Active substance for medical use

Abstract

The present invention relates to an amine (AM) of general formula (I), a carbonate adduct (KA), and a pharmaceutical composition (PZ) for use in the treatment of Aspergillus fumigatus infections and co-infections caused by influenza virus and species of the genus Aspergillus.

Description

Technical Field

[0001] The present invention relates to amines (AM) of general formula (I), carbonate adducts (KA), and pharmaceutical compositions (PZ) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus.

Background Art

[0002] Technical Background Influenza virus continues to cause severe respiratory tract disorders that contribute to significant morbidity and mortality. Seasonal epidemics result in 3 to 5 million severe cases and an estimated 300,000 to 500,000 deaths annually worldwide (1). Furthermore, influenza A virus has the potential to cause a pandemic, which, as was evident from the Spanish flu outbreak in 1918 / 19, has killed millions of people in the past (2). While most people recover from the infection, some experience complications such as lung inflammation caused by the virus itself or other pathogens including bacteria, among which Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae play a major role (3). In the case of co-infection with influenza virus and bacteria, the reasons for the severe progression have been well investigated and new treatment options have been attracting attention. However, this does not apply to co-infection with influenza virus and fungi (4, 5).

[0003] Nevertheless, infections by species of the genus Aspergillus, particularly fungi such as Aspergillus fumigatus, have been shown to occur in patients infected with influenza virus, increasing morbidity and mortality (5-9). A common problem with secondary fungal infections is that they are often detected too late (10, 11). As with the increased pathogenicity in cases of coinfection with influenza virus and Aspergillus fumigatus, the limited availability of potent anti-infective drugs against various pathogens is primarily important (5, 6, 12). Combined with the late detection of fungal infections (10, 11), the high mutability of influenza virus and the constant emergence of new strains, as well as the rapid development of resistance to available pharmaceuticals by influenza virus (13-16) are the main reasons for the limited treatment options. Treating coinfection with influenza virus and fungi with a single active ingredient is not yet possible at present.

[0004] Despite intensive research over the past century and the remarkable progress of possible treatment methods, influenza virus still remains a serious threat to the population. Seasonal epidemics are due to continuous point mutations (antigenic drift) in the genomes of influenza A and B viruses, which change the protein structure. Furthermore, influenza A virus has the potential to cause pandemic outbreaks (2, 20-22). When an individual is infected with multiple virus subtypes, gene segment exchange (antigenic shift) can result in virus subtypes that contain new combinations of the properties of the parental strains (20, 21). As a result, the immune system of the infected host becomes naive and is unable to effectively fight the new pathogen. There have been several pandemics in the previous century, among which the "Spanish flu" in 1918 / 19 had the most serious consequences (23). The influenza virus strain that caused the pandemic outbreak in 2009, together with two different strains of the 1968 H3N2 strain and influenza B virus, still circulates in the population (20).

[0005] Coinfections with viruses and bacteria have been well studied in recent years, but coinfections with viruses and fungi are poorly understood. Bacterial coinfections generally occur within the first 7 days after influenza virus infection and, in combination with lung inflammation, cause more severe disorders and increased mortality (24, 25). However, in some cases, bacterial coinfections may occur only after the viral infection appears to have resolved. There are several descriptions of influenza virus infection paving the way for bacterial coinfections. As a result of influenza virus infection, the ciliary clearance function is disrupted, the mucosal layer is dissolved, and as a result, additional receptors for bacteria are exposed. Furthermore, when abnormalities occur in the immune response, the defense function decreases and the inflammatory process is enhanced (4, 26).

[0006] In addition, in recent years, severe influenza virus-infected patients have been reported to develop invasive pulmonary aspergillosis, which was caused by coinfection with influenza virus and species of the genus Aspergillus, especially fungi such as Aspergillus fumigatus. For this reason, the mortality rate was even higher compared to simple infection with influenza virus (27, 28).

[0007] Species of the genus Aspergillus are filamentous saprophytic fungi that inhabit the air and soil (11, 29). In healthy humans, inhaled conidia are eliminated by mucociliary clearance and the initial immune defense mechanism (11). In patients with a weakened immune system or transplant patients, the risk of complications is high and the mortality rate also increases (5, 28). The possibility of developing invasive pulmonary aspergillosis, characterized by the invasion of Aspergillus fumigatus hyphae into lung tissue, is even higher in patients with a weakened immune system and is associated with an increased mortality rate (10). A relatively new and understudied clinical case is aspergillosis after influenza, which is difficult to diagnose. Recently, it has been revealed that influenza A and B virus infections cause severe fungal infections in both immunocompromised and non-immunocompromised patients (6, 30, 31). Similar to the case of severe bacterial infections, it is presumed that the loss of the ciliary function of the mucosa makes patients more susceptible to severe fungal infections and more likely to develop invasive fungal infections (31).

[0008] The most efficient way to protect oneself from the annual influenza virus epidemic is vaccination (1, 13). Despite the production of new vaccines every year, the vaccination rate is low, the efficiency is unstable, and when a completely new subtype of influenza A virus emerges, the adapted vaccine may not be available in time. New vaccines have to be tailored and produced for each new viral variant, which takes at least six months. Thus, there is a period when the population is vulnerable between the emergence of the pathogen and the introduction of the new vaccine. Therefore, antiviral alternatives are needed for infection control.

[0009] Regarding antiviral therapy, the European Medicines Agency (EMA) has approved three classes of compounds that target either the ion channel protein (M2), neuraminidase, or the CAP-dependent endonuclease. Neuraminidase inhibitors are effective against both influenza A and B viruses, while M2 inhibitors are ineffective against influenza B viruses (13). Unfortunately, influenza viruses rapidly develop resistance to therapeutic agents. There have been several reports of resistant mutants of influenza B virus to oseltamivir, as well as of influenza A viruses of the H5N1 and pandemic H1N1v types. Since resistant mutants to adamantanes are frequent in clinical isolates, it has been recommended not to use M2 inhibitors for treatment and prevention until susceptibility to these medications is re-established in circulating influenza A viruses (16). A further weakness of existing antiviral treatment approaches is that antiviral treatment must be initiated as soon as possible after symptoms appear.

[0010] New antiviral strategies include (a) inhibition of virus-supporting cell functions, (b) promotion of antiviral defenses, or (c) alleviation of inflammation (32).

[0011] The most promising antiviral strategy against influenza infection is based on the fact that influenza virus, as an intracellular pathogen, highly depends on the cellular signaling mechanism. Influenza virus can manipulate cytokines for its own purposes to ensure replication and spread. Furthermore, influenza virus can counteract the host's innate immune response. Considering such dependencies, the viral supportive functions of cells become targets for antiviral intervention (32). In recent years, it has become possible to identify various cytokines as suitable targets for antiviral intervention (33), including the Raf / MEK / ERK mitogen kinase cascade (32, 34 - 39), the IKK / NFκB module (40 - 42), and the PI3K signaling pathway (33, 43 - 48). Attacking most of these factors has been found to be effective against influenza virus infection not only in vitro but also in in vivo mouse models. LASAG's first clinical trial has suggested its antiviral effect against influenza virus infection in hospitalized patients (61). Attacking cytokines rather than viral factors reduces the possibility of resistance development because it is more difficult for pathogens to compensate for the lack of cellular functions.

[0012] Among antifungal drugs, triazoles are the first choice for aspergillosis, but echinocandins and polyene amphotericin B are also used (29). There are concerns about the recent emergence of resistance, particularly in Aspergillus fumigatus variants of the Aspergillus genus. Azole resistance is increasing worldwide, and thus new guidelines recommend the combination of voriconazole - eninocandin or amphotericin B (5). Generally, prophylactic treatment for aspergillosis is not initiated. Empirical antifungal therapy is started only when fungal infection is obvious or detected. This is a combination of immunomodulatory therapy and antifungal therapy (29).

