spp.

[0045] In one embodiment in formula (I) R1R2, R3, R4, R5, R6is H; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; The salt (S) comprises at least one cation selected from Na + , K + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ and Mn 2+ , preferably Na + Furthermore, the salt (S) comprises at least one anion selected from Cl-, Br-- - , J-, F, SO4 2- , SO3 2- , HSO4- HSO3-, -HCO3-, CO3 2- , PO4 3- , HPO4 2- , H2PO4-, SiO4 4- , AIO2-, SiO3- and / or [AIO2) 12 (SiO2)2] 2- , preferably CI and Br -- , especially preferred CI-.

[0046] The production of the carbonic acid adduct (KA) is also disclosed in W02006 / 007835, DE 10 2013 015 035 A1 and WO2019 / 048590, which are hereby referenced.

[0047] The invention further relates to a carbonic acid adduct (KA) comprising carbonic acid, at least one amine (AM) according to the general formula (I) and at least one salt (S), where in formula (I) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 according to formula (I) may optionally also be used in the form of a salt; for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp.

[0048] In one embodiment in formula (I), R1R2, R4, R5, R6ist H; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl;

[0049] 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) during step b), if an acid addition salt of the amine (AM) is used. The salt (S) can also be added directly in one of steps a), b), and / or c). Direct addition of the salt (S) is preferred if the amine (AM) is not used in its salt form and / or step b) is not carried out.

[0050] Preferably, the carbonic acid adduct (KA) remains stable for at least 12 months when stored at a temperature of 2 to 10 °C, more preferably for at least 13 months, even more preferably for at least 20 months, particularly preferably for at least 23 months, and most preferably for at least 27 months.

[0051] The carbonic acid adduct (CA) is no longer considered stable if the specific bands of at least one amine (AM) can be detected by IR spectroscopy, particularly in the solid form of the carbonic acid adduct (CA). The specific IR bands of the amine are those bands that are also observed in the IR spectroscopic examination of the pure adduct. Amines (AM) are detected. As long as the amine (AM) is bound in the stable carbonic acid adduct (KA), the specific IR bands of the amine (AM) are not detected.

[0052] In certain embodiments, the loss of stability can also be accompanied by an increase in pH or by the measurement of two melting / decomposition ranges, i.e., a range corresponding to the amine (KA) and a range corresponding to the carbonic acid adduct (KA). The carbonic acid adduct, which has become unstable through at least partial decomposition into the amine (AM) and CO₂ and / or water, may also exhibit a change in its solubility. The unstable carbonic acid adduct (KA) may prove to be sparingly soluble or at least partially insoluble.

[0053] The carbonic acid adduct (KA) can be produced by a process comprising steps a), optionally b), c), d) and e).

[0054] In step a) a solution (A) is provided which comprises at least one solvent and CO2 dissolved in at least one solvent.

[0055] Solution (A) comprises at least one solvent and CO2 in dissolved form. Within the scope of this invention, CO2 is understood to mean carbon dioxide. Within the scope of this invention, CO2 in dissolved form is understood to mean all forms of CO2 that it assumes upon dissolution. For example, it is known that in aqueous solutions, the dissolved CO2 can exist in equilibrium as CO2, as carbonic acid, or as singly or doubly deprotonated carbonic acid, i.e., as hydrogen carbonate or carbonate.

[0056] Solution (A) is obtained by introducing CO2 into at least one solvent. The CO2 can be introduced into the solvent in any form known and suitable to those skilled in the art. Preferably, gaseous or frozen CO2 in the form of dry ice, more preferably gaseous CO2, is introduced into the solvent. Preferably, the gaseous or frozen CO2 is of at least food grade, more preferably a grade suitable for pharmaceutical purposes. The gaseous and / or frozen CO2 used preferably has a purity of at least 99.5%, more preferably 99.9%.

[0057] Preferably, in the context of this invention, food quality means that the relevant provisions of German and European food law are met. These preferably include Regulation (EC) No. 1215 / 2004. Regulation (EC) No 852 / 2004 and Regulation (EC) No 178 / 2002 as well as Regulation (EC) No 1333 / 2008 and Regulation (EU) 231 / 2012.

[0058] Preferably, pharmaceutical quality means that the relevant provisions of the European Pharmacopoeia (Ph. Eur.) are met.

[0059] The CO2 can also be introduced under pressure, particularly when gaseous CO2 is introduced into the solution. Introducing under pressure in this context means using a pressure greater than atmospheric pressure, preferably greater than 1.01325 bar. For this purpose, the CO2 can be introduced into the solvent in a container that isolates the solvent from the environment in such a way that pressure can be generated in the container, particularly by supplying CO2, which is above atmospheric pressure, preferably above 1.01325 bar. The introduction of the CO2 into the solution, especially in gaseous form, can be carried out in one step or in intervals.

[0060] In step a), the person skilled in the art can use any suitable solvent. Preferably, a polar-protic solvent is used; more preferably, water is used. Depending on the intended use of the carbonic acid adduct (CA), the solvent can be of varying purity. For example, water with the purity grade "aqua ad iniectabilia" can be used if the carbonic acid adduct (CA) is intended for pharmaceutical or medical purposes.

[0061] Step a) can include substep a1), wherein the solvent is cooled to 3 to 8 °C, preferably to 5 °C, preferably before the CO2 is introduced. Cooling can be carried out using any method known to those skilled in the art and identified as suitable. For example, cooling can be achieved by storing the solvent in a refrigerator for a sufficiently long time until it reaches the target temperature. Alternatively, external cooling can be used.

[0062] Step a) can include substep a2), wherein the CO2 is introduced into the solvent, preferably until a saturation concentration of 3 to 10 g / l is reached, more preferably until a saturation concentration of 4.5 to 7.5 g / l is reached, based on the total volume of the solution. Preferably, the pH of the solution after saturation with CO2 is ≤ 3.0 to ≤ 6.0, more preferably ≤ 4.3 to ≤ 4.8. Preferably, the CO2 in substep a2) is dissolved under pressure, wherein the pressure is 1.5 to 10 bar, more preferably 1.9 to 7 bar, and even more preferably 2 to 5 bar.

