Active substances for medical use

Abstract

To provide an amine of a specific compound, a carbonic acid adduct and a pharmaceutical composition for use in the treatment of atypical pneumonia and in the therapy of viral diseases.SOLUTION: The present invention provides an amine (AM) of the general formula (I) for use in the treatment of atypical pneumonia and in the therapy of viral diseases.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The subject of the present invention relates to amines (AM) of general formula (I); carbonate adducts (KA), and pharmaceutical compositions (PZ) for use in the treatment of atypical pneumonia and in the therapy of viral diseases. [Background technology]

[0002] Technical background Procaine and structurally related compounds of general formula (I) are used as local anesthetics. Procaine hydrochloride's ionic nature prevents it from passing through the intestinal wall, making oral application for systemic pain relief impossible. Procaine hydrochloride is essentially used exclusively parenterally. Procaine remains essentially unchanged in the stomach upon oral administration. The higher the pH, the greater the rate of procaine adsorption in the stomach.

[0003] The carbonate adducts of procaine and structurally related local anesthetics have a neutral surface and are therefore membrane-permeable, even passing through the intestinal wall. Because of their improved tissue penetration, the carbonate form of procaine is not rapidly degraded by pseudocholinesterase in plasma. Therefore, the carbonate adducts of procaine and structurally related local anesthetics are more widely used than procaine hydrochloride.

[0004] WO2006 / 007835 A2 discloses ammonium salts and stable, storable ammonium salt-mineral salt clathrates having an acidic dibasic acid residue such as a bicarbonate residue, methods for their preparation, and pharmacological and chemical synthetic uses of these compounds. The use of procaine and structurally related local anesthetics, or their carbonate adducts, in the treatment of atypical pneumonia is not disclosed.

[0005] The aim of application DE 10 2013 015 035 A1, which directly references WO 2006 / 007835 A2, is to remedy some of the drawbacks of the procaine carbonate mineral salt clusters by developing suitable formulations that make the clusters suitable for pharmaceutical use and thus meet higher requirements with regard to stability, efficacy, and tolerability. To this end, a method for preparing procaine carbonate mineral salt clusters and their use in formulations for parenteral application, inhalation solutions, ointments, and tablets is described. Similar to WO 2006 / 007835 A2, this document discloses the presence of both salt and CO2 in the reaction solution for the preparation of procaine carbonate mineral salt clusters. DE 10 2013 015 035 A1 also fails to disclose the use of procaine and structurally related local anesthetics, or their carbonate adducts, in the treatment of atypical pneumonia.

[0006] WO2019048590 also discloses amine-based carbonate adducts, particularly those based on procaine and structurally related local anesthetics, as well as pharmaceutical preparations thereof and methods for their preparation. Furthermore, the use of the carbon adducts in medicine is disclosed, but not in the treatment of atypical pneumonia.

[0007] Atypical pneumonia refers to inflammation of the alveolar space and / or pulmonary interstitium, which can be specifically triggered by viruses, bacteria, or fungi. During inflammation [1], adrenaline is released, causing arteriole constriction and venule dilation. Exudation then occurs. The capillary walls become more permeable to the passage of proteins and neutrophils. Inflammatory swelling develops. Increased permeability of the vascular wall is caused by vascular mediators such as histamine, prostaglandins, kinins, and serotonin, leading to congestion. Pain occurs as nerve endings are stimulated by increased tissue pressure, peptides, and lactic acid. A cellular response then begins: neutrophils emerge from the blood vessels and reach the site of irritation or injury, primarily via chemotaxis (an acidic environment). Phagocytosis occurs. The resulting breakdown products can induce fever and lead to suppuration. Furthermore, more mast cells flood into the inflamed tissue.

[0008] A potentially fatal complication, especially in combination with atypical pneumonia, is an exaggerated inflammatory response, which can lead to acute respiratory distress syndrome (ARDS) [2]. Increased vascular permeability and lung injury during the inflammatory process lead to the formation of interstitial pulmonary edema. Inflammatory factors such as TNF-α, IL-6, and IL-8 induce the migration of neutrophilic granulocytes, which release free radicals such as O, H2O2, OH, and HOCl, as well as lytic enzymes, further enhancing the inflammatory response. Under the influence of inflammatory mediators, significant "capillary leakage" occurs, resulting in the formation of alveolar edema. This leads to the destruction of surfactant on the alveolar surface, resulting in microatelectasis. Gas exchange between the lungs and the blood is disrupted.

[0009] S. Pecher et al. [3] disclose that local anesthetics such as lidocaine have anti-inflammatory effects. Pecher et al. cite a study by Mikawa et al. on rabbits that were incubated with E. coli and administered lidocaine. Lidocaine administration resulted in p aIt was found that O2 increased and pulmonary mechanics improved in terms of improved compliance and decreased resistance. Furthermore, the incidence of pulmonary edema was reduced compared with the control group. Bronchoalveolar lavage tests showed fewer white blood cells and lower albumin content in the lidocaine group. Lidocaine significantly reduced hemorrhage formation, alveolar septal thickening, and the number of inflammatory cells in the alveolar space. However, S. Pecher did not disclose the use of procaine or structurally related local anesthetics or their carbonate adducts in the treatment of atypical pneumonia, particularly atypical pneumonia caused by viruses or fungi.

[0010] Globally, research efforts to discover drugs for the treatment of COVID-19 disease are proceeding at full speed. It has already become clear that there will likely be no single drug, due to the highly variable nature of the disease process and the stage of the disease playing an essential role in the selection of pharmaceutical treatments. In the early stages, the focus is on preventing invasion and reducing viral replication. In the second and third stages, reducing inflammation and thus preventing the cytokine storm are of paramount importance. Currently, systemic inflammatory processes (especially in the blood vessels) are increasingly important in the pathophysiology of COVID-19 infection. However, this has led to the use of vaccines as preventative measures and specific antiviral treatment strategies, as well as the availability of rare therapeutic options. Furthermore, substances directed against the virus itself usually induce the rapid development of resistance, rendering them ineffective. Therefore, novel antiviral strategies target viral supportive cellular factors used by the virus to support its own replication and propagation. Another point of attack is the inhibition of excessive immune responses or the active resolution of the inflammatory process.