[0013] The treatment options for viral / fungal co-infections are limited. In fact, corticosteroid treatment, which is frequently used in the ER, is contraindicated due to an increased mortality and an extended viral shedding associated with an increase in invasive pulmonary aspergillosis (5). Recent studies have shown significant interference between Aspergillus fumigatus and its host during invasive aspergillosis, so specific fungal-supporting cytokines and the harmful inflammatory processes induced by fungi are alternative attack options (29, 49, 50).

[0014] Since there is a phylogenetic relationship between fungi and humans, there are various factors that are highly conserved (51). For example, these homologs can be simultaneously attacked by host cells, Aspergillus species, or chemical inhibitors that act later on pathogen-induced cellular functions. Among these, the mitogen-activated protein kinase (MAPK) cascades have been identified (49, 52 - 54), and these regulate fungal processes such as biofilm formation (55), stress tolerance (52, 53), virulence (49), and host cell functions such as inflammatory processes (50). Interestingly, recently, antifungal drugs such as itraconazole have been shown to have an inhibitory effect on influenza virus replication (56, 57) and SARS-CoV-2 infection (58). These effects are likely due to different mechanisms of action of the compounds during the replication of different viruses. In the case of influenza virus infection, there is a discussion that the efflux of cholesterol from the lysosomal compartment is inhibited, resulting in a decrease in replication (56).

[0015] Surprisingly, MAPKs have also been identified as potential targets for influenza virus intervention, and these are involved in virus replication and virus-induced excessive inflammation (59, 60).

[0016] Therefore, there is a continuing need for new therapeutic agents for the treatment of co-infections caused by influenza virus, Aspergillus species, and especially influenza virus and Aspergillus species. SUMMARY OF THE INVENTION

[0017] The present invention relates to an amine (AM) of general formula (I) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus, wherein In formula (I), R 1 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 2 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2; R 8 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 9 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 4 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 -C 14 )aryl, (C 5~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; R 5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; R 6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; R 7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; Here, the amine of formula (I) may optionally be used in the form of a salt. Relates to an amine (AM) of general formula (I).

[0018] In a further aspect, the present invention relates to a carbonate adduct (KA) containing at least one structural element of general formula (II), (III), and / or (IV) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus, TIFF2025516068000002.tif155140TIFF2025516068000003.tif70137In formulas (II), (III), and (IV), R 1 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, or (C 5 ~C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 2 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, or (C 5 ~C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 9 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 4is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 5 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 6 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 7 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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 from 0.5 to 30; (S) is a salt, relating to a carbonate adduct (KA).

[0019] In a further aspect, the present invention provides a carbonate adduct (KA) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus, the carbonate adduct (KA) comprising a carbonate, at least one amine (AM) of general formula (I), and at least one salt (S), In formula (I) of TIFF2025516068000004.tif55128, R 1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, or (C 5 ~C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R 2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, or (C 5 ~C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2; R 8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R 9 is (C 1~10) alkyl, preferably (C 1~2 ) alkyl; R 4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; R 5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; R 6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; R 7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 ~C 14 ) aryl, (C 5 ~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; Here, at least one amine of formula (I) may optionally be used in the form of a salt; The carbonic acid adduct (KA) is obtained by the following steps: (a) Providing a solution (A) comprising at least one solvent and CO 2 dissolved in at least one solvent, Optionally (b) Dissolving a base (BA) not corresponding to the amine (AM) in the solution (A) to obtain a solution (A1), (c) Dissolving at least one amine (AM) in the solution (A) or (A1) to obtain a solution (B), (d) Freezing the solution obtained at the end of step (c), (e) Storing the solution frozen in step (d) at -100 to 0 °C for up to 4 days It can be prepared by a process comprising Regarding the carbonic acid adduct (KA).

[0020] The present invention further relates to a pharmaceutical composition comprising an amine or a carbonic acid adduct for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus.

[0021] The underlying substances of the present invention disclosure can cause influenza virus infection and influenza virus-induced cytokine expression, and can also block hyphal formation by Aspergillus fumigatus. The present invention thus provides a new approach for the anti-pathogenic therapy of both pathogens with a single active ingredient. Furthermore, the potential impact of pathogen-induced cytokines enables the control of excessive immune responses in co-infection scenarios.

Brief Description of the Drawings

[0022]

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Mode for Carrying Out the Invention

[0023] Detailed Description of the Invention The present invention relates to an amine (AM) of general formula (I) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and a species of the genus Aspergillus, preferably co-infections caused by influenza virus and a species of the genus Aspergillus, TIFF2025516068000005.tif56128wherein in formula (I), R 1 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 2 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is 1-5, preferably 1-3, more preferably 1-2; R 8 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 9 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 4 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 5 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 6 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 7 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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 of formula (I) may optionally be used in the form of a salt, relates to the amine (AM) of general formula (I).

[0024] The influenza virus is preferably selected from the group consisting of influenza A virus, influenza B virus, and influenza C virus, preferably influenza A virus.

[0025] The species of the genus Aspergillus is preferably Aspergillus fumigatus.

[0026] In the context of the present invention, the treatment of an infection by Aspergillus fumigatus preferably means the treatment of aspergillosis caused by an infection by Aspergillus fumigatus.

[0027] In the context of the present invention, superinfection means that a subject (e.g., a patient) is first infected with a certain pathogen, and subsequently, before the infection by the first pathogen is overcome, the subject is infected with at least one second pathogen such that the subject is at least temporarily simultaneously infected with the first pathogen and the second pathogen with a time delay. Thus, in this context, an initial infection by an influenza virus, preferably influenza A virus, may be followed by an additional infection by a species of the genus Aspergillus, preferably Aspergillus fumigatus, or an initial infection by a species of the genus Aspergillus may be followed by an additional infection by an influenza virus, preferably influenza A virus, preferably, an initial infection by an influenza virus, preferably influenza A virus, may be followed by an additional infection by a species of the genus Aspergillus. Preferably, in the context of superinfection, an infection by a species of the genus Aspergillus, preferably Aspergillus fumugatus, induces aspergillosis in the infected subject. Preferably, during the process of superinfection, an infection by an influenza virus induces influenza in the infected subject.

[0028] Use in the treatment of viral diseases, especially influenza, involves the utilization of antiviral effects. Typically, the antiviral active ingredient does not directly attack the virus but inhibits the generation and growth cycle.

[0029] Without being bound by any specific theoretical explanations, currently, it is presumed that the observed antiviral effect of the compounds of the present invention is likely to be preferably mediated indirectly by interaction with the metabolic pathways of the infectious organisms responsible for virus growth.

[0030] Use in the treatment of fungal infections involves the utilization of antifungal effects. Typically, antifungal substances have a destructive effect on the cell wall of fungi.

[0031] Without being bound by any specific theoretical explanations, currently, it is presumed that the observed antifungal effect of the compounds of the present invention is likely to be preferably mediated indirectly by interaction with the metabolic pathways of the fungi responsible for vitality.

[0032] In one embodiment, in formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 is H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R 9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl.

[0033] In the present invention, for example, as defined for the R 1 group of formula (I), (C1~10 ) Definitions such as alkyl mean that this substituent (group) is a saturated alkyl group having 1 to 10 carbon atoms. The alkyl group can be linear, branched, or optionally cyclic. Alkyl groups having both cyclic and linear components are also included by this definition. The same applies to other alkyl groups, such as C 1~2 alkyl groups. The alkyl group may also be mono- or polysubstituted by functional groups such as amino, hydroxyl, halogen, aryl, or heteroaryl. Unless otherwise specified, the alkyl group preferably has no functional groups as substituents. Examples of alkyl groups are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, isopropyl (also called 2-propyl or 1-methylethyl), isobutyl, tert-butyl, sec-pentyl, neopentyl, 1,2-dimethylpropyl, isoamyl, isohexyl, isoheptyl.

[0034] In the present invention, for example, R of formula (I) 1 groups, such as those defined for C 2~10 ) Definitions such as alkenyl mean that this substituent (group) is an alkenyl group having 2 to 10 carbon atoms and at least one unsaturated carbon-carbon bond. The alkenyl group can be linear, branched, or optionally cyclic. Alkenyl groups having both cyclic and linear components are also included by this definition. The same applies to other alkenyl groups, such as C 2~4This also applies to alkenyl groups. The alkenyl group may also be mono- or polysubstituted by functional groups such as amino, hydroxyl, halogen, aryl or heteroaryl. The alkenyl group preferably has no further functional groups as substituents. Examples of alkenyl groups 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, 2-nonenyl.