[0063] Step a) may include substep a3), wherein the solution (A) preferably obtained in substep a2) is stored at 1 to 10 °C, preferably for at least 30 min, more preferably for at least 50 min, and even more preferably for at least 60 min, for a maximum of 5 days (120 h). Preferably, the solution (A) preferably obtained in substep a2) is stored at 3 to 8 °C for at least 30 min, more preferably for at least 50 min, and even more preferably for at least 60 min, for a maximum of 5 days (120 h).

[0064] Preferably, step a) includes all sub-steps a1), a2) and a3).

[0065] Preferably, the sub-steps a1), a2) and a3) are carried out in the order a2) follows a1) and a3) follows a2).

[0066] Optionally, step b) can be carried out, wherein the base (BA), which is not the amine (AM), is dissolved in solution (A) to obtain solution (A1). Preferably, the base (BA) is a hydrogen carbonate or a carbonate, more preferably a hydrogen carbonate, and even more preferably sodium hydrogen carbonate.

[0067] In step c) or c1), the at least one amine (AM) is dissolved in solution (A) or (A1) to obtain solution (B).

[0068] The at least one amine (AM), as defined above, can be used in step c) in either its neutral form or as a salt. Optionally, the at least one amine (AM) can also be used as a mixture of the neutral form of the amine (AM) with the salt form of the amine (AM). Therefore, the at least one amine (AM) can comprise the neutral amine (AM) and / or the salt form of the at least one amine (AM). Preferably, the salt form of the at least one amine (AM) is an acid addition salt; more preferably, the acid addition salt is a hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, hydrotosylate, hydroacetate, hydroformate, hydropropanoate, hydromalonate, hydrosuccinate, hydrofumarate, hydroxalate, hydrotartrate, hydrocitrate, hydromaleate, more preferably a hydrochloride or hydrobromide, and even more preferably a hydrochloride of the at least one amine (AM).

[0069] Preferably the concentration of the amine (AM) in solution (B) is 0.01 to 0.25 g / ml, preferably 0.03 to 0.20 g / ml, more preferably 0.08 to 0.15 g / ml.

[0070] Step c) can include substep c2), where the at least one amine (AM) is dissolved in solution (A), or, if step b) is performed, in solution (A1) while obtaining solution (B).

[0071] In one possible embodiment, the ratio of the amine (AM) to the base (BA), when carrying out step b), 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]].

[0072] In another possible embodiment, the molar ratio of the amine (AM) to the base equivalents of the base (BA) when performing step b) in solution (B) is 0.8:1 to 1.5:1, preferably 1.2:1, more preferably 1:1. Base equivalents in this context means that when using a monovalent base, such as NaHCO3, the molar ratio of the base (BA) to the amine (AM) corresponds to the ratio specified above. When using a divalent base (BA), such as Na2CO3, only half the amount of base (BA) is required relative to the amount of substance in moles of base (BA) compared to using a monovalent base to introduce the same amount of base equivalents. For example, with a ratio of 1:1, when using 10 mmol of amine (AM), 10 mmol of NaHCO3 are required, but only 5 mmol of Na2CO3.

[0073] In a further embodiment, step b) is carried out and in sub-step c1) the amine (AM) is added in the form of the acid addition salt, wherein the amine (AM) with the acid bound to it is added in such an amount that the acid bound to the amine (AM) is able to neutralize the base (BA) to such an extent that the solution (B) assumes a pH value of 6 to 8.

[0074] Step c) can include substep c2), where solution (A) is given to solution (B) while preserving solution (B1).

[0075] Preferably the concentration of the amine (AM) in solution (B1) is 0.01 to 0.25 g / ml, preferably 0.03 to 0.20 g / ml, more preferably 0.08 to 0.15 g / ml.

[0076] Step c) may include substep c3), wherein solution (B) or, if substep c2) is carried out, solution (B1) is enriched with CO2. Preferably, solution (B) is enriched with 2.5 g / l to 9 g / l, more preferably with 5 to 7.5 g / l CO2.

[0077] Step c) may include substep c4), wherein the solution (B) or, if substep c2) is carried out, the solution (B1) is stored at 1 to 10°C, preferably 3 to 8°C, for at least 1 h, preferably 24 h to 120 h, more preferably 24 to 72 h.

[0078] Step c) may include substep c5), wherein solution (B) or, if substep b2) is carried out, 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, most preferably at least 14 g / l, and most preferably at least 15 g / l. Preferably, in substep c5), a further 0.4 to 4.7 g / l, more preferably 1 to 3.5 g / l of CO2 is introduced or dissolved into solution (B) or (B1) until the required total concentration is reached.

[0079] The term "total concentration" here refers 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 additive result of the weight increase of the solution due to the added CO2 in all preceding enrichment steps a2) and / or c3), if carried out, and c5), without taking into account CO2 that is optionally added to the solution as a base (BA) in the form of bicarbonate or carbonate.

[0080] The enrichment of solution (B) or solution (B1) with CO2 to the required total concentration in step c5) can be carried out 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, and most preferably 6.5 to 10 bar. Preferably, solution (B) or (B1) has a temperature of 3 to 8 °C, more preferably 5 °C, when enriched with CO2 in step c5).

[0081] The enrichment of the solution (B) or (B1) in substeps c3) and c5) can be carried out in the same way as described for step a).

[0082] Preferably the pH value of solution (B) or, if partial step c2) is carried out, of solution (B1) after step c5) is ≤ 7.0.

[0083] Preferably, step c) includes all sub-steps c1), c2), c3), c4) and c5).

[0084] Preferably, the sub-steps c1), c2), c3), c4) and c5) are carried out in the order c2) follows c1), c3) follows c2), c4) follows c3), c5) follows c4).

[0085] In step d), the solution obtained after completion of step c) is frozen. Preferably, in step d), solution (B) is frozen, or, after completion of substep c2), solution (B1) is frozen.

[0086] The solution, preferably solution (B) or (B1), which is subjected to step d), 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.

[0087] Preferably, the solution obtained after completion 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 and most preferably at -70 °C to -50 °C.