[0011] Considering the recent pandemic triggered by the SARS-CoV-2 virus and the sometimes fatal course, including the development of acute respiratory distress syndrome (ARDS), it is clear that there is a further need for therapeutic agents that can help to at least make the course of atypical pneumonia, particularly viral and fungal-induced atypical pneumonia, more moderate. There is also a need for additional antiviral substances, particularly for the treatment of COVID-19 disease. Summary of the Invention

[0012] The present invention relates to amines (AM) of general formula (I) for use in the treatment of atypical pneumonia and in the therapy of viral diseases: TIFF2025169345000001.tif57128 In formula (I), R1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or —O—(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; R7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O—(C 1~10 ) alkyl; The amines of formula (I) herein may optionally be used in the form of salts.

[0013] In a further aspect, the present invention relates to carbonate adducts (KA) comprising at least one structural element of general formula (II), (III), and / or (IV) for use in the treatment of atypical pneumonia and in the therapy of viral diseases: TIFF2025169345000002.tif226140In formulas (II), (III), and (IV), R1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14) Aryl, (C5-C 10 ) heteroaryl, or —O—(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; R7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; x is 0.5 to 30; (S) is salt.

[0014] In another aspect, the present invention 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 atypical pneumonia and in the therapy of viral diseases, wherein: TIFF2025169345000003.tif57128 In formula (I), R1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10) alkyl, more preferably H; R2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or —O—(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C1~10 ) 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 said at least one amine of formula (I) may optionally be used in the form of a salt; The following steps: a) providing a solution (A) comprising at least one solvent and CO2 dissolved in the at least one solvent; optionally, b) dissolving a base (BA) other than said amine (AM) in solution (A) to obtain solution (A1); c) dissolving said at least one amine (AM) in 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 more than 4 days; The present invention relates to a carbonate adduct that can be prepared by a method comprising the steps of:

[0015] The present invention further relates to pharmaceutical compositions comprising said amines or said carbonate adducts for use in the treatment of atypical pneumonia and in the therapy of viral diseases. [Brief explanation of the drawings]

[0016] [Figure 1]A: Test for antiviral activity against influenza virus. B and C: Test for antiviral activity against SARS-CoV-2. ProcCluster corresponds to the carbonate adduct (KA) prepared according to Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention The present invention relates to amines (AM) of general formula (I) for use in the treatment of atypical pneumonia and in the therapy of viral diseases: TIFF2025169345000004.tif60128 In formula (I), R1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or —O—(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; R7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O—(C 1~10 ) alkyl; The amines of formula (I) herein may optionally be used in the form of salts.

[0018] In one embodiment, in formula (I), R1, R2, R3, R4, R5, and R6 are H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl.

[0019] In the present invention, for example, the R group of formula (I) is defined as (C 1~10 The definition of alkyl, etc. means that the substituent (group) is a saturated alkyl group having from 1 to 10 carbon atoms. Alkyl groups can be both linear and branched, and optionally cyclic. Alkyl groups having both cyclic and linear components are also within the scope of this definition. This includes C 1~2 The same applies to other alkyl groups, such as alkyl groups. If appropriate, the alkyl groups may be mono- or polysubstituted with functional groups such as amino, hydroxy, halogen, aryl, or heteroaryl. Unless otherwise specified, it is preferred that the alkyl groups have no functional groups as substituents. Examples of alkyl groups include 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, and isoheptyl.

[0020] In the present invention, for example, C as defined for the R group of formula (I) 2~10 Definitions such as alkenyl mean that the substituent (group) is an alkenyl group having from 2 to 10 carbon atoms and at least one unsaturated carbon-carbon bond. Alkenyl groups can be linear or branched, and optionally cyclic. Alkenyl groups having both cyclic and linear components are also within the scope of this definition. This includes C 2~4This also applies to other alkenyl groups such as alkenyl groups. If appropriate, the alkenyl group may be mono- or polysubstituted with functional groups such as amino, hydroxy, halogen, aryl, or heteroaryl. Preferably, the alkenyl group does not have other functional groups as substituents. Examples of alkenyl groups include 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.

[0021] In the present invention, the definition of aryl refers to an aromatic or heteroaromatic group. An aromatic group is an aromatic cyclic hydrocarbon, which may contain one ring or a ring system of multiple condensed rings. For example, the aromatic group may be monocyclic, bicyclic, or tricyclic. Preferably, a monocyclic aromatic group forms a 5- or 6-membered ring. Preferably, a bicyclic aromatic ring forms a 9- or 10-membered ring. Preferably, a tricyclic aromatic ring forms a 13- or 14-membered ring. (C5-C 14 The definition of aryl, etc., means that the aryl group contains 5 to 14 carbon atoms. Preferably, the aryl group contains 3 to 14, more preferably 4 to 6, carbon atoms. Where appropriate, the aryl group may be mono- or polysubstituted with functional groups such as alkyl, alkenyl, amino, cyano, -CF3, hydroxy, halogen, aryl, or heteroaryl; preferably, the aryl group has no further substituents. Examples of aromatic groups include phenyl and naphthyl.

[0022] In the present invention, the definition of heteroaryl means that it is a heteroaromatic group. A heteroaromatic ring means that in the aromatic group defined above, the ring system is formed by carbon atoms, one or more of which are replaced by a heteroatom such as O, N, or S. (C5-C 10The definition of heteroaryl, etc. is based on the corresponding definition for aryl group, and means that the heteroaryl group has 5 to 10 atoms in the ring. However, one or more carbon atoms are replaced by heteroatoms, as defined above. This means that (C5-C 10 ) means that a heteroaryl group has 5 to 10 atoms in the ring, but not all of them are carbon atoms. Thus, for example, furanyl would be a C5-heteroaryl group. Where appropriate, heteroaryl groups may be mono- or polysubstituted with functional groups such as alkyl, alkenyl, amino, cyano, -CF3, hydroxy, halogen, aryl, or heteroaryl; preferably, heteroaryl groups have no other substituents. Examples of heteroaromatic groups within the definition of aryl in this invention include furanyl, thienyl, oxazolyl, pyrazolyl, pyridyl, and indolyl.

[0023] In the present invention, the definition of halogen as defined above for example for the R group of formula (I) means that it is a chlorine, bromine, iodine or fluorine substituent. Preferably, it is a chlorine or fluorine substituent.