[0035] In the present invention, the definition of aryl means an aromatic or heteroaromatic group. The aromatic group is an aromatic cyclic hydrocarbon which may consist of a ring or a ring system composed of two or more fused rings. The aromatic group can be, for example, monocyclic, bicyclic or tricyclic. The monocyclic aromatic group preferably forms a 5- or 6-membered ring. The bicyclic aromatic ring preferably forms a 9- or 10-membered ring. The tricyclic aromatic ring preferably forms a 13- or 14-membered ring. (C 5 ~C 14 ) Definitions such as aryl mean that the aryl group contains 5 to 14 carbon atoms. The aryl group preferably contains 3 to 14, more preferably 4 to 6 carbon atoms. The aryl group may also be mono- or polysubstituted by functional groups such as alkyl, alkenyl, amino, cyano, -CF 3 , hydroxyl, halogen, aryl or heteroaryl; the aryl group preferably has no further substituents. Examples of aromatic groups are phenyl and naphthyl.

[0036] In the present invention, the definition of heteroaryl means a heteroaromatic group. What is meant by "aromatic heterocycle" is that in the aromatic group defined above, in which the ring system is formed by carbon atoms, one or more of these carbon atoms are replaced by heteroatoms such as O, N or S. (C5 ~C 10 ) Definitions such as heteroaryl are based on the corresponding definitions for aryl groups and mean 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. This means (C 5 ~C 10 ) that the heteroaryl group has 5 to 10 atoms in the ring, but not all of them are carbon atoms. Thus, for example, furanyl is a C 5 -heteroaryl group. The heteroaryl group may also be mono- or polysubstituted by functional groups such as alkyl, alkenyl, amino, cyano, -CF 3 , hydroxyl, halogen, aryl or heteroaryl; preferably, the heteroaryl group has no further substituents. Examples of heteroaromatic groups encompassed by the definition of aryl in the present invention are furanyl, thienyl, oxazolyl, pyrazolyl, pyridyl and indolyl.

[0037] In the present invention, for example, for the R 4 group of formula (I) as defined above, the definition of halogen means a chlorine, bromine, iodine or fluorine substituent. It is preferably a chlorine or fluorine substituent.

[0038] The amine (AM) of general formula (I) is preferably selected from the group consisting of 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine), ethyl 4-aminobenzoate (benzocaine), 2-(diethylamino)ethyl 4-amino-2-chlorobenzoate (chloroprocaine), 2-diethylaminoethyl 4-amino-3-butoxybenzoate (oxybuprocaine), (2-(dimethylamino)ethyl) 4-(butylamino)benzoate (tetracaine), more preferably 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine).

[0039] The amine (AM) of the general formula (I) and the amines (AM) specifically mentioned above are used for medical use as local anesthetics and are accordingly commercially available.

[0040] The present invention further relates to a carbonate adduct (KA) containing at least one structural element of general formula (II), (III), and / or (IV) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus, preferably co-infections caused by influenza virus and species of the genus Aspergillus, In formulas (II), (III), and (IV), R 1 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, or (C 5 ~C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 2 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, or (C 5 ~C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 9 is (C 1~10) alkyl, preferably (C 1~2 ) alkyl; R 4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 -C 14 ) aryl, (C 5 -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; R 5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 -C 14 ) aryl, (C 5 -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; R 6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 -C 14 ) aryl, (C 5 -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; R 7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C 5 -C 14 ) aryl, (C 5 -C 10 ) heteroaryl, or -O(C 1~10Alkyl, preferably H, halogen, (C 1~10 )alkyl, or -O(C 1~10 )alkyl, more preferably H or -O(C 1~10 )alkyl; x is from 0.5 to 30; (S) is a salt, relating to the carbonate adduct (KA).

[0041] In one embodiment, in formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 is H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2; R 8 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 9 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl.

[0042] The salt (S) contains at least one cation selected from Na + , K + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ , and Mn 2+ , preferably Na + . The salt (S) contains Cl - , Br - , I - , F - , SO 4 2- , SO 3 2- , HSO 4 - , HSO3 - and - HCO 3 - CO 3 2- PO 4 3- HPO 4 2- H 2 PO 4 - SiO 4 4- AlO 2 - SiO 3 - and / or [AlO 2 ) 12 (SiO 2 ) 2 2- preferably Cl - and Br - more preferably Cl - and further comprises at least one anion selected therefrom.

[0043] The preparation of the carbonate adduct (KA) is also disclosed in WO2006 / 007835, DE 10 2013 015 035 A1 and WO2019 / 048590, which are hereby incorporated by reference.

[0044] The present invention further provides a carbonate adduct (KA) comprising carbonic acid, at least one amine (AM) of general formula (I), and at least one salt (S) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and species of the genus Aspergillus, wherein TIFF2025516068000007.tif55128In formula (I), R 1 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, or (C 5 ~C 10 )heteroaryl, preferably H or (C 1~10 ​) is alkyl, more preferably H; R 2 is H, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, or (C 5 ~C 10 )heteroaryl, preferably H or (C 1~10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 9 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl; R 4 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 5 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~C 10 )heteroaryl, or -O-(C 1~10 )alkyl, preferably H, halogen, (C 1~10 )alkyl, or -O(C 1~10is alkyl, more preferably H or halogen; R 6 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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; R 7 is H, halogen, (C 1~10 )alkyl, (C 2~10 )alkenyl, (C 5 ~C 14 )aryl, (C 5 ~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 at least one amine of formula (I) may optionally be used in the form of a salt, relates to a carbonic acid adduct (KA).

[0045] In one embodiment, in formula (I), R 1 , R 2 , R 4 , R 5 , R 6 are H; R 3 is -(CH 2 ) n NR 8 R 9 ; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 is (C 1~10 )alkyl, preferably (C 1~2) is alkyl; R 9 is (C 1~10 )alkyl, preferably (C 1~2 )alkyl.

[0046] The salt(s) (S) can be formed, for example, by an acid-base reaction between the acid added onto the amine (AM) when using an acid addition salt of the amine (AM) and the base (BA) when carrying out step (b). The salt(s) (S) can also be added directly in any one of steps (a), (b), and / or (c). When the amine (AM) is not used in salt form and / or step (b) is not carried out, direct addition of the salt (S) is preferred.

[0047] The carbonate adduct (KA) preferably remains stable for at least 12 months, more preferably at least 13 months, even more preferably at least 20 months, particularly preferably at least 23 months, most preferably at least 27 months when stored at a temperature of 2 - 10 °C.

[0048] The carbonate adduct (KA) is no longer considered stable when a specific band of at least one amine (AM) can be detected by IR spectroscopy, particularly in the solid state carbonate adduct (KA). The specific IR band of the amine is a band also detected in the IR spectroscopic analysis of pure amine (AM). When the amine (AM) is bound in a stable carbonate adduct (KA), the specific IR band of the amine (AM) is not detected.

[0049] The loss of stability in individual embodiments can also be related to an increase in pH or the measurement of two melting / decomposition ranges (i.e., one range corresponds to the amine (KA) and one range corresponds to the carbonate adduct (KA)). In the carbonate adduct that has become unstable as a result of at least partial decomposition into the amine (AM) and CO 2 and / or water, a change in dissolution characteristics may also exist. The unstable carbonate adduct (KA) may be found to be slightly insoluble or at least partially incompletely soluble.

[0050] The carbonic acid adduct (KA) can be prepared by a process comprising steps (a), optionally (b), (c), (d), and (e).

[0051] In step (a), a solution (A) is provided that comprises at least one solvent and CO 2 dissolved in the at least one solvent.