[0088] Freezing the solution obtained after step c), preferably solution (B) or (B1), can in principle be carried out by any method known to those skilled in the art and identified as suitable. For example, freezing can be carried out by transferring the solution obtained in step c) into a suitable vessel immersed in a cooling medium. Preferably, the vessel is flask-shaped. Preferably, the vessel containing the solution obtained in step c) is immersed in the cooling medium at an angle of 40°. The cooling medium can, for example, consist of a solvent such as methanol, ethanol, or acetone, which is brought to the desired temperature by adding dry ice or suitable cooling equipment such as cryostats.

[0089] Preferably, freezing takes place at atmospheric pressure, more preferably at 1.01325 bar.

[0090] Preferably, the solution obtained after completion 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, and most preferably within 1.5 to 5 minutes.

[0091] The solution obtained after completion of step c), preferably solution (B) or (B1), is preferably frozen at a cooling rate of 10 to 100 K / min, more preferably at 20 to 80 K / min, even more preferably at 30 to 70 K / min and particularly preferably at 40 to 60 K / min.

[0092] Preferably, the vessel containing the solution obtained after completion of step c), preferably solution (B) or (B1), is located in the cooling medium at 10 to 1000 rpm, more preferably at 50 to 600 rpm, even more preferably at 100 to 400 rpm and particularly preferably at 200 to 300 rpm.

[0093] Freezing can be done using the shell-freeze method.

[0094] In step e), the solution frozen in step d), preferably solution (B) or (B1), is stored at -100 to 0 °C for no longer than 4 days.

[0095] Preferably, the solution frozen in step d) is stored in step e), preferably solution (B) or (B1), for 1.5 to 4 days, more preferably for 2.5 to 4 days.

[0096] Preferably, the solution frozen in step d) is stored in step e), preferably solution (B) or (B1) at -50 to 0 °C, more preferably at -30 to -5 °C, even more preferably at -25 to -10 °C, and particularly preferably at -20 to -15 °C.

[0097] Storage at the defined temperature can, in principle, take place in any refrigeration unit known to a specialist. For example, storage can be carried out in a freezer or a cold storage room.

[0098] The process by which the carbonic acid adduct (KA) can be produced may include a further step f), which is carried out after step e). In step f), the solution stored in step e), preferably solution (B) or (B1), is dried to obtain dried carbonic acid adduct (KA).

[0099] Preferably in step f) the water is removed from the solution stored in step e), preferably solution (B) or (B1) to a residual content of < 0.8 wt.%, more preferably to a residual content of < 0.1 wt.% based on the total weight of the dried carbonic acid adduct (KA).

[0100] Preferably in step f) CO2 not bound in the carbonic acid adduct (KA) is removed from the solution stored in step e), preferably (B) or (B1), to a residual content of < 0.8 wt.%, more preferably to a residual content of < 0.1 wt.% based on the total weight of the dried carbonic acid adduct (KA).

[0101] Drying can be carried out using any method known to a person skilled in the art and identified as suitable. Preferably, drying is carried out by freeze-drying, also called lyophilization. In the case of using the freeze-drying process, step d) represents the freezing step and step e) the maturation step.

[0102] Preferably, the pressure during drying is 0.01 to 30 mbar, more preferably 0.02 to 20 mbar, more preferably 0.03 to 10 mbar, even more preferably 0.03 to 0.5 mbar, and most preferably 0.05 to 0.1 mbar. Preferably, the pressure The pressure is maintained throughout the entire drying process. Preferably, the pressure defined above is reached within 7 hours, more preferably within 5 hours, and most preferably within 4 hours from the start of evacuation.

[0103] The endpoint of the drying process can be determined by a person skilled in the art from the temperature profile records. Preferably, the total drying time in step f) is 10 to 60 h, more preferably 30 to 55 h, and particularly preferably 41 to 52 h. The total drying time is defined as the period between the completion of storage in step e) and the completion of drying in step f).

[0104] Preferably the temperature during the entire drying process in step f) is 0 to 20 °C, preferably 4 to 18 °C, more preferably 8 to 16 °C.

[0105] Furthermore, the invention comprises a pharmaceutical composition (PZ) comprising the amine (AM) or the carbonic acid adduct (KA) as described above for use in the treatment of atypical pneumonia.

[0106] Pharmaceutical compositions that also contain the carbonic acid adduct (KA) are described in WO2019 / 048590.

[0107] The pharmaceutical preparation (PZ) within the scope of this invention is generally understood to be a composition comprising the amine (AM) or carbonic acid adduct (KA) and may furthermore include excipients or additives suitable for pharmaceutical-medical use.

[0108] Furthermore, the pharmaceutical preparation (PZ) may include additional bases that do not correspond to the amine (AM) and may differ from the base (BA). In principle, the person skilled in the art can select the additives according to the intended use. They will take the desired dosage form into account.

[0109] The pharmaceutical preparation (PZ) can, in principle, be in any suitable dosage form. For example, the pharmaceutical preparation (PZ) can be in capsule form, as a tablet, as a solution, as an ointment, cream, gel, paste, poultice, or medicated patch.

[0110] The pharmaceutical preparation (PZ) can, in principle, be administered in any suitable dosage form. The person skilled in the art will select a suitable dosage form according to the intended route of administration. For example, the Pharmaceutical preparation (PZ) administered orally, by inhalation, by injection, as a patch, cutaneously, including at least dermal application, ophthalmic application, nasal application, rectal application and vaginal application.

[0111] In preparing the pharmaceutical preparation (PZ), the person skilled in the art may, in principle, make use of methods known in the prior art.

[0112] Preferably, the temperature of the mixture of the carbonic acid adduct (KA) and the excipients and optionally further bases used during the preparation of the pharmaceutical preparation (PZ) is less than 60 °C, preferably less than 50 °C, more preferably 0 to 50 °C.

[0113] In the preparation of the pharmaceutical formulation (PZ), preferably in ointment form, dispersion, preferably using an ointment maker, can also be employed. A rotational speed of < 2000 rpm is preferably used.