[0024] Preferably, the amine (AM) of 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).

[0025] Amines of general formula (I) (AM), and the amines specifically mentioned above, are used medically as local anesthetics and are therefore commercially available.

[0026] As already mentioned above, atypical pneumonia, in particular within the scope of the present invention, refers to pneumonia caused by a virus, a bacterium, or a fungus, preferably a virus. Also as explained above, atypical pneumonia can be accompanied by the development of acute respiratory distress syndrome (ARDS) as a result of excessive inflammation in the lungs in atypical pneumonia.

[0027] In one embodiment, the atypical pneumonia is caused by a bacterium. Preferably, the bacterium is selected from the group consisting of Mycoplasma, Legionella, and Chlamydia.

[0028] In another embodiment, the atypical pneumonia is caused by a fungus. Preferably, the fungus is selected from the group consisting of Aspergillus, Pneumocystis, and Candida.

[0029] In another embodiment, the atypical pneumonia is caused by a virus. The pneumonia is preferably caused by a virus selected from coronavirus, influenza virus, adenovirus, and respiratory syncytial virus. The virus SARS CoV-2 is more preferred.

[0030] Use in the treatment of viral diseases involves the use of antiviral effects. Typically, antiviral active substances inhibit the development and replication cycle of viruses instead of directly attacking them.

[0031] Without being bound to any particular theoretical explanation, it is presently believed that the observed antiviral effects of the compounds of the present invention are preferably indirectly mediated, possibly by interaction with metabolic pathways of the infected organism necessary for viral replication.

[0032] Preferably, the treatment of viral diseases relates to diseases caused by RNA viruses, more preferably coronaviruses, influenza viruses, adenoviruses and respiratory syncytial viruses, even more preferably influenza viruses and coronaviruses, particularly preferably coronaviruses, very particularly preferably SARS CoV-2.

[0033] In one aspect, patients not requiring intensive medical treatment are treated in the treatment of viral diseases.

[0034] In one embodiment, the amine (AM), carbonate (KA), or pharmaceutical composition (PZ), particularly when used in the treatment of viral diseases, is not administered in combination with dexamethasone.

[0035] In a further embodiment, the pharmaceutical composition (PZ) does not comprise dexamethasone, particularly for use in the treatment of viral diseases.

[0036] Furthermore, the present invention relates to carbonate adducts (KA) comprising at least one structural element of general formula (II), (III) and / or (IV) for use in the treatment of atypical pneumonia and in the therapy of viral diseases as defined above: TIFF2025169345000005.tif243140In formulas (II), (III), and (IV), R1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10) alkyl, preferably (C 1~2 ) alkyl; R4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or —O—(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; R7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; x is 0.5 to 30; (S) is salt.

[0037] In one embodiment, in formula (I), R1, R2, R3, R4, R5, and R6 are H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl.

[0038] Salt (S) is Na + , K. + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ , and Mn 2+ , preferably Na + Furthermore, the salt (S) contains at least one cation selected from Cl - , Br - , J - , F - , SO4 2- , SO3 2- , HSO4 - , HSO3 - , HCO3 - , CO3 2- , PO4 3- , HPO4 2- , H2PO4 - , SiO4 4- , AlO2 - , SiO3 - , and / or [AlO2) 12 (SiO2)2] 2- , preferably Cl - and Br - , more preferably Cl - The compound contains at least one anion selected from the group consisting of:

[0039] The preparation of carbonate adducts (KA) is also disclosed in WO2006 / 007835, DE 10 2013 015 035 A1, and WO2019 / 048590, which are hereby incorporated by reference.

[0040] Furthermore, the present invention relates to 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 atypical pneumonia and in the therapy of viral diseases as defined above: TIFF2025169345000006.tif57128 In formula (I), R1 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R2 is H, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) aryl, or (C5-C 10 ) heteroaryl, preferably H or (C 1~10 ) alkyl, more preferably H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl; R4 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C1~10 ) alkyl, more preferably H or halogen; R5 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or —O—(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or halogen; R6 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; R7 is H, halogen, (C 1~10 ) alkyl, (C 2~10 ) alkenyl, (C5-C 14 ) Aryl, (C5-C 10 ) heteroaryl, or -O(C 1~10 ) alkyl, preferably H, halogen, (C 1~10 ) alkyl, or -O(C 1~10 ) alkyl, more preferably H or —O(C 1~10 ) alkyl; Here, the at least one amine of formula (I) may optionally be used in the form of a salt.

[0041] In one embodiment, in formula (I), R1, R2, R3, R4, R5, and R6 are H; R3 is -(CH2) n NR8R9; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, R8 is (C 1~10 ) alkyl, preferably (C1~2 ) alkyl, R9 is (C 1~10 ) alkyl, preferably (C 1~2 ) alkyl.

[0042] When an acid addition salt of the amine (AM) is used, the salt (S) can be formed, for example, by an acid-base reaction between the base (BA) and the acid added to the amine (AM) when performing step b). The salt (S) may be added directly in one of steps a), b), and / or c). When the amine (AM) is not used in salt form and / or step b) is not performed, direct addition of the salt (S) is preferred.

[0043] Preferably, the carbonate adduct (KA) remains stable during storage at a temperature between 2 and 10°C for at least 12 months, more preferably at least 13 months, even more preferably at least 20 months, particularly preferably at least 23 months, and most preferably at least 27 months.

[0044] If at least one characteristic band of the amine (AM) can be detected by IR spectroscopy, especially in the solid form of the carbonate adduct (KA), the carbonate adduct (KA) is no longer considered stable. The characteristic IR band of the amine is a band that is also detected in the IR spectroscopy of the pure amine (AM). As long as the amine (AM) is bound in the stable carbonate adduct (KA), the characteristic IR band of the amine (AM) will not be detected.

[0045] In particular embodiments, the decrease in stability may involve an increase in pH or measurement of two melting / decomposition ranges, one corresponding to the amine (KA) and the other to the carbonate adduct (KA). The carbonate adduct, rendered unstable by at least partial decomposition to the amine (AM) and CO and / or water, may undergo a change in solution behavior. The destabilized carbonate adduct (KA) may prove more difficult to dissolve or may be at least partially incompletely dissolved.