[0052] Solution (A) comprises at least one solvent and CO 2 in dissolved form. CO 2 means carbon dioxide in the context of the present invention. CO 2 in dissolved form means all forms of CO 2 that dissolve and enter. For example, with respect to an aqueous solution, dissolved CO 2 in the solution is known to be able to exist in equilibrium, in particular, as CO 2 , as carbonic acid, as monovalent or divalent deprotonated carbonic acid, i.e., as hydrogen carbonate or carbonate.

[0053] Solution (A) is obtained by introducing CO 2 into at least one solvent. CO 2 can be introduced into the solvent in any suitable form known to those skilled in the art. Preferably, gaseous CO 2 or frozen CO in the form of dry ice 2 is introduced into the solvent, more preferably gaseous CO 2 is introduced into the solvent. Gaseous CO 2 or frozen CO 2 is preferably of at least food quality, more preferably of a quality suitable for pharmaceutical purposes. The gaseous and / or frozen CO 2 used preferably has a purity of at least 99.5%, even more preferably 99.9%.

[0054] What is preferably meant by "food quality" is, in the context of the present invention, that it complies with the relevant provisions of German and European food law. These preferably include Regulation (EC) No. 852 / 2004 and Regulation (EC) No. 178 / 2002, as well as also Regulation (EC) No. 1333 / 2008 and Regulation (EU) 231 / 2012.

[0055] What is preferably meant by "pharmaceutical quality" is that it complies with the relevant provisions of the European Pharmacopoeia (Ph. Eur.).

[0056] In particular, when gaseous CO 2 is introduced into the solution, CO 2 can also be introduced under pressure. What is meant by "introducing under pressure" in this context is to use a pressure greater than atmospheric pressure, preferably greater than 1.01325 bar. For this purpose, the introduction of CO 2 into the solvent can, in particular, be carried out in a container that isolates the solvent from the environment so that the introduction of CO 2 above atmospheric pressure, preferably above 1.01325 bar, can generate pressure inside the container. The introduction of CO 2 into the solution, especially in gaseous form, can be carried out either once or at intervals.

[0057] A person skilled in the art can use any suitable solvent in step (a). The solvent used is preferably a polar protic solvent; more preferably, the solvent is water. Depending on the intended end use of the carbonated adduct (KA), the solvent can be used in various purities. For example, when the carbonated adduct (KA) is used for pharmaceutical and medical purposes, it is possible to use water of "Aqua ad iniectabilia" purity.

[0058] Step (a) can include component step (a1), where the solvent is preferably CO 2Before introduction of , cool to 3 - 8°C, preferably up to 5°C. Cooling can be carried out by any method known to those skilled in the art who have determined it to be suitable. For example, cooling can be carried out by maintaining the solvent in a refrigerator for a period long enough for the solvent to have the target temperature. For example, it is similarly possible to use external cooling.

[0059] Step (a) may include component step (a2), where CO 2 is introduced into the solvent, preferably until a saturation concentration of 3 - 10 g / l is achieved, more preferably until a saturation concentration of 4.5 - 7.5 g / l is achieved, based on the total volume of the solution. 2 The pH of the solution after saturation with CO 2 is preferably ≤ 3.0 - ≤ 6.0, even more preferably ≤ 4.3 - ≤ 4.8. CO

[0060] Step (a) may include component step (a3), where preferably the solution (A) obtained in component step (a2) is stored at 1 - 10°C, preferably for at least 30 minutes, more preferably for at least 50 minutes, even more preferably for at least 60 minutes; up to 5 days (120 hours) at most. Preferably, the solution (A) obtained in component step (a2) is stored at 3 - 8°C, for at least 30 minutes, more preferably for at least 50 minutes, even more preferably for at least 60 minutes; up to 5 days (120 hours) at most.

[0061] Preferably, step (a) includes all of component steps (a1), (a2), and (a3).

[0062] Preferably, component steps (a1), (a2), and (a3) are carried out in the order of (a1) followed by (a2), and then (a2) followed by (a3).

[0063] Step (b) can be carried out optionally, where, to obtain solution (A1), a base (BA) that does not correspond to the amine (AM) is dissolved in solution (A). The base (BA) is preferably a hydrogencarbonate or a carbonate, more preferably a hydrogencarbonate, and even more preferably sodium hydrogencarbonate.

[0064] In step (c) or (c1), at least one amine (AM) is dissolved in solution (A) or (A1) to obtain solution (B).

[0065] At least one amine (AM) as defined above may be used in step (c) in either the neutral form or the salt form. Optionally, at least one amine (AM) may also be used as a mixture of the neutral form of the amine (AM) and the salt form of the amine (AM). Thus, at least one amine (AM) may comprise a neutral amine (AM) and / or a salt form of at least one amine (AM). The salt form of at least one amine (AM) is preferably an acid addition salt; the acid addition salt is preferably a hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, bisulfite, hydrogen phosphate, hydro mesylate, hydro tosylate, hydro acetate, hydro formate, hydro propanoate, hydro malonate, hydro succinate, hydro fumarate, hydro oxalate, hydro tartrate, hydro citrate, hydro maleate of at least one amine (AM), more preferably a hydrochloride or a hydrobromide, and even more preferably a hydrochloride.

[0066] 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, and more preferably 0.08 to 0.15 g / ml.

[0067] Step (c) may include component step (c2), where, to obtain solution (B), at least one amine (AM) is dissolved in solution (A) or, when step (b) is carried out, in solution (A1).

[0068] In one possible embodiment, the ratio of amine (AM) to base (BA) in solution (B) when performing step (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].

[0069] In a further possible embodiment, the molar ratio of amine (AM) to base equivalent of base (BA) in solution (B) when performing step (b) is 0.8:1 to 1.5:1, preferably 1.2:1, more preferably 1:1. What is meant by base equivalent in this context is a monobasic base, for example NaHCO 3 When using, it is that the molar ratio of base (BA) to amine (AM) follows the specified ratio above. For a dibasic base (BA), for example Na 2 CO 3 When using, based on the molar amount of base (BA) relative to the use of a monobasic base, only half the amount of base is required to introduce the same amount of base equivalent. For example, in the case of a 1:1 ratio, when using 10 mmol of amine (AM), 10 mmol of NaHCO 3 is required, but only 5 mmol of Na 2 CO 3 is required.

[0070] In a further embodiment, step (b) is carried out and in component step (c1), the amine (AM) is added in the form of an acid addition salt, where the amine (AM) is added, together with the acid bound thereto, in an amount such that the acid bound to the amine (AM) can neutralize the base (BA) to the extent that solution (B) is assumed to have a pH of 6 to 8.

[0071] Step (c) may include component step (c2), where solution (A) is added to solution (B) to obtain solution (B1).

[0072] Preferably, the concentration of 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.

[0073] Step (c) may include component step (c3), where solution (B), or solution (B1) when performing component step (c2), is enriched with CO 2 Preferably, solution (B) is enriched with 2.5 g / l to 9 g / l, more preferably 5 to 7.5 g / l of CO 2

[0074] Step (c) may include component step (c4), where solution (B), or solution (B1) when performing component step (c2), is stored at 1 to 10°C, preferably 3 to 8°C, for at least 1 hour, preferably 24 hours to 120 hours, even more preferably 24 to 72 hours.

[0075] Step (c) may include component step (c5), where solution (B), or solution (B1) when performing component step (b2), is preferably enriched with CO to a total concentration of at least 6 g / l, more preferably at least 10 g / l, even more preferably at least 12 g / l, very particularly preferably at least 14 g / l, and most preferably at least 15 g / l. 2 Preferably, in component step (c5), an additional 0.4 to 4.7 g / l, more preferably 1 to 3.5 g / l of CO 2 is introduced or dissolved into solution (B) or (B1) until the required total concentration is achieved.

[0076] The expression "total concentration" in this specification relates to the total concentration of dissolved CO 2 in solution (B) or (B1) including that bound in the carbonate adduct (KA). The total concentration does not consider CO 2 optionally added to the solution in the form of bicarbonate or carbonate as the base (BA), and when implemented, all preceding enrichment steps (a2) and / or (c3), and the CO supplied in (c5). 2 2 ​​It is the result of summing up the increase in the weight of the solution as a result.