[0114] The carbonic acid adduct (CA) can be triturated to a powder before processing into the oral dosage forms described below, such as tablets, capsules, or semi-solid dosage forms, either alone or in the presence of other excipients or bases. A person skilled in the art may, in principle, use suitable and known technical means for the respective purpose. For example, mortars or similar suitable equipment can be used for the trituration steps. Preferably, a technical aid is used in the trituration steps that minimizes the mechanical stress on the carbonic acid adduct. Preferably, the trituration is carried out with a mortar.

[0115] The resulting powder can then be pressed into tablets, filled into commercially available capsules, or mixed with suitable excipients and processed into semi-solid dosage forms.

[0116] One embodiment of the pharmaceutical preparation (PZ) relates to a pharmaceutical preparation (PZ) comprising the carbonic acid adduct (KA) and administered orally. In this embodiment, the pharmaceutical preparation (PZ) is preferably administered in capsules, more preferably in hard gelatin or cellulose capsules, and particularly preferably in hard gelatin capsules. Likewise, in this embodiment, the pharmaceutical preparation (PZ) can be administered in tablet form.

[0117] Preferably, the pharmaceutical preparation (PZ) in this embodiment comprises at least one excipient (H), preferably selected from starch, in particular maize starch and / or rice starch, dextran, cellulose esters and SiO2.

[0118] Furthermore, in this embodiment, the pharmaceutical preparation (PZ) can comprise at least one base (BA1) that is not the amine (AM) and is identical or different from the base (BA). Preferably, the base (BA1) is selected from NaHCO3 or KHCO3, more preferably NaHCO3.

[0119] Preferably, the above general information on the pharmaceutical preparation (PZ) also applies to this embodiment, in particular also to the preparation of the pharmaceutical preparation (PZ), insofar as this is technically applicable to this embodiment.

[0120] Preferably, the pharmaceutical preparation (PZ) in this embodiment comprises: a) 1 to 99 wt.%, more preferably 15 to 95 wt.% of the carbonic acid adduct (KA), b) 0 to 60 wt.%, more preferably 3 to 50 wt.% of the base (BA1) and 1 to 90 wt.%, more preferably 2 to 75 wt.% of the excipient (H) based on the total weight of the pharmaceutical preparation.

[0121] Another embodiment of the pharmaceutical preparation (PZ) relates to a semi-solid pharmaceutical preparation (PZ) comprising the carbonic acid adduct (CA) and applied cutaneously. The pharmaceutical preparation (PZ) in this embodiment can be applied, for example, in the form of an ointment, cream, gel, paste, poultice, or medicated patch.

[0122] Preferably, the above general information on the pharmaceutical preparation (PZ) also applies to this embodiment, in particular also to the manufacture of the pharmaceutical preparation (PZ), insofar as this is technically applicable to this embodiment.

[0123] In this embodiment, the pharmaceutical preparation (PZ) preferably comprises at least one excipient (H1) selected from paraffins, in particular thick and thin liquid paraffins, wool wax, wool wax alcohols, hydrophobic base gel, vegetable oils, animal fats, synthetic glycerides, liquid polyalkylsiloxanes, waxes, petrolatum and starch, in particular corn starch, preferably petrolatum.

[0124] Thick paraffins (Paraffinum subliquidum) are defined as paraffins that have a viscosity of 110 to 230 mPas, while thin paraffins (Paraffinum perliquidum) have a viscosity of 25 to 80 mPas.

[0125] Preferably, the pharmaceutical preparation (PZ) in this embodiment comprises: a) 0.1 to 40 wt.%, preferably 0.4 to 10 wt.% of the carbonic acid adduct (KA) and b) 60 to 99.9 wt.%, preferably 80 to 96 wt.% of the excipient (H1) based on the total amount of the pharmaceutical preparation (PZ).

[0126] Another embodiment of the pharmaceutical preparation (PZ) comprising the carbonic acid adduct (KA) relates to a pharmaceutical preparation that is administered parenterally, nasally and / or by inhalation.

[0127] Preferably, the above general information on the pharmaceutical preparation (PZ) also applies to this embodiment, in particular also to the preparation of the pharmaceutical preparation (PZ), insofar as this is technically applicable to this embodiment.

[0128] Preferably, in this embodiment, the pharmaceutical preparation (PZ) is in the form of a solution (A2) comprising the carbonic acid adduct (KA), dissolved CO2 and at least one excipient (H2).

[0129] The excipient (H2) is preferably selected from an alkali halide or alkaline earth halide, more preferably NaCl and MgCl2, and even more preferably NaCl. The excipient (H2) can be identical to the salt (S). Quantity specifications relating to the excipient (H2), insofar as it is identical to the salt (S) in individual embodiments, refer within the scope of this invention to additional quantities of the excipient (H2) that were not introduced into the pharmaceutical preparation (PZ) in the form of the salt (S) as part of the carbonic acid adduct (KA).

[0130] Preferably, solution (A2) is obtained by introducing CO2 into a solvent. Preferably, the solvent is water. Preferably, the CO2 is introduced into the solvent at a temperature of 0 to 8 °C, more preferably at 0 to 5 °C. The CO2 can be introduced into the solvent in gaseous form or in solid form, for example as dry ice. Preferably, the CO2 in gaseous form is introduced into the solvent. The CO2 can also be introduced into the solution under pressure until the desired concentration is reached, as described above for example in step a2).

[0131] Preferably, the CO2 is introduced into the solvent to produce the solution (A2) up to a concentration of at least 3 g / l, more preferably up to 4 g / l, even more preferably 4 g / l to 8 g / l.

[0132] Preferably, the CO2 used to produce the solution (A2) has a purity of at least 99.9%, more preferably also a quality suitable for pharmaceutical applications as defined above.