[0046] The carbonate adduct (KA) can be prepared by a method comprising step a), optionally step b), step c), step d), and step e).

[0047] In step a), a solution (A) is obtained that comprises at least one solvent and CO2 dissolved in said at least one solvent.

[0048] Solution (A) comprises at least one solvent and CO2 in dissolved form. In the present invention, CO2 is understood to mean carbon dioxide. In the present invention, dissolved CO2 is understood to mean all forms of CO2 that enter during dissolution. For example, for aqueous solutions, it is known that dissolved CO2 can exist in solution, especially in equilibrium, as CO2, as carbonic acid, as singly or doubly deprotonated carbonic acid, i.e., as bicarbonate or carbonate.

[0049] Solution (A) is obtained by introducing CO2 into at least one solvent. CO2 can be introduced into the solvent in any suitable form known to those skilled in the art. Preferably, gaseous CO2 or frozen CO2 in the form of dry ice, more preferably gaseous CO2, is introduced into the solvent. Preferably, the gaseous CO2 or frozen CO2 is at least food grade, more preferably a grade suitable for pharmaceutical use. The gaseous and / or frozen CO2 used preferably has a purity of at least 99.5%, more preferably 99.9%.

[0050] Preferably, food quality in the context of the present invention means that the relevant regulations of German and European food legislation are met, preferably including Regulation (EC) No. 852 / 2004 and Regulation (EC) No. 178 / 2002 as well as Regulation (EC) No. 1333 / 2008 and Regulation (EU) No. 231 / 2012.

[0051] Preferably, pharmaceutical quality means that the relevant regulations of the European Pharmacopoeia (Ph. Eur.) are met.

[0052] In particular, when gaseous CO is introduced into the solution, CO may be introduced under pressure. In this context, introduction under pressure means using a pressure above atmospheric pressure, preferably above 1.01325 bar. For this purpose, the introduction of CO into the solvent can be carried out in a vessel that isolates the solvent from the environment so that pressure can build up in the vessel, in particular by supplying CO above atmospheric pressure, preferably above 1.01325 bar. The introduction of CO into the solution, in particular in gaseous form, can be carried out in one step or intermittently.

[0053] In step a), the skilled artisan can use any suitable solvent. Preferably, the solvent used is a polar protic solvent, more preferably, the solvent is water. Depending on the intended use of the carbonate adduct (KA), the solvent can be used in various purities. For example, if the carbonate adduct (KA) is to be used for pharmacological purposes, water of the purity grade "aqua ad iniectabilia" (water for injection) can be used.

[0054] Step a) may comprise a partial step a1), in which the solvent is cooled to 3-8°C, preferably 5°C, before the introduction of CO2. Cooling can be carried out by any method known to those skilled in the art and identified as suitable. For example, cooling can be carried out by storing the solvent in a refrigerator for a long enough time until the solvent reaches the target temperature. Likewise, external cooling can be used, for example.

[0055] Step a) may comprise a substep a2) in which CO2 is introduced into the solvent until a saturation concentration of 3 to 10 g / L, more preferably 4.5 to 7.5 g / L, based on the total volume of the solution is reached. Preferably, the pH of the solution after saturation with CO2 is ≦3.0 to ≦6.0, more preferably ≦4.3 to ≦4.8. Preferably, in substep a2), CO2 is dissolved under pressure, the pressure being 1.5 to 10 bar, more preferably 1.9 to 7 bar, even more preferably 2 to 5 bar.

[0056] Step a) may comprise a partial step a3) in which solution (A) preferably obtained in partial step a2) is stored at 1 to 10° C., preferably for at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; for a maximum of 5 days (120 hours). Preferably, solution (A) preferably obtained in partial step a2) is stored at 3 to 8° C., preferably for at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; for a maximum of 5 days (120 hours).

[0057] Preferably, step a) comprises all substeps a1), a2) and a3).

[0058] Preferably, the partial steps a1), a2) and a3) are carried out in the order a1) followed by a2) and a2) followed by a3).

[0059] Optionally, step b) may be carried out in which a base (BA) other than an amine (AM) is dissolved in solution (A) to obtain solution (A1). Preferably, the base (BA) is a bicarbonate or a carbonate, more preferably a bicarbonate, and even more preferably sodium bicarbonate.

[0060] In step c), at least one amine (AM) is dissolved in solution (A) or (A1) to obtain solution (B).

[0061] In step c), the at least one amine (AM) as defined above can be used in either neutral or salt form. Optionally, the at least one amine (AM) can be used as a mixture of the neutral form of the amine (AM) and the salt form of the amine (AM). Thus, the at least one amine (AM) can include a neutral amine (AM) and / or a 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, and preferably, the acid addition salt is the hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydrogen mesylate, hydrogen tosylate, hydrogen acetate, hydrogen formate, hydrogen propanoate, hydrogen malonate, hydrogen succinate, hydrogen fumarate, hydrogen oxalate, hydrogen tartrate, hydrogen citrate, or hydrogen maleate salt of the at least one amine (AM), more preferably the hydrochloride or hydrobromide, even more preferably the hydrochloride.

[0062] The concentration of the amine (AM) in the solution (B) is preferably 0.01 to 0.25 g / ml, more preferably 0.03 to 0.20 g / ml, and even more preferably 0.08 to 0.15 g / ml.

[0063] Step c) may comprise a substep c2) of dissolving at least one amine (AM) in solution (A) or, if step b) is carried out, in solution (A1) to obtain solution (B).

[0064] In one possible embodiment, the ratio of amine (AM) to base (BA) in solution (B) when carrying out step b) is 2:1 to 5:1, more preferably 3:1 to 4:1, and even more preferably 3.23:1 to 3.26:1 [g / g].

[0065] In another possible embodiment, the molar ratio of base equivalents of amine (AM) to base (BA) in solution (B) when performing step b) is 0.8:1 to 1.5:1, preferably 1.2:1, and more preferably 1:1. In this context, base equivalent means that when a monovalent base such as NaHCO is used, the molar ratio of base (BA) to amine (AM) corresponds to the ratio shown above. When a divalent base (BA) such as NaCO is used, only half the amount of base (BA) is required to introduce the same amount of base equivalent, in terms of the amount of substance in moles of base (BA), compared to when a monovalent base is used. For example, at a 1:1 ratio, when 10 mmol of amine (AM) is used, 10 mmol of NaHCO is required, but only 5 mmol of NaCO is required.