[0077] CO to the required total concentration 2 The enrichment of solution (B) or solution (B1) in component step (c5) using is 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. Solution (B) or (B1) is at a temperature of 3 to 8 °C, more preferably 5 °C, during the enrichment using CO in component step (c5). 2 It is at a temperature of 3 to 8 °C, more preferably 5 °C, during the enrichment using.

[0078] The enrichment of solution (B) or (B1) in component steps (c3) and (c5) can be carried out in the same manner as described for step (a).

[0079] The pH of solution (B) or, when carrying out component step (c2), solution (B1) after the implementation of step (c5) is ≤ 7.0.

[0080] Preferably, step (c) includes all component steps (c1), (c2), (c3), (c4), and (c5).

[0081] Preferably, component steps (c1), (c2), (c3), (c4), and (c5) are carried out in the order of (c2) after (c1), (c3) after (c2), (c4) after (c3), and (c5) after (c4).

[0082] In step (d), the solution obtained at the end of step (c) is frozen. Preferably, in step (d), solution (B) or, after carrying out component step (c2), solution (B1) is frozen.

[0083] The solution, preferably solution (B) or (B1), to be fed to step (d) has a CO 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. 2 It has a content.

[0084] Preferably, the solution obtained at the end of step (c), preferably solution (B) or (B1), is frozen at -100°C to -20°C, more preferably at -90°C to -30°C, even more preferably at -80°C to -40°C, and most preferably at -70°C to -50°C.

[0085] The freezing of the solution obtained at the end of step (c), preferably solution (B) or (B1), can in principle be carried out by any of the methods known to those skilled in the art who have determined it to be suitable. For example, the freezing can be carried out by transferring the solution obtained in step (c) to a suitable container immersed in a cooling medium. The container is preferably in the form of a valve. The container containing the solution obtained in step (c) is preferably immersed in the cooling medium at an angle of 40°. The cooling medium can consist of a solvent such as methanol, ethanol, or acetone, and this is brought to the desired temperature by the addition of dry ice or a suitable cooling device such as a cryostat.

[0086] The freezing is preferably carried out at atmospheric pressure, more preferably at 1.01325 bar.

[0087] Preferably, the solution obtained at the end of step (c), preferably solution (B) or (B1), is frozen within 0.3 to 60 minutes, more preferably within 1 to 30 minutes, even more preferably within 1.1 to 10 minutes, and particularly preferably within 1.5 to 5 minutes.

[0088] The solution obtained at the end of step (c), preferably solution (B) or (B1), is preferably frozen at a cooling rate of 10 to 100 K / min, more preferably 20 to 80 K / min, even more preferably 30 to 70 K / min, and particularly preferably 40 to 60 K / min.

[0089] During the freezing operation, the container in which the solution obtained at the end of step (c), preferably solution (B) or (B1), is present is rotated preferably 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 in a cooling medium.

[0090] Freezing can be carried out by the shelf-freezing method.

[0091] In step (e), the solution frozen in step (d), preferably solution (B) or (B1), is stored at -100 to 0 °C for up to 4 days.

[0092] The solution frozen in step (d), preferably solution (B) or (B1), is preferably stored in step (e) for 1.5 to 4 days, more preferably for 2.5 to 4 days.

[0093] The solution frozen in step (d), preferably solution (B) or (B1), is stored in step (e) 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.

[0094] In principle, the storage can be carried out at a defined temperature in any cooling device known to those skilled in the art. For example, the storage can be carried out in an upright freezer or a freezer compartment.

[0095] The process by which the carbonated adduct (KA) can be prepared may include a further step (f) that is carried out after step (e). In step (f), the solution stored in step (e), preferably solution (B) or (B1), is dried in order to obtain the dried carbonated adduct (KA).

[0096] Preferably, in step (f), water is removed from the solution stored in step (e), preferably solution (B) or (B1), to a residual content of <0.8% by weight, more preferably to a residual content of <0.1% by weight, based on the total weight of the dried carbonate adduct (KA).

[0097] Preferably, in step (f), CO not bound in the carbonate adduct (KA) 2 is removed from the solution stored in step (e), preferably (B) or (B1), to a residual content of <0.8% by weight, more preferably to a residual content of <0.1% by weight, based on the total weight of the dried carbonate adduct (KA).

[0098] Drying can be carried out by any method known to those skilled in the art who have determined it to be suitable. Drying is preferably carried out by freeze-drying, also known as lyophilization. When using the freeze-drying method, step (d) constitutes a freezing step and step (e) constitutes an aging step.

[0099] Preferably, the pressure during drying is 0.01 - 30 mbar, preferably 0.02 - 20 mbar, more preferably 0.03 - 10 mbar, even more preferably 0.03 - 0.5 mbar, and most preferably 0.05 - 0.1 mbar. The pressure is preferably maintained during the drying operation. During drying, the pressure defined above is preferably achieved within 7 hours, more preferably within 5 hours, and particularly preferably within 4 hours from the start of evacuation.

[0100] The end point of drying can be confirmed by those skilled in the art from the temperature progress record. The total drying time in step (f) is preferably 10 - 60 hours, more preferably 30 - 55 hours, and particularly preferably 41 - 52 hours. The total drying time is defined as the period between the end of storage in step (e) and the end of drying in step (f).

[0101] Preferably, the temperature during drying in step (f) is 0 - 20°C, preferably 4 - 18°C, and more preferably 8 - 16°C.

[0102] The present invention further comprises a pharmaceutical composition (PZ) comprising the above-mentioned amine (AM) or carbonate adduct (KA) for use in the treatment of SARS-CoV-2 pneumonia.

[0103] A pharmaceutical composition further containing a carbonate adduct (KA) is described in WO2019 / 048590.

[0104] In principle, a pharmaceutical formulation (PZ) in the context of the present invention means a composition comprising an amine (AM) or a carbonate adduct (KA), which may further comprise further auxiliaries or additives suitable for pharmaceutical and medical use.

[0105] Furthermore, the pharmaceutical formulation (PZ) may comprise further bases which do not correspond to the amine (AM) and may be different from the base (BA). In principle, the person skilled in the art will be able to select the additives according to the desired end use. In doing so, the desired dosage form will be taken into account.

[0106] The pharmaceutical formulation (PZ) can in principle be in any suitable dosage form. For example, the pharmaceutical formulation (PZ) can be in the form of capsules, or in the form of tablets, solutions, ointments, creams, gels, pastes, compresses or patches containing the active ingredient.

[0107] The pharmaceutical formulation (PZ) can in principle be applied in any suitable dosage form. The person skilled in the art will select a suitable dosage form according to the intended dosage form. For example, the pharmaceutical formulation (PZ) can be administered orally, by inhalation, by injection, as a patch, dermally, including at least dermal application, ocular application, nasal application, rectal application and vaginal application.

[0108] In the formulation of the pharmaceutical formulation (PZ), the person skilled in the art can basically use methods known in the prior art.

[0109] Preferably, during the formulation of the pharmaceutical preparation (PZ), the temperature of the mixture of the carbonate adduct (KA) and the auxiliaries and any further bases used is less than 60°C, preferably less than 50°C, more preferably 0 to 50°C.

[0110] In the formulation of the pharmaceutical preparation (PZ), preferably in ointment form, it is also possible to use dispersion, preferably by means of an ointment mixer. Preferably, a speed of <2000 rpm is used herein.

[0111] Before processing to provide oral dosage forms such as tablets, capsules, semi-solid dosage forms, etc., which will be described later, the carbonate adduct (KA) may be ground alone or in the presence of further auxiliaries or bases to provide a powder. Those skilled in the art may, in principle, utilize known technical means suitable for each purpose. For the grinding process, for example, a mortar or similarly suitable means can be used. In the grinding process, preferably, technical auxiliaries that minimize mechanical stress on the carbonate adduct are used. The grinding is preferably carried out using a mortar.

[0112] The powder thus obtained can then be, for example, compressed into tablets, dispensed into ordinary capsules, mixed with suitable auxiliaries, and processed to provide a semi-solid dosage form.