[0133] Preferably, the pharmaceutical preparation (PZ) in this embodiment, insofar as it is obtained by dissolving the carbonic acid adduct (KA) in the solution (A2), comprises: a) 0.05 to 100 mg / ml, more preferably 0.08 to 50 mg / ml of the carbonic acid adduct (KA) and b) 0 to 20 mg / ml, more preferably 3 to 10 mg / ml of the excipient (H2), each based on the total volume of the pharmaceutical preparation (PZ). EXAMPLES OF INVENTION

[0129] 1. Exemplary embodiment 1, Preparation of the carbonic acid adduct (KA) 1.1 Materials: • Amine (AM): 68.8 to 110.1 g of procaine hydrochloride (e.g., pure, for use as a pharmaceutical active ingredient; Ph. Eur. or of a quality suitable for this purpose) • Base (BA): 22.2 to 33.9 g sodium bicarbonate (e.g. pure or of a quality suitable for this purpose), • Solvent: 630 to 900 ml water (Aqua ad iniectabiliä) • CO2: min. 12.0 g / l carbon dioxide from pressurized steel cylinders (CO2 of suitable quality) • Dry ice for preparing freezing mixtures and for cooling • Methanol, used for technical purposes in the preparation of refrigeration mixtures

[0130] 1.2 Step a) Water (e.g. Aqua ad iniectabiliä) is filled into a cleaned plastic pressure bottle up to the mark (approx. 800 to 900 ml) and pre-cooled for at least 1 hour in the refrigerator (3 to 8 °C) or by means of external cooling to 5 °C. A carbon dioxide-saturated solution is prepared. For this, CO₂ is introduced into pre-chilled water in intervals under pressure (1.6 to 8 bar). The hissing sound (escaping gas via the pressure relief valve) indicates that the solution is saturated with CO₂. Saturation is checked by weight until 4.0 to 6.0 g of CO₂ (corresponding to 4.5 to 7.5 g / L) are dissolved. The saturated solution has a pH value of ≤ 4.3 to 4.8. This carbonated water is immediately sealed and stored in the refrigerator for at least 1 hour.

[0131] 1.3 Step b) In a second plastic pressure bottle, 21.2 g of sodium bicarbonate is placed, mixed with 320 ml of chilled carbonated water and dissolved by swirling.

[0132] 1.4 Step e) To this solution, the equivalent amount of solid procaine hydrochloride is added at a constant temperature, forming a nearly neutral solution. After the addition of a further 320 ml of cold carbonated water, a clear, weakly acidic solution is obtained. The solution is then enriched with CO2. The solution prepared in this way is stored in a refrigerator for at least one hour. The solution is then conditioned again with CO2 until a CO2 concentration of 12 g / l is reached. The pH value is checked using pH indicator strips. The pH value is ≤ 6.6.

[0133] 1.5 Step d) Round-bottom flasks are pre-cooled. For freezing, the reaction solution is measured in a pre-cooled graduated cylinder, transferred in portions into round-bottom flasks, and frozen by immersion in a dry ice / methanol freezing mixture (<-60°C) using the shell-freezing method within 1.5 to 3.5 minutes per flask (~200 rpm). The immersion angle of the flask on the rotary evaporator is set to approximately 40°.

[0134] 1.6 Step e) The flasks containing the frozen goods are sealed with a ground glass stopper and stored in a freezer at -15 to -20 °C for 2 to 4 days.

[0135] 1.7 Step f) The flasks, heated to the correct temperature, are encased in pre-cooled polystyrene containers and immediately connected individually to an evacuated (0.060 ± 0.01 mbar, approx. -46 °C, leak test) freeze-drying system via a flexible rubber cone. The valves are carefully opened, and the individual flasks are placed under vacuum. Finally, all flasks must be completely evacuated. To monitor the process, temperature sensors are placed at the bottom of the polystyrene casing, recording the entire temperature profile throughout the drying process. Before the start of lyophilization, the temperature sensors indicate temperatures below -5 °C. During lyophilization, the pressure is 0.07 ± 0.02 mbar. This sublimation pressure is reached within 4 hours and maintained throughout the entire lyophilization period. The cooling chamber is kept at a temperature of 9 to 15 °C throughout the drying process. The endpoint of lyophilization is determined graphically from the temperature profile recordings. The total drying time was a maximum of 52 hours. The dry lyophilisate is transferred to an amber glass jar with a twist-off lid, fitted with a desiccant bag, and stored in a refrigerator at 0 to 15 °C.

[0136] 2. Examples of pharmaceutical preparations (PZ)

[0137] 2.1 Capsules and tablets The following describes, by way of example, the composition of the pharmaceutical preparation (PZ) according to the invention in the embodiment as a capsule or tablet containing procaine as an amine (AM). For the production of the capsules, commercially available snap-in capsules in standard sizes (5 to 1000) can be used, which are filled with the powder containing the carbonic acid adduct (KA), comprising procaine as an amine (AM) (trituration of the active ingredient carbonic acid adduct (KA), comprising procaine as an amine (AM), optionally with additives, fillers, and flow regulators). The carbonic acid adduct (KA) was prepared according to Example 1. It has been shown that hard gelatin capsules are more suitable than cellulose capsules with regard to stability. Thus, the filled hard gelatin capsules, for example hard gelatin capsules with 60 and 100 mg of active ingredient according to Table 1, showed no changes even after 12 months of storage in the refrigerator and are therefore stable.Stability was investigated using IR spectroscopy. In the case of the hard gelatin capsules, no procaine was detected by IR spectroscopy within the 12-month period. Procaine was detected, whereas for cellulose capsules, a procaine band was measured in the IR spectrum after only a few days. The content was determined at room temperature using UV / VIS spectroscopy. For compounded medications, a tolerance range of ±15% is prescribed according to Pharmacopoea Europaea section 2.9.6, based on the total content including by-products. The applicable and generally accepted pharmaceutical rules for the manufacture of (compounded) medicines are applied (for example, Pharmacopoea Europaea, German Drug Codex). Table 1: Example composition of capsules with NaHCO3 additive and carbonic acid adduct (KA) as active ingredient produced according to embodiment 1. Table 2: Example composition of a tablet with added NaHCO3 and carbonic acid adduct (KA) as active ingredient produced according to embodiment 1.