[0066] In a further embodiment, step b) is carried out and in substep c1) the amine (AM) is added in the form of an acid addition salt, wherein the acid-bound amine (AM) is added in an amount that allows the acid bound to the amine (AM) to neutralize the base (BA) to such an extent that the solution (B) has a pH value of 6 to 8.

[0067] Step c) may comprise a substep c2) of adding solution (A) to solution (B) to obtain solution (B1).

[0068] The concentration of the amine (AM) in the solution (B1) is preferably 0.01 to 0.25 g / ml, more preferably 0.03 to 0.20 g / ml, and even more preferably 0.08 to 0.15 g / ml.

[0069] Step c) may comprise a substep c3) of concentrating CO2 in solution (B) or, if substep c2) is performed, solution (B1). Preferably, CO2 in solution (B) is concentrated to 2.5 g / L to 9 g / L, more preferably 5 to 7.5 g / L.

[0070] Step c) may comprise a substep c4) of storing solution (B), or solution (B1) if substep c2) is performed, at 1 to 10°C, preferably 3 to 8°C, for at least 1 hour, preferably 24 to 120 hours, more preferably 24 to 72 hours.

[0071] Step c) may comprise a substep c5) in which CO2 in solution (B) or, if substep b2) is performed, solution (B1) is concentrated to a total concentration of preferably 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, 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 in solution (B) or (B1) until the required total concentration is reached.

[0072] The term "total concentration" here means the total concentration of dissolved CO2 in solution (B) or (B1), including CO2 bound in carbonate adducts (KA). The total concentration is obtained additively by the weight increase of the solution due to added CO2 in all preceding concentration steps a2) and / or c3) (if performed) and c5), without taking into account CO2 that may be added to the solution as base (BA) in the form of bicarbonate or carbonate.

[0073] Concentrating CO2 in solution (B) or (B1) to the required total concentration in partial 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, most preferably 6.5 to 10 bar. Preferably, when CO2 is concentrated in partial step c5), solution (B) or (B1) has a temperature of 3 to 8°C, more preferably 5°C.

[0074] The concentration of solution (B) or (B1) in partial steps c3) and c5) can be carried out in the same manner as described for step a).

[0075] Preferably, the pH of solution (B) after step c5) has been carried out, or of solution (B1) if partial step c2) is carried out, is ≦7.0.

[0076] Preferably, step c) comprises all substeps c1), c2), c3), c4) and c5).

[0077] Preferably, the substeps c1), c2), c3), c4) and c5) are performed in the following order: c1) followed by c2), c2) followed by c3), c3) followed by c4), c4) followed by c5).

[0078] In step d), the solution obtained after completing step c) is frozen. Preferably, in step d), solution (B) or solution (B1) after carrying out partial step c2) is frozen.

[0079] The solution subjected to step d), preferably solution (B) or (B1), 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 very particularly preferably at least 15 g / l.

[0080] Preferably, the solution obtained after completion of step c), preferably solution (B) or (B1), is frozen at -100°C to -20°C, more preferably -90°C to -30°C, even more preferably -80°C to -40°C, and most preferably -70°C to -50°C.

[0081] Freezing of 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 container immersed in a cooling medium. Preferably, the container has the shape of a flask. Preferably, the container containing the solution obtained in step c) is 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 is brought to the desired temperature by adding dry ice or by a suitable cooling device, such as a cryostat.

[0082] Preferably, the freezing is carried out at atmospheric pressure, more preferably at 1.01325 bar.

[0083] 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.

[0084] The solution obtained after completion of step c), preferably solution (B) or (B1), is frozen at a cooling rate of preferably 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.

[0085] Preferably, during the freezing process, the solution obtained after completion of step c), preferably the container in which solution (B) or (B1) is located, is rotated in the cooling medium at 10 to 1000 rpm, more preferably 50 to 600 rpm, even more preferably 100 to 400 rpm, particularly preferably 200 to 300 rpm.

[0086] Freezing can be done according to a shell freezing procedure.

[0087] In step e), the solution frozen in step d), preferably solution (B) or (B1), is stored at -100 to 0°C for no more than 4 days.

[0088] Preferably, in step e), the solution frozen in step d), preferably solution (B) or (B1), is stored for 1.5 to 4 days, more preferably 2.5 to 4 days.

[0089] Preferably, in step e), the solution frozen in step d), preferably solution (B) or (B1), is stored at -50 to 0°C, more preferably -30 to -5°C, even more preferably -25 to -10°C, and particularly preferably -20 to -15°C.

[0090] In principle, storage at a defined temperature can take place in any refrigeration facility known to those skilled in the art, for example, storage can take place in a freezer or ultra-low temperature freezer.

[0091] The process according to which the carbonate adduct (KA) can be produced may comprise a further step f) carried out after step e), in which the solution stored in step e), preferably solution (B) or (B1), is dried to obtain the dried carbonate adduct (KA).

[0092] 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 <0.1% by weight, relative to the total weight of the dry carbonate adduct (KA).

[0093] Preferably, in step f), the CO2 not bound in the carbonate adduct (KA) is removed from the solution stored in step e), preferably (B) or (B1), to a residual content of <0.8% by weight, more preferably <0.1% by weight, relative to the total weight of the dry carbonate adduct (KA).

[0094] Drying can be carried out using any method known to those skilled in the art and identified as suitable. Preferably, drying is carried out by freeze-drying, also known as lyophilisation. When using the freeze-drying method, step d) is a freezing step and step e) is a maturation step.

[0095] Preferably, the pressure during drying 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 very particularly preferably 0.05 to 0.1 mbar. Preferably, the pressure is maintained throughout the drying process. Preferably, during drying, the above-specified pressure is reached within 7 hours, more preferably within 5 hours, and particularly preferably within 4 hours from the start of evacuation.

[0096] The drying endpoint can be determined by a person skilled in the art from the temperature curve recording. Preferably, the total drying time in step f) is 10 to 60 hours, more preferably 30 to 55 hours, and particularly preferably 41 to 52 hours. The total drying time is defined as the time span between the completion of storage in step e) and the completion of drying in step f).