[0113] One aspect of the pharmaceutical preparation (PZ) relates to a pharmaceutical preparation (PZ) that contains a carbonate adduct (KA) and is administered orally. In this aspect, the pharmaceutical preparation (PZ) is preferably in capsule form, more preferably in hard gelatin or cellulose capsule form, and even more preferably in hard gelatin capsule form. In this aspect, it is equally possible to administer the pharmaceutical preparation (PZ) in tablet form.

[0114] The pharmaceutical preparation (PZ) in this aspect preferably contains at least one auxiliary (H) that is more preferably selected. 2 Preferably, it contains at least one auxiliary (H) that is more preferably selected.

[0115] Furthermore, the pharmaceutical preparation (PZ) in this embodiment may contain at least one base (BA1) that does not correspond to the amine (AM) and is the same as or different from the base (BA). The base (BA1) is preferably NaHCO 3 and KHCO 3 , more preferably NaHCO 3 is selected.

[0116] The general description given above for the pharmaceutical preparation (PZ) is preferably also applicable to this embodiment, and in particular, when technically applicable to this embodiment, it is also applicable to the formulation of the pharmaceutical preparation (PZ).

[0117] The pharmaceutical preparation (PZ) in this embodiment preferably (a) 1% to 99% by weight, more preferably 15% to 95% by weight of the carbonate adduct (KA), (b) 0% to 60% by weight, more preferably 3% to 50% by weight of the base (BA1), and 1% to 90% by weight, more preferably 2% to 75% by weight of the adjuvant (H) are included based on the total weight of the pharmaceutical preparation.

[0118] A further embodiment of the pharmaceutical preparation (PZ) relates to a semi-solid pharmaceutical preparation (PZ) that contains a carbonate adduct (KA) and is administered topically to the skin. The pharmaceutical preparation (PZ) in this embodiment can be applied, for example, in the form of an ointment, or in the form of a cream, gel, paste, compress or active ingredient-containing patch.

[0119] The general description given above for the pharmaceutical preparation (PZ) is preferably also applicable to this embodiment, and in particular, when technically applicable to this embodiment, it is also applicable to the preparation of the pharmaceutical preparation (PZ).

[0120] The pharmaceutical preparation (PZ) in this embodiment preferably contains at least one auxiliary agent (H1) selected from paraffin, particularly viscous and liquid paraffin, wool wax, wool wax alcohol, hydrophobic base gel, vegetable oil, animal fat, synthetic glyceride, liquid polyalkylsiloxane, wax, petrolatum and starch, particularly corn starch, preferably petrolatum.

[0121] Viscous paraffin (Paraffinum subliquidum) means paraffin having a viscosity of 110 - 230 mPas, while liquid paraffin (Paraffinum perliquidum) has a viscosity of 25 - 80 mPas.

[0122] The pharmaceutical preparation (PZ) in this embodiment preferably (a) 0.1 wt% - 40 wt%, preferably 0.4 wt% - 10 wt% of a carbonate additive (KA), and (b) 60 wt% - 99.9 wt%, preferably 80 wt% - 96 wt% of an auxiliary agent (H1) are included based on the total amount of the pharmaceutical preparation (PZ).

[0123] A further embodiment of the pharmaceutical preparation (PZ) containing a carbonate additive (KA) relates to pharmaceutical preparations administered by parenteral, nasal, and / or inhalation routes.

[0124] The general description given above for the pharmaceutical preparation (PZ) is preferably also applicable to this embodiment, and in particular, when technically applicable to this embodiment, it is also applicable to the formulation of the pharmaceutical preparation (PZ).

[0125] The pharmaceutical preparation (PZ) in this embodiment is preferably in the form of a solution (A2) containing a carbonate additive (KA), dissolved CO 2 and at least one auxiliary agent (H2).

[0126] The auxiliary agent (H2) is preferably an alkali metal halide or an alkaline earth metal halide, more preferably NaCl and MgCl 2 and even more preferably selected from NaCl. The auxiliary agent (H2) may be the same as the salt (S). The amount described based on the auxiliary agent (H2), when it is the same as the salt (S) in the individual embodiments, relates in the context of the present invention to the additional amount of the auxiliary agent (H2) not introduced in the form of the salt (S) into the pharmaceutical preparation (PZ) as part of the carbonate adduct (KA).

[0127] The solution (A2) is preferably obtained by introducing CO 2 into the solvent. The solvent is preferably water. For the preparation of the solution (A2), CO 2 is preferably introduced into the solvent at a temperature of 0 to 8 °C, more preferably 0 to 5 °C. CO 2 can be introduced into the solvent in gaseous form or in solid form, for example as dry ice. CO 2 is preferably introduced into the solvent in gaseous form. CO 2 may also be introduced into the solution under pressure until the desired concentration is achieved, as described above for example for component step (a2).

[0128] For the preparation of the solution (A2), CO 2 is preferably introduced into the solvent to a concentration of at least 3 g / l, more preferably 4 g / l, and even more preferably 4 g / l to 8 g / l.

[0129] The CO 2 used for the preparation of the solution (A2) has a purity of at least 99.9% and more preferably also has a quality suitable for pharmaceutical use as defined above.

[0130] In this embodiment, the pharmaceutical preparation (PZ), when it is obtained by dissolving the carbonate adduct (KA) in the solution (A2), preferably (a) 0.05 to 100 mg / ml, more preferably 0.08 to 50 mg / ml of the carbonate adduct (KA), and (b) An auxiliary agent (H2) of 0 to 20 mg / ml, more preferably 3 to 10 mg / ml is included in each case based on the total volume of the pharmaceutical preparation (PZ).

Examples

[0131] Examples of the invention 1. Example 1, Preparation of Carbonate Adduct (KA) 1.1 Materials: · Amine (AM): 68.8 to 110.1 g of procaine hydrochloride (for example, for use as a pharmaceutically active ingredient, ultra-high purity; Ph. Eur., or a quality suitable for that purpose) · Base (BA): 22.2 to 33.9 g of sodium bicarbonate (for example, ultra-high purity, or a quality suitable for that purpose) · Solvent: 630 to 900 ml of water (Aqua ad iniectabilia) · CO 2 : At least 12.0 g / l of carbon dioxide from a steel pressurized gas bottle (CO of suitable quality 2 ) · Dry ice for providing and cooling the cold mixture · Methanol, technical grade for providing the cold mixture.

[0132] 1.2 Step (a) Introduce water (for example, Aqua ad iniectabilia) into a washed plastic squeeze bottle up to the mark (about 800 - 900 ml) and pre-cool to at least 5°C for at least 1 hour in a refrigerator (3 - 8°C) or by external cooling.

[0133] Prepare a carbon dioxide-saturated carbonic acid solution. For this purpose, introduce CO 2 into the pre-cooled water under pressure (1.6 - 8 bar) at intervals. Hissing (gas leaking through the pressure relief valve) indicates saturation of the solution with CO 2 . 4.0 to 6.0 g of CO 2Monitor saturation by weight until dissolution of (corresponding to 4.5 - 7.5 g / l). The saturated solution has a pH of ≤ 4.3 - 4.8. Immediately seal this carbonated water and store it in the refrigerator for at least 1 hour.

[0134] 1.3 Step (b) Charge 21.2 g of sodium bicarbonate in another plastic squeeze bottle into 320 ml of chilled carbonated water, invert the bottle and dissolve.

[0135] 1.4 Step (c) Add an equivalent amount of solid procaine hydrochloride to this solution at a constant temperature to form a substantially neutral solution. After adding an additional 320 ml of cold carbonated water, a clear, weakly acidic solution is obtained. Enrich the solution with CO 2 . Store the solution prepared in this way in the refrigerator for at least 1 hour.

[0136] Then, adjust the solution with CO 2 again until a concentration of 12 g / l of CO 2 in the solution is achieved. Monitor the pH with a pH indicator stick. The pH is ≤ 6.6.