[0138] 2.2 Ointments The composition of the pharmaceutical preparation (PZ) according to the invention, in its embodiment as an ointment, is explained below using procaine as an amine (AM) in the carbonic acid adduct (KA) as an example. The preparation of the ointment follows the applicable and generally accepted pharmaceutical rules for the manufacture of (compounded) medicinal products (for example, Pharmacopoea Europaea, Deutscher Arzneimittel-Codex). Significant shear forces are avoided during the preparation of the ointment. Furthermore, the temperature during preparation is kept below 60 °C, even locally. The ground carbonic acid adduct (KA) comprising procaine as an amine (AM) is mixed into the ointment base, for example, petrolatum, in a mortar or mortar and pestle heated by a water bath at 40 to 45 °C. Alternatively, electric mixing systems, such as those commonly used in pharmacies, can also be used. Table 3: Example composition of ointment and carbonic acid adduct (CA) as active ingredient produced according to embodiment 1.

[0139] 2.3 Parenteral solutions To prepare a parenteral solution containing the carbonic acid adduct (KA) comprising procaine as the amine (AM), the required amount of water (aqua ad iniectabiliä) is cooled to approximately 5 ±3 °C in a suitable container using a magnetic stir bar or similar device and maintained at this temperature. The water is then enriched with gaseous carbon dioxide of the required quality to approximately 3.2 g / L. The appropriate amount of carbonic acid adduct (KA) comprising procaine as the amine (AM) and sodium chloride is dissolved in this carbonated water to achieve an isotonic concentration.

[0140] Alternatively, water heated to approximately 5 ± 3 °C is pressurized in a closed system and enriched with CO2 to a significant excess (4.5 to 7.5 g / l). The corresponding amounts of carbonic acid adduct (KA) comprising procaine as an amine (AM) and sodium chloride are then added to this carbonated water.

[0141] This cold solution containing the carbonic acid adduct (KA) comprising procaine as an amine (AM) and sodium chloride is sterile-filtered under suitable conditions and filled into appropriate vials. The applicable and generally accepted pharmaceutical rules for the preparation of (compounded) medicinal products are applied (for example, the European Pharmacopoeia). Table 4: Example compositions for parenteral preparations with added NaCl and carbonic acid adduct (KA) as active ingredient produced according to embodiment 1.

[0142] 3. Solubility in octanol Solubility tests were carried out in octanol, and the content in the organic phase was investigated using UV / VIS spectroscopy, as were the pH values. Table 5: Solubility of different dosage forms

[0143] The determined pH values ​​confirm that the procaine carbonic acid adduct exists as such and is not converted into procaine. In this form, it is soluble in the organic phase and thus permeable to membranes. Similarly, the UV / VIS spectroscopic content measurement shows that the procaine carbonic acid adduct is more similar to procaine than to procaine HCl in terms of lipophilicity. It behaves like the basic component—the lipid-soluble base that is formed depending on the pH value. The procaine carbonic acid adduct exhibits this property regardless of the pH value; that is, unlike procaine HCl, it does not need to be converted into its lipophilic form by a change in pH. Procaine HCl has a significantly lower value, at 8%, which is on the order of 6% for protein binding. LITERATURE 1. Clayville LR. 2011. Influenza update: a review of currently available vaccines. PT 36:659-84. 2. Taubenberger JK, Kash JC, Morens DM. 2019. 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Diagn Microbiol Infect Dis 91:147-152. 32. Ludwig S. 2009. Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti-influenza therapy. J Antimicrob Chemother 64:1-4. 33. Meineke R, Rimmelzwaan GF, Elbahesh H. 2019. Influenza Virus Infections and Cellular Kinases. Viruses 11. 34. Haasbach E, Muller C, Ehrhardt C, Schreiber A, Pleschka S, Ludwig S, Planz O. 2017. The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo. Antiviral Res 142:178-184. 35. Holzberg M, Boergeling Y, Schrader T, Ludwig S, Ehrhardt C. 2017. Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways. Front Microbiol 8:2426. 36. Ludwig S, Wolff T, Ehrhardt C, Wurzer WJ, Reinhardt J, Planz O, Pleschka S. 2004. MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett 561 :37-43. 37. Marjuki H, Alam Ml, Ehrhardt C, Wagner R, Planz O, Klenk HD, Ludwig S, Pleschka S. 2006. Membrane accumulation of influenza A virus hemagglutinin triggers nuclear export of the viral genome via protein kinase Calpha-mediated activation of ERK signaling. J Biol Chem 281:16707-15. 38. Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O, Rapp UR, Ludwig S. 2001. Influenza virus propagation is impaired by inhibition of the Raf / MEK / ERK signaling cascade. Nat Cell Biol 3:301–5. 39. Schrader T, Dudek SE, Schreiber A, Ehrhardt C, Planz O, Ludwig S. 2018. The clinically approved MEK inhibitor trametinib efficiently blocks influenza A virus propagation and cytokine expression. Antiviral Res 157:80-92. 40. Ehrhardt C, Ruckle A, Hrincius ER, Haasbach E, Anhlan D, Ahmann K, Banning C, Reiling SJ, Kuhn J, Strobl S, Vitt D, Leban J, Planz O, Ludwig S. 2013. The NF-kappaB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell Microbiol 15:1198–211. 41. Haasbach E, Reiling SJ, Ehrhardt C, Droebner K, Ruckle A, Hrincius ER, Leban J, Strobl S, Vitt D, Ludwig S, Planz O. 2013. The NF-kappaB inhibitor SC75741 protects mice against highly pathogenic avian influenza A virus. Antiviral Res 99:336–44. 42. Mazur I, Wurzer WJ, Ehrhardt C, Pleschka S, Puthavathana P, Silberzahn T, Wolff T, Planz O, Ludwig S. 2007. Acetylsalicylic acid (ASA) blocks influenza virus propagation via its NF-kappaB-inhibiting activity. Cell Microbiol 9:1683-94. 43. Deinhardt-Emmer S, Jäckel L, Haring C, Böttcher S, Wilden JJ, Gluck B, Heller R, Schmidtke M, Koch M, Löffler B, Ludwig S, Ehrhardt C. 2021. Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice. Biomolecules 11. 44. Ehrhardt C, Ludwig S. 2009. A new player in a deadly game: influenza viruses and the PI3K / Akt signaling pathway. Cell Microbiol 11:863–71. 45. Ehrhardt C, Marjuki H, Wolff T, Nürnberg B, Planz O, Pleschka S, Ludwig S. 2006. Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell Microbiol 8:1336-48. 46. Ehrhardt C, Wolff T, Ludwig S. 2007. Activation of phosphatidylinositol 3-kinase signaling by the nonstructural NS1 protein is not conserved among type A and B influenza viruses. J Virol 81 :12097-100. 47. Ehrhardt C, Wolff T, Pleschka S, Planz O, Beermann W, Bode JG, Schmolke M, Ludwig S. 2007. Influenza A virus NS1 protein activates the PI3K / Akt pathway to mediate antiapoptotic signaling responses. J Virol 81 :3058-67. 48. Eierhoff T, Hrincius ER, Rescher U, Ludwig S, Ehrhardt C. 2010. The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. PLoS Pathog 6:e1001099. 49. Day AM, Quinn J. 2019. Stress-Activated Protein Kinases in Human Fungal Pathogens. Front Cell Infect Microbiol 9:261. 50. Song J, Pan W, Sun Y, Han J, Shi W, Liao W. 2017. Aspergillus fumigatus-induced early inflammatory response in pulmonary microvascular endothelial cells: Role of p38 MARK and inhibition by silibinin. Int Immunopharmacol 49:195-202. 51. Denning DW, Hope WW. 2010. Therapy for fungal diseases: opportunities and priorities. Trends Microbiol 18:195-204. 52. Ji Y, Yang F, Ma D, Zhang J, Wan Z, Liu W, Li R. 2012. HOG-MAPK signaling regulates the adaptive responses of Aspergillus fumigatus to thermal stress and other related stress. Mycopathologia 174:273-82. 53. Hagiwara D, Suzuki S, Kamei K, Gonoi T, Kawamoto S. 2014. The role of AtfA and HOG MARK pathway in stress tolerance in conidia of Aspergillus fumigatus. Fungal Genet Biol 73:138-49. 54. Yang G, Cao X, Ma G, Qin L, Wu Y, Lin J, Ye P, Yuan J, Wang S. 2020. MAPK pathway-related tyrosine phosphatases regulate development, secondary metabolism and pathogenicity in fungus Aspergillus flavus. Environ Microbiol 22:5232-5247. 55. Manfiolli AO, Dos Reis TF, de Assis LJ, de Castro PA, Silva LP, Hori JI, Walker LA, Munro CA, Rajendran R, Ramage G, Goldman GH. 2018. Mitogen activated protein kinases (MARK) and protein phosphatases are involved in Aspergillus fumigatus adhesion and biofilm formation. Cell Surf 1 :43-56. 56. Schloer S, Goretzko J, Kuhnl A, Brunotte L, Ludwig S, Rescher U. 2019. The clinically licensed antifungal drug itraconazole inhibits influenza virus in vitro and in vivo. Emerg Microbes Infect 8:80-93. 57. Schloer S, Goretzko J, Pleschka S, Ludwig S, Rescher U. 2020. Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection. Viruses 12. 58. Schloer S, Brunotte L, Mecate-Zambrano A, Zheng S, Tang J, Ludwig S, Rescher U. 2021. Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharmacol 178:2339-2350. 59. Borgeling Y, Schmolke M, Viemann D, Nordhoff C, Roth J, Ludwig S. 2014. Inhibition of p38 mitogen-activated protein kinase impairs influenza virus-induced primary and secondary host gene responses and protects mice from lethal H5N1 infection. J Biol Chem 289:13-27. 60. Yu J, Sun X, Goie JYG, Zhang Y. 2020. Regulation of Host Immune Responses against Influenza A Virus Infection by Mitogen-Activated Protein Kinases (MAPKs). Microorganisms 8. 61. Scheuch G, Canisius S, Nocker K, Hofmann T, Naumann R, Pleschka S, Ludwig S, Welte T, Planz O. 2018. Targeting intracellular signaling as an antiviral strategy: aerosolized LASAG for the treatment of influenza in hospitalized patients. Emerg Microbes Infect 7:21.