[0097] Preferably, the temperature throughout the drying in step f) is 0 to 20°C, preferably 4 to 18°C, more preferably 8 to 16°C.

[0098] Furthermore, the present invention includes a pharmaceutical composition (PZ) comprising the above-described amine (AM) or carbonate adduct (KA) for use in the treatment of atypical pneumonia.

[0099] Pharmaceutical compositions also containing carbonate adducts (KA) are described in WO2019 / 048590.

[0100] A pharmaceutical preparation (PZ) according to the present invention is basically understood to be a composition comprising an amine (AM) or a carbonate adduct (KA), and may further comprise other excipients or additives suitable for pharmacological use.

[0101] Furthermore, the pharmaceutical preparation (PZ) may contain an additional base that does not correspond to the amine (AM) and may be different from the base (BA). Those skilled in the art can basically select additives according to the desired application. In doing so, they take into account the desired application form.

[0102] The pharmaceutical preparation (PZ) can be in principle in any suitable dosage form, for example, in the form of a capsule, as a tablet, as a solution, as an ointment, as a cream, as a gel, as a paste, as an enveloped paste or as an active substance-containing patch.

[0103] Pharmaceutical preparations (PZ) can be applied in any suitable application form. Those skilled in the art will select a suitable dosage form according to the intended application form. For example, pharmaceutical preparations (PZ) can be administered orally, by inhalation, by injection, as a patch, by skin administration, including at least transdermal administration, by eye administration, by nasal administration, by rectal administration, or by vaginal administration.

[0104] For preparing pharmaceutical preparations (PZ), the skilled person can use methods that are basically known in the art.

[0105] Preferably, the temperature of mixing the carbonate adduct (KA) with the excipients used and optionally further base during the preparation of the pharmaceutical preparation (PZ) is below 60°C, preferably below 50°C, more preferably between 0 and 50°C.

[0106] When preparing the pharmaceutical preparation (PZ), preferably in the form of an ointment, dispersion may be used, preferably in an ointment preparation machine, where speeds of <2000 rpm are preferably used.

[0107] Before being processed into the oral dosage forms described below, such as tablets or capsules, or semi-solid dosage forms, the carbonate adduct (KA) can be ground into powder alone or in the presence of other excipients or bases. In principle, those skilled in the art can use any suitable and known technical means for a particular purpose. For example, a mortar or similar suitable equipment can be used for the grinding process. Preferably, technical aids that keep the mechanical stress on the carbonate adduct as low as possible are used for the grinding process. Preferably, grinding is carried out using a mortar.

[0108] The powder thus obtained can then be processed into a semi-solid dosage form, for example by compression into tablets, or by filling into commercially available capsules, or by mixing with suitable excipients.

[0109] One embodiment of the pharmaceutical preparation (PZ) relates to a pharmaceutical preparation (PZ) containing carbonate adduct (KA) and administered orally. In this embodiment, the pharmaceutical preparation (PZ) is preferably administered as a capsule, more preferably as a hard gelatin capsule or cellulose capsule, particularly preferably as a hard gelatin capsule. Similarly, in this embodiment, the pharmaceutical preparation (PZ) may be administered in the form of a tablet.

[0110] Preferably, the pharmaceutical preparation (PZ) in this embodiment comprises at least one excipient (H), preferably selected from starch, in particular corn starch and / or rice starch, dextran, cellulose esters, and SiO2.

[0111] Furthermore, in this embodiment, the pharmaceutical preparation (PZ) may contain at least one base (BA1) other than the amine (AM), which may be the same as or different from the base (BA). Preferably, the base (BA1) is selected from NaHCO3 or KHCO3, more preferably NaHCO3.

[0112] Preferably, the general instructions given above with respect to pharmaceutical preparations (PZ) also apply to this embodiment, in particular to the preparation of pharmaceutical preparations (PZ), insofar as they are technically applicable to this embodiment.

[0113] Preferably, the pharmaceutical preparation (PZ) in this embodiment is a) 1 to 99% by weight, more preferably 15 to 95% by weight, of a carbonate adduct (KA), b) Contains 0 to 60% by weight, more preferably 3 to 50% by weight, of a base (BA1) and 1 to 90% by weight, more preferably 2 to 75% by weight, of an excipient (H).

[0114] A further embodiment of the pharmaceutical preparation (PZ) relates to a semi-solid pharmaceutical preparation (PZ) containing carbonate adduct (KA) and applied to the skin. In this embodiment, the pharmaceutical preparation (PZ) can be applied, for example, in the form of an ointment, a cream, a gel, a paste, an envelope paste or as an active substance-containing patch.

[0115] Preferably, the general information given above regarding pharmaceutical preparations (PZ) also applies to this embodiment, in particular to the manufacture of pharmaceutical preparations (PZ), insofar as it is technically applicable to this embodiment.

[0116] In this embodiment, the pharmaceutical preparation (PZ) preferably comprises at least one excipient (H1) selected from paraffin, in particular viscous and light paraffin, wool wax, wool wax alcohol, hydrophobic base gel, vegetable oil, animal fat, synthetic glyceride, liquid polyalkylsiloxane, wax, petrolatum, and starch, in particular corn starch, preferably petrolatum.

[0117] Viscous paraffin (paraffinum subliquidum) is a paraffin with a viscosity of 110 to 230 mPas, while light paraffin (paraffinum perliquidum) has a viscosity of 25 to 80 mPas.

[0118] Preferably, the pharmaceutical preparation (PZ) in this embodiment is a) 0.1 to 40% by weight, preferably 0.4 to 10% by weight, of a carbonate adduct (KA), and b) Contains 60 to 99.9% by weight, preferably 80 to 96% by weight, of excipient (H1).

[0119] Further embodiments of the pharmaceutical preparations (PZ) comprising carbonate adducts (KA) relate to pharmaceutical preparations that are applied bucally, parenterally, nasally and / or by inhalation.

[0120] In the buccal application embodiment, the carbonate adduct (KA) is administered in the form of a preparation containing the carbonate adduct (KA) and polyvinylpyrrolidone. Preferably, the weight ratio of the carbonate adduct (KA) to polyvinylpyrrolidone is 1:1 to 1:10, more preferably 1:3. Polyvinylpyrrolidone of various chain lengths can be used. Preferably, the preparation contains water as a solvent. More preferably, the water contains CO2. Even more preferably, the water contains at least 3 g / L of CO2, more preferably 3 to 7 g / L of CO2, and most preferably 6 to 7 g / L of CO2.