[0137] 1.5 Step (d) Pre - cool the round - bottom flask. For freezing, aliquot the reaction solution into a pre - cooled graduated cylinder, divide and transfer it to the round - bottom flask, and freeze each flask by immersion in a dry - ice / methanol cold mixture (< - 60 °C) by the shelf - freezing method (about 200 rpm) within 1.5 - 3.5 minutes. Set the immersion angle of the flask in the rotary evaporator to about 40°.

[0138] 1.6 Step (e) Close the flask containing the material frozen in this way with a ground - glass stopper and temporarily store it in the freezer at - 15 to - 20 °C for 2 - 4 days.

[0139] 1.7 Step (f) Wrap the flask subjected to such temperature with a pre-cooled Styropor container and immediately connect it individually via a flexible rubber cone to a freeze-drying system that has been evacuated (0.060 ± 0.01 mbar, approximately -46 °C, leak inspection). Carefully open the valve tap to place the individual flasks under vacuum. All flasks must ultimately be evacuated.

[0140] For process monitoring, place a temperature sensor at the bottom of the Styropor shell, which records the entire temperature profile over the drying operation. Before the start of freeze-drying, the temperature sensor indicates a temperature of < -5 °C.

[0141] During freeze-drying, the pressure is 0.07 ± 0.02 mbar. This sublimation pressure is achieved within 4 hours and maintained over the freeze-drying time. Adjust the cooling chamber to a temperature of 9 - 15 °C over the drying operation. The end point of freeze-drying is confirmed by a graph from the temperature progression record. The total drying time is within 52 hours. Transfer the dried lyophilizate to a brown glass container with a twist-off cap provided with a desiccant pouch and store it at 0 - 15 °C in a refrigerator.

[0142] 2. Examples of Pharmaceutical Preparations (PZ) 2.1 Capsules and Tablets The following is an explanation of a composition of a pharmaceutical preparation (PZ) according to the present invention in the form of a capsule or a tablet for procaine as an amine (AM). For the preparation of capsules, it is possible to use commercial two-piece capsules of commercial size (5 to 000) filled with a powder containing a carbonate adduct (KA) containing procaine as an amine (AM) (optionally including auxiliaries, fillers, and flow regulators, grinding of the carbonate adduct (KA) active ingredient containing procaine as an amine (AM)). The carbonate adduct (KA) was prepared according to Example 1. Hard gelatin capsules were found to be more suitable in terms of stability compared to cellulose capsules. For example, filled hard gelatin capsules showed no change even after 12 months of storage in a refrigerator for hard gelatin capsules containing 60 and 100 mg of active ingredient according to Table 1, and thus were stable. The stability was examined by IR spectroscopy. For example, in the case of hard gelatin capsules, procaine was not detected by IR spectroscopy within 12 months, while for cellulose capsules, procaine bands were measured in the IR spectrum after only a few days. The content was determined at room temperature by UV / VIS spectroscopy. For pharmaceutical preparations, according to European Pharmacopoeia point 2.9.6, a tolerance range of ±15% is defined based on the total content including by-products. Current general pharmaceutical rules regarding the preparation of (pharmaceutical) preparations apply (e.g., European Pharmacopoeia, German Pharmacopoeia (Deutscher Arzneimittel-Codex)).

[0143] (Table 1) Composition example of a capsule containing added NaHCO 3 and carbonate adduct (KA) as an active ingredient prepared according to Example 1 TIFF2025516068000008.tif32156

[0144] (Table 2) Composition example of a tablet containing added NaHCO 3 and carbonate adduct (KA) as an active ingredient prepared according to Example 1 TIFF2025516068000009.tif25154

[0145] 2.2 Ointments The following is, by way of example, an explanation of the composition of a pharmaceutical preparation (PZ) according to the invention in the form of an ointment, for procaine as an amine (AM) in a carbonate adduct (KA). In the preparation of the ointment, current general pharmaceutical rules regarding the preparation of (the preparation) pharmaceuticals are applied (for example, the European Pharmacopoeia, the German Pharmaceutical Codex). In the preparation of the ointment, relatively high shear forces are avoided. Furthermore, the temperature during the formulation process is maintained locally even below 60 °C. Therefore, the carbonate adduct (KA) containing procaine as an amine (AM), which has been ground in a mortar, is introduced into an ointment base, such as petrolatum, in a standard mortar or a Fanta-type mortar adjusted to a temperature of 40 - 45 °C by a water bath. Alternatively, it is also possible to use an electrical mixing system as is customary in pharmacy.

[0146] (Table 3) Example of the composition of a carbonate adduct (KA) as an active ingredient and an ointment prepared according to Example 1 TIFF2025516068000010.tif25145

[0147] 2.3 Parenteral Solutions To provide a parenteral solution containing a carbonate adduct (KA) containing procaine as an amine (AM), the required amount of water (Aqua ad iniectabilia) is cooled to about 5 ± 3 °C in a suitable container containing a stir bar or the like and kept at that temperature. The water is enriched with gaseous carbon dioxide of the required quality up to about 3.2 g / l. The appropriate amounts of sodium chloride for isotonic content and the carbonate adduct (KA) containing procaine as an amine (AM) are dissolved in this carbonated water.

[0148] Alternatively, water at a temperature of about 5 ± 3 °C is pressurized in a closed system so that a distinct excess (4.5 - 7.5 g / l) of CO 2Enrich it. The corresponding amounts of the carbonate adduct (KA) containing procaine as sodium chloride and amine (AM) are similarly added to this carbonated water.

[0149] This cold solution provided with the carbonate adduct (KA) containing procaine as amine (AM) and sodium chloride is aseptically filtered under suitable ambient conditions and dispensed into suitable vials. The current general pharmaceutical rules regarding the preparation of pharmaceuticals apply (for example, the European Pharmacopoeia).

[0150] (Table 4) Composition example of a parenteral preparation containing added NaCl and carbonate adduct (KA) as the active ingredient, prepared according to Example 1 TIFF2025516068000011.tif35151

[0151] 3. Solubility in Octanol A solubility test was carried out in octanol, the content in the organic phase was examined by UV / VIS spectroscopy, and the pH value was also examined.

[0152] (Table 5) Solubility of various dosage forms TIFF2025516068000012.tif37148

[0153] The confirmed pH value indicates that the carbonate adduct of procaine is converted as such and not to procaine, is soluble in the organic phase in this form, and is thus membrane-permeable. It is also clear from the measurement of the content by UV / VIS spectroscopy that the carbonate adduct of procaine is more similar to procaine than procaine HCl in terms of lipophilicity. Therefore, it behaves like a basic component (a lipophilic base formed depending on the pH). The carbonate adduct of procaine has this property regardless of the pH, which means that it does not need to be converted to a lipophilic form by a change in pH like procaine HCl. Procaine HCl has a much lower value, which is 8% and on the scale of 6% protein binding.

[0154] Literature TIFF2025516068000013.tif225165TIFF2025516068000014.tif238165TIFF2025516068000015.tif245165TIFF2025516068000016.tif252165TIFF2025516068000017.tif204165

Claims

1. An amine (AM) of general formula (I) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and a species of the genus Aspergillus, wherein, In formula (I), R 1 is H, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1～10 )alkyl, more preferably H; R 2 is H, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1～10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 and; n is from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2; R 8 is (C 1～10 )alkyl, preferably (C 1～2 )alkyl; R 9 is (C 1～10 )alkyl, preferably (C 1～2 )alkyl; R 4 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 5 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 6 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 7 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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 of formula (I) may optionally be used in the form of a salt, The amine (AM) of general formula (I).

2. A carbonate adduct (KA) comprising at least one structural element of general formula (II), (III), and / or (IV) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and a species of the genus Aspergillus, wherein, In formula (II), (III), and (IV), R 1 is H, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1～10 )alkyl, more preferably H; R 2 is H, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1～10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 and; n is from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2; R 8 is (C 1～10 )alkyl, preferably (C 1～2 )alkyl; R 9 is (C 1～10 )alkyl, preferably (C 1～2 )alkyl; R 4 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 5 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 6 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 7 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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 from 0.5 to 30; (S) is a salt, The carbonate adduct (KA).