Claims

REQUIREMENTS 1. An amine (AM) according to the general formula (I) where in formula (I) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 amine according to formula (I) can optionally also be used in the form of a salt, for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp..

2. A carbonic acid adduct (KA) comprising at least one structural element according to the general formula (II), (III) and / or (IV) where in formulas (II), (III), and (IV) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10)Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 to 30; (S) is a salt for use in the treatment of infections with Aspergillus fumigatus and superinfections with influenza viruses and Aspergillus spp.

3. A carbonic acid adduct (KA) comprising carbonic acid, at least one amine (AM) according to the general formula (I) and at least one salt (S), where in formula (I) R1ist 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; R2ist 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; R3ist -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl, R9ist (C 1-10 )Alkyl, preferably (C 1-2 )Alkyl; R4ist 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; R5ist 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; R6ist 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 according to formula (I) may optionally also be used in the form of a salt; prepareable by a process comprising the steps of: 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) not corresponding to the amine (AM) in the solution (A) to obtain solution (A1), c) dissolving the at least one amine (AM) in the solution (A) or (A1) to obtain solution (B), d) freezing the solution obtained after completion of step c), e) storing the solution frozen in step d) at -100 to 0 °C for no longer than 4 days; for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp.

4. A pharmaceutical composition (PZ) comprising the amine (AM) according to claim 1, or the carbonic acid adduct according to one of claims 2 or 3 for use in the treatment of infections with Aspergillus fumigatus and of superinfections with influenza viruses and Aspergillus spp.