[0121] Preferably, the general information given above regarding pharmaceutical preparations (PZ) also applies to this embodiment, in particular to the preparation of pharmaceutical preparations (PZ), insofar as it is technically applicable to this embodiment.

[0122] Preferably, the pharmaceutical preparation (PZ) in this embodiment is present as a solution (A2) comprising a carbonate adduct (KA), dissolved CO2, and at least one excipient (H2).

[0123] The excipient (H2) is preferably selected from alkali or alkaline earth halides, more preferably NaCl and MgCl2, and even more preferably NaCl. The excipient (H2) can be identical to the salt (S). The amount of the excipient (H2) refers in the present invention to the additional amount of the excipient (H2) that is not introduced into the pharmaceutical preparation (PZ) in the form of a salt (S) as part of the carbonate adduct (KA), insofar as this is identical to the salt (S) in the individual embodiment.

[0124] Preferably, solution (A2) is obtained by introducing CO2 into a solvent. Preferably, the solvent is water. Preferably, solution (A2) is produced by introducing CO2 into the solvent at a temperature of 0-8°C, more preferably 0-5°C. CO2 may be introduced into the solvent in gaseous form or in solid form, for example as dry ice. Preferably, CO2 is introduced into the solvent in gaseous form. As described above for partial step a2), CO2 may be introduced into the solution under pressure until the desired concentration is reached.

[0125] Preferably, the solution (A2) is prepared by introducing CO2 into the solvent at a concentration of at least 3 g / l, more preferably at most 4 g / l, and even more preferably from 4 g / l to 8 g / l.

[0126] Preferably, the CO2 used to prepare solution (A2) has a purity of at least 99.9% and, more preferably, also has a quality suitable for pharmaceutical applications as defined above.

[0127] Preferably, the pharmaceutical preparation (PZ) in this embodiment is obtained by dissolving the carbonate adduct (KA) in the solution (A2), and each of the carbonate adducts (KA) is about 100% by weight relative to the total amount of the pharmaceutical preparation (PZ). a) 0.05 to 100 mg / ml, more preferably 0.08 to 50 mg / ml of carbonate adduct (KA), and b) Contains 0 to 20 mg / ml, more preferably 3 to 10 mg / ml, of an excipient (H2). [Example]

[0128] Examples of the invention 1. Example 1, Preparation of Carbonate Adduct (KA) 1.1 Materials Amine (AM): 68.8-110.1 g of procaine hydrochloride (e.g. ultra-pure, for use as a pharmaceutically active substance; European Pharmacopoeia or of a quality suitable for this purpose). Base (BA): 22.2-33.9 g sodium bicarbonate (e.g., ultrapure or of a quality suitable for this purpose). · Solvent: 630-900ml of water (water for injection). CO2: Minimum 12.0g / l carbon dioxide from a pressurized gas cylinder (good quality CO2) Dry ice for preparing and cooling refrigerated mixtures Methanol, technical grade for the preparation of refrigerated mixtures

[0129] 1.2 Process a) Pour water (e.g., water for injection) into a cleaned plastic pressure bottle up to the mark (approximately 800-900 ml) and pre-cool to 5°C in a refrigerator (3-8°C) or by external cooling for at least 1 hour.

[0130] A carbon dioxide saturated carbonated solution is prepared. To do this, CO2 is intermittently introduced under pressure (1.6-8 bar) into pre-chilled water. A hiss (gas escaping through the pressure relief valve) indicates saturation of the solution with CO2. Saturation is controlled by weight until 4.0-6.0 g of CO2 (corresponding to 4.5-7.5 g / L) is dissolved. The saturated solution has a pH value of ≦4.3-4.8. The carbonated water is immediately sealed and stored in the refrigerator for at least 1 hour.

[0131] 1.3 Process b) 21.2 g of sodium bicarbonate is placed in a second plastic pressure bottle and mixed with 320 ml of chilled water containing CO2, and dissolved with stirring.

[0132] 1.4 Process c) Add an equal amount of solid procaine hydrochloride to this solution at a constant temperature to form a nearly neutral solution, and then add 320 ml of cold carbonated water to obtain a clear, slightly acidic solution. The CO2 in the solution is concentrated. Store the resulting solution in the refrigerator for at least 1 hour.

[0133] The solution is then adjusted again with CO2 until the CO2 concentration in the solution reaches 12 g / l. The pH value is checked using a pH test strip. The pH value is ≦6.6.

[0134] 1.5 Process d) Pre-cool the round-bottom flask. For freezing, measure the reaction mixture in a pre-cooled measuring cylinder, transfer it to the round-bottom flask in several portions, and freeze it by immersing it in a refrigerated dry ice / methanol mixture (below -60 °C) for 1.5 to 3.5 minutes per flask (approximately 200 rpm) according to the shell freezing method. Set the immersion angle of the flask on the rotary evaporator to approximately 40°.

[0135] 1.6 Process e) The flasks containing the frozen material are sealed with ground glass stoppers and temporarily stored in a freezer at -15 to -20°C for 2 to 4 days.

[0136] 1.7 Process f) The temperature-controlled flasks are placed in polystyrene containers, which are pre-cooled and immediately connected individually to an evacuated (0.060 ± 0.01 mbar, approximately -46 °C, leak-tested) freeze-drying apparatus via soft rubber cones. The valve cocks are carefully opened and each piston is placed under vacuum. Finally, all pistons must be evacuated.

[0137] To monitor the process, a temperature sensor is placed at the bottom of the polystyrene jacket to record the entire temperature curve throughout the drying process. Before the start of freeze-drying, the temperature sensor indicates a temperature below -5°C.

[0138] During freeze-drying, the pressure is 0.07 ± 0.02 mbar. This sublimation pressure is reached within 4 hours and maintained throughout the freezing period. The temperature of the cooling chamber is maintained between 9 and 15°C throughout the drying process. The freeze-drying endpoint is determined graphically from the temperature curve recording. The total drying time is limited to a maximum of 52 hours. The freeze-dried material is transferred to amber glass jars with twist-off lids, fitted with drying bags, and stored in a refrigerator at 0–15°C.