3. A carbonate adduct (KA) comprising carbonic acid, at least one amine (AM) of general formula (I), and at least one salt (S) for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and a species of the genus Aspergillus, wherein, In formula (I), R 1 is H, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1～10 )alkyl, more preferably H; R 2 is H, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, or (C 5 -C 10 )heteroaryl, preferably H or (C 1～10 )alkyl, more preferably H; R 3 is -(CH 2 ) n NR 8 R 9 and; n is from 1 to 5, preferably from 1 to 3, more preferably from 1 to 2; R 8 is (C 1～10 )alkyl, preferably (C 1～2 )alkyl; R 9 is (C 1～10 )alkyl, preferably (C 1～2 )alkyl; R 4 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 5 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 6 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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; R 7 is H, halogen, (C 1～10 )alkyl, (C 2～10 )alkenyl, (C 5 -C 14 )aryl, (C 5 -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 at least one amine of formula (I) may optionally be used in the form of a salt; The carbonate adduct (KA) can be prepared by a process comprising the following steps: (a) Providing a solution (A) comprising at least one solvent and CO dissolved in the at least one solvent 2 and Optionally (b) dissolving a base (BA) not corresponding to the amine (AM) in solution (A) to obtain solution (A1), (c) dissolving the at least one amine (AM) in solution (A) or (A1) to obtain solution (B), (d) freezing the solution obtained at the end of step (c), (e) storing the solution frozen in step (d) at -100 to 0 °C for up to 4 days The carbonate adduct (KA).

4. A pharmaceutical composition (PZ) comprising the amine (AM) according to claim 1 or the carbonate adduct according to any one of claims 2 and 3 for use in the treatment of infections caused by Aspergillus fumigatus and co-infections caused by influenza virus and a species of the genus Aspergillus.

5. ​ (i) The amines in general formula (I) and general formulas (II), (III), and (IV) are selected from the group consisting of 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine), ethyl 4-aminobenzoate (benzocaine), 2-(diethylamino)ethyl 4-amino-2-chlorobenzoate (chloroprocaine), 2-diethylaminoethyl 4-amino-3-butoxybenzoate (oxybuprocaine), (2-(dimethylamino)ethyl) 4-(butylamino)benzoate (tetracaine), preferably 2-(N,N-diethylamino)ethyl 4-aminobenzoate (procaine), and / or (ii) the salt (S) is Na + , K + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ , and Mn 2+ , preferably at least one cation selected from Na + , and Cl - , Br - , I - , F - , SO 4 2- , SO 3 2- , HSO 4 - , HSO 3 - , - HCO 3 - , CO 3 2- , PO 4 3- , HPO 4 2- , H 2 PO 4 - , SiO 4 4- , AlO 2 - , SiO 3 - , and / or [AlO 2 ) 12 (SiO 2 ) 2 2- , preferably Cl - and Br - , more preferably Cl - , and is a salt composed of at least one anion selected from​ The amine for use according to claim 1, the carbonate adduct (KA) for use according to any one of claims 2 and 3, and the pharmaceutical composition (PZ) for use according to claim 4.

6. Step (a) comprises the following component steps: (a1) Cooling the solvent, preferably water, to 3 - 8°C, preferably to 5°C, and / or (a2) CO 2 A step of introducing it 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, wherein CO 2 The pH of the solution after saturation with CO is preferably ≤ 3.0 to 6.0, even more preferably ≤ 4.3 to 4.8, this step, and / or (a3) Storing solution (A) at 1 - 10°C, preferably for at least 30 minutes, more preferably for at least 50 minutes, even more preferably for at least 60 minutes; up to 5 days (120 hours) at most, with the storage preferably being carried out at 3 - 8°C, preferably for at least 30 minutes, more preferably for at least 50 minutes, even more preferably for at least 60 minutes; up to 5 days (120 hours) at most, this step includes at least one of them, preferably, step (a) includes all component steps (a1), (a2), and (a3); preferably, component steps (a1), (a2), and (a3) are carried out in the order of (a1) followed by (a2), and then (a2) followed by (a3), The carbonate adduct (KA) for use according to any one of claims 3 and 5.

7. (i) The base (BA) in step (b) is a hydrogencarbonate or carbonate, more preferably a hydrogencarbonate, even more preferably sodium hydrogencarbonate, and / or (ii) The content of CO in the solution to be subjected to step (d) 2 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) may be used in the form of a salt. The carbonate adduct (KA) for use according to any one of claims 3, 5, and 6.

8. Step (c) comprises the following component steps: (c1) Dissolving the at least one amine (AM) in solution (A) or (A1) to obtain solution (B), and / or (c2) A step of adding solution (A) to solution (B) to obtain solution (B1), and / or (c3) The step of enriching solution (B) or (B1) with CO 2 and / or (c4) A step of storing solution (B) or (B1) at 1 - 10 °C, preferably 3 - 8 °C, for at least 1 hour, preferably 24 hours to 120 hours, more preferably 24 - 72 hours, and / or (c5) Enriching solution (B) or (B1) to a concentration of at least 6 g / l, preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably at least 14 g / l, and most preferably at least 15 g / l with CO 2 ​ includes at least one of the following, wherein, optionally, (i) The concentration of the amine (AM) in solution (B) or in solution (B1) when performing component step (c2) is 0.01 - 0.25 g / ml, preferably 0.03 - 0.20 g / ml, more preferably 0.08 - 0.15 g / ml, and / or (ii) The pH of solution (B) or (B1) after the implementation of step (c5) is ≤ 7.0, and / or (iii) The ratio of the amine (AM) to the base (BA) in solution (B) when performing step (b) is 2 - 5, more preferably 3 - 4, even more preferably 3.23 - 3.26 [g / g], and / or (iv) In step (c1), the at least one amine (AM) includes at least one amine (AM) as an acid addition salt, preferably as a hydrohalide, bisulfate, bisulfite, hydrogen phosphate, hydro mesylate, hydro tosylate, hydro acetate, hydro formate, hydro propanoate, hydro malonate, hydro succinate, hydro fumarate, hydro oxalate, hydro tartrate, hydro citrate, hydro maleate, more preferably as a hydrochloride or hydrobromide; Preferably, step (c) includes all component steps (c1), (c2), (c3), (c4), and (c5); Preferably, component steps (c1), (c2), (c3), (c4), and (c5) are carried out in the order of (c2) after (c1), (c3) after (c2), (c4) after (c3), and (c5) after (c4), The carbonate adduct (KA) for use according to any one of claims 3 and 5 - 7.

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

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

11. A further step (f) that is carried out after step (e) of the method: (f) A step of drying the solution stored in step (e) to obtain a dried carbonate adduct (KA) comprising, wherein, in step (f), optionally, (i) the water is removed from solution (B) or (B1) to a residue content of < 0.8 wt%, preferably < 0.1 wt% based on the total weight of the dried product (C), and / or (ii) CO not bound within the carbonate adduct (KA) 2 is removed from solution (B) or (B1) to a residual content of < 0.8% by weight, preferably < 0.1% by weight, based on the total weight of the dry product (C), and / or (iii) the drying is carried out by freeze-drying, 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, most preferably 0.05 to 0.1 mbar, and preferably is maintained during the drying operation, and / or (v) the pressure during drying in (iv) is achieved within 10 hours, preferably within 7 hours, more preferably within 5 hours, particularly preferably within 4 hours from the start of evacuation, and / or (vi) The temperature during drying in step (f) is from 0 to 20°C, preferably from 4 to 18°C, more preferably from 8 to 16°C, and / or (vii) The total drying time is from 10 to 60, preferably from 30 to 55 hours, more preferably from 41 to 52 hours, The carbonate adduct (KA) for use according to any one of claims 3 and 5 to 10.

12. The amine (AM) according to claim 1, the carbonate 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 co-infection by influenza virus and a species of the genus Aspergillus, preferably Aspergillus fumigatus.

13. The amine (AM) according to claim 1, the carbonate 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 any one of claims 4 and 12, wherein the administration is by oral, parenteral, nasal, inhalation, or transdermal route.

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