5. The amine for use according to claim 1, the carbonic acid adduct (KA) for use according to one of claims 2 or 3, and the pharmaceutical composition (PZ) for use according to claim 4, wherein (i) the amine according to general formula (I) as well as in general formulas (II), (III) and (IV) is selected from the group consisting of 4-aminobenzoic acid 2-(N,N-diethylamino)ethyl ester (procaine), 4-aminobenzoic acid ethyl ester (benzocaine), 2-(diethylamino)ethyl 4-amino-2-chlorobenzoate (chloroprocaine), 4-amino-3-butoxybenzoic acid 2-diethylaminoethyl ester (oxybuprocaine), (2-(dimethylamino)ethyl)-4-(butylamino)benzoate (tetracaine), preferably 4-aminobenzoic acid 2-(N,N-diethylamino)ethyl ester (procaine) and / or ii) the salt (S) is a composite salt made up of at least one cation selected from Na + , K + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ and Mn 2+ , preferably Na +and at least one anion selected from Cl- Br -- , J-, F-, SO4 2- , SO3 2- , HSO4- HSO3-, -HCO3-, CO3 2- , PO4 3- , HPO4 2- , H2PO4-, SiO4 4- , AIO2, SiO3 and / or [AIO2) 12 (SiO2)2] 2- , preferably Cl- and Br- , particularly preferably Cl- 6. The carbonic acid adduct (KA) for use according to claims 3 and 5, wherein step a) comprises at least one of the following sub-steps: a1) cooling the solvent, preferably water, to 3 to 8 °C, preferably 5 °C and / or a2) introducing CO2 into the solvent, preferably to a saturation concentration of 3 to 10 g / l, more preferably to a saturation concentration of 4.5 to 7.5 g / l, preferably the pH of the solution after saturation with CO2 is ≤ 3.0 to 6.0, more preferably ≤ 4.3 to 4.8 and / or a3) storing the solution (A) at 1 to 10 °C, preferably for at least 30 min, more preferably for at least 50 min, more preferably for at least 60 min; for a maximum of 5 days (120 h); Storage preferably takes place at 3 to 8 °C, preferably for at least 30 min, more preferably for at least 50 min, even more preferably for at least 60 min; up to a maximum of 5 days (120 h);preferably step a) comprises all sub-steps a1), a2) and a3), preferably the sub-steps a1), a2) and a3) are carried out in the order a2) follows a1) and a3) follows 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 a hydrogen carbonate or a carbonate, more preferably a hydrogen carbonate, even more preferably sodium hydrogen carbonate and / or ii) the CO2 content in the solution undergoing 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. The carbonic acid 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 sub-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 solution (B) or (B1) at 1 to 10°C, preferably 3 to 8°C, for at least 1 h, preferably 24 h to 120 h, more preferably 24 to 72 h, 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, and even more preferably at least 14 g / l and most preferably at least 15 g / l; wherein optionally i) the concentration of the amine (AM) in solution (B) or, when carrying out substep c2), in solution (B1) is 0.01 to 0.25 g / ml, preferably 0.03 to 0.20 g / ml,more preferably 0.08 to 0.15 g / ml and / or ii) the pH of solution (B) or (B1) after carrying out step c5) is ≤ 7.0 and / or iii) the ratio of the amine (AM) to the base (BA), when carrying out step b), in solution (B) is 2 to 5, more preferably 3 to 4, even more preferably 3.23 to 3.26 [g / g] and / or iv) in step c1) the at least one amine (AM) comprises the at least one amine (AM) as an acid addition salt, preferably as a hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, hydrotosylate, hydroacetate, hydroformate, hydropropanoate, hydromalonate, hydrosuccinate, hydrofumarate, hydroxalate, hydrotartrate, hydrocitrate, hydromaleate, more preferably as hydrochloride or hydrobromide. preferably step c) comprises all sub-steps c1), c2), c3), c4) and c5); preferably the sub-steps c1), c2), c3), c4) and c5) are in the order c2) follows c1), c3) follows c2), c4) follows c3),c5) follows 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) the solution (B) or (B1) is frozen at -100 °C to -20 °C, preferably at -90 °C to -30 °C, more preferably at -80 °C to -40 °C and most preferably at -70 °C to -50 °C and / or ii) the solution (B) or (B1) is frozen within 0.3 to 60 min, preferably within 1 to 30 min, more preferably within 1.1 to 10 min, more preferably within 1.5 to 5 min and / or iii) the vessel in which the solution (B) or (B1) is located during the freezing process, preferably in the cooling medium, is rotated at 10 to 1000 rpm, preferably at 50 to 600 rpm, more preferably at 100 to 400 rpm and even more preferably rotated at 200 to 300 rpm and / or iv) the solution (B) or (B1) is frozen at a cooling rate of 10 to 100 K / min, preferably at 20 to 80 K / min, more preferably at 30 to 70 K / min and particularly preferably at 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 to 4 days, preferably for 2.5 to 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. The carbonic acid adduct (KA) for use according to any one of claims 3 and 5 to 10, wherein the process comprises a further step f) carried out after step e), f) drying the solution stored in step e) to obtain dried carbonic acid adduct (KA), wherein in step f) optionally i) the water is removed from solution (B) or (B1) to a residual content of < 0.8 wt.%, preferably < 0.1 wt.% based on the total weight of the dried product (C) and / or ii) CO2 not bound in the carbonic acid adduct (KA) from solution (B) or (B1) to a residual content of < 0.8 wt.%, preferably < 0.1 wt.%.-% based on the total weight of the dried product (C) is removed and / or iii) the drying is carried out by means of lyophilization and / or iv) during drying the pressure is 0.01 to 30 mbar, preferably 0.02 to 20 mbar, more preferably 0.03 to 10 mbar, even more preferably 0.03 to 0.5 mbar and most preferably 0.05 to 0.1 mbar and is preferably maintained throughout the entire drying process and / or v) the pressure during drying according to iv) is reached within 10 h, preferably within 7 h, more preferably within 5 h and most preferably within 4 h from the start of evacuation and / or vi) the temperature during the entire drying in step f) is 0 to 20 °C, preferably 4 to 18 °C, more preferably 8 to 16 °C and / or vii) the total drying time is 10 to 60, preferably 30 up to 55 hours, preferably 41 to 52 hours.

12. The amine (AM) according to claim 1, as well as the carbonic acid adduct (KA) for use according to any one of claims 2, 3 and 5 to 11 and the pharmaceutical composition (PZ) for use according to claim 4, in the treatment of superinfections with influenza viruses and Aspergillus spp., preferably Aspergillus fumigatus.

13. The amine (AM) according to claim 1, as well as the carbonic acid adduct (KA) for use according to any one of claims 2, 3 and 5 to 12 and the pharmaceutical composition (PZ) for use according to claims 4 and 12, wherein the application is oral, parenteral, nasal, inhalational or cutaneous.

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