[0139] 2. Examples of Pharmaceutical Preparations (PZ) 2.1 Capsules and Tablets The following is an exemplary description of the composition of the pharmaceutical preparation (PZ) of the present invention in the form of a capsule or tablet, in which procaine is the amine (AM). To prepare the capsules, commercially available plug capsules of commercial sizes (5,000) can be used. The capsules are filled with a powder containing a carbonate adduct (KA) containing procaine as the amine (AM) (a ground product of the active substance carbonate adduct (KA) containing procaine as the amine (AM), optionally with additives, fillers, and flow modifiers). The carbonate adduct (KA) was prepared according to Example 1. It has been shown that hard gelatin capsules are more suitable than cellulose capsules in terms of stability. For example, filled hard gelatin capsules, exemplified by the hard gelatin capsules in Table 1 containing 60 mg and 100 mg of active substance, showed no change even after 12 months of storage in a refrigerator and are therefore stable (Figure 2). Stability was investigated by IR spectroscopy. In the case of hard gelatin capsules, procaine was not detected by IR spectroscopy within a 12-month period, whereas a procaine band was measured in the IR spectrum of the cellulose capsules after only a few days. The content was determined by UV / VIS spectroscopy at room temperature. According to European Pharmacopoeia section 2.9.6, for prescription medicinal products, a tolerance range of ±15% is specified for the total content, including by-products.

[0140] Valid and generally accepted pharmaceutical regulations regarding the manufacture of (prescription) medicinal products apply (e.g. European Pharmacopoeia, German Pharmacopoeia).

[0141] Table 1: Exemplary composition of capsules containing added NaHCO3 and carbonate adduct (KA) as the active substance prepared according to Example 1 TIFF2025169345000007.tif32157

[0142] Table 2: Exemplary compositions of tablets containing added NaHCO3 and carbonate adduct (KA) as the active agent prepared according to Example 1 TIFF2025169345000008.tif25154

[0143] 2.2 Ointments The following exemplifies the composition of the pharmaceutical preparation (PZ) of the present invention in the form of an ointment, in which procaine is used as an amine (AM) in a carbonate adduct (KA). The preparation of ointments is governed by applicable and generally accepted pharmaceutical regulations for the preparation of (prescription) medicinal products (e.g., the European Pharmacopoeia, the German Pharmacopoeia). During the preparation of the ointment, large shear forces are avoided. Furthermore, the temperature is kept locally below 60°C during the preparation. Therefore, the carbonate adduct (KA) containing procaine as an amine (AM) is introduced into the ointment base, e.g., petrolatum, in a mortar or melamine bowl, the temperature of which is controlled at 40-45°C by a water bath. Alternatively, an electric mixing system, such as those used in conventional pharmaceutical practice, can be used.

[0144] Table 3: Exemplary compositions of ointments containing carbonate adduct (KA) as the active substance prepared according to Example 1 TIFF2025169345000009.tif25145

[0145] 2.3 Parenteral Solutions To prepare a parenteral solution containing procaine as the amine (AM), the carbonate adduct (KA) is cooled to approximately 5±3°C in a suitable container equipped with a magnetic stirrer or similar device and allowed to stand at this temperature. The required quality of gaseous carbon dioxide is concentrated in the water to approximately 3.2 g / L. The appropriate amount of procaine as the amine (AM), the carbonate adduct (KA), and sodium chloride are dissolved in the CO2-containing water to an isotonic amount.

[0146] Alternatively, CO2 is concentrated in water at a controlled temperature of approximately 5 ± 3°C under pressure in a closed system to a clear excess (4.5-7.5 g / L). This carbonated water is also supplemented with a corresponding amount of carbonate adduct (KA) containing procaine as the amine (AM) and sodium chloride.

[0147] This cold solution of procaine as the amine (AM), carbonate adduct (KA), and sodium chloride is sterile filtered under suitable space conditions and filled into suitable vials. Applicable and generally accepted pharmaceutical regulations for the preparation of (prescription) medicinal products apply (e.g., the European Pharmacopoeia).

[0148] Table 4: Exemplary composition of a parenteral preparation containing NaCl additive and carbonate adduct (KA) as the active agent prepared according to Example 1 TIFF2025169345000010.tif36151

[0149] 2.4 Buccal application as a pump-action spray 285 mg of ProcCluster (carbonate adduct of Example 1) and 852 mg of PVP25 (mass ratio 1:3) were added to CO2 water (e.g., commercially available mineral water, CO 2- ) and apply using a pump spray bottle. PVP = Polyvinylpyrrolidone, also known as Polyvidone or Povidone.

[0150] Other PVP products, such as PVP30 and PVP17, can be used → other ratios (available in 1:1 to 1:10 ratios relative to the amount of ProcCluster, applies to all PVPs used)

[0151] PVP: CAS Number Designation 9003-39-8 Polyvinylpyrrolidone (2-Pyrrolidinone, 1-Ethenyl-, Homopolymer) EINECS Number: 618-363-4 - REACH Regulation Number: - (Polymer) - INCI Name: PVP.

[0152] 3. Solubility in octanol The solubility test was carried out in octanol and the content in the organic phase was investigated by UV / VIS spectroscopy and pH value.

[0153] Table 5. Solubility of various dosage forms TIFF2025169345000011.tif46148

[0154] The established pH values ​​demonstrate that the carbonate adduct of procaine is soluble in the organic phase, and therefore membrane-permeable, and is not converted to procaine. Similarly, UV / VIS spectroscopic measurements of the content indicate that the carbonate adduct of procaine is more similar to procaine in terms of lipophilicity than ProcHCl. Therefore, the carbonate adduct behaves like a basic component, i.e., a fat-soluble base that forms depending on the pH value. The carbonate adduct of procaine exhibits this property independently of pH, i.e., it does not necessarily convert to a lipophilic form upon pH change, as does ProcHCl. ProcHCl exhibits significantly lower values, at 8%, of around 6% for protein binding.

[0155] 4. Antiviral activity test 4.1 Antiviral activity test against influenza virus A549 cells were cultured in DMEM containing the indicated concentrations of ProcCluster® (= carbonate adduct (KA) from Example 1) or procaine HCl. INF After pre-treatment with a solution of 0.2% BSA, 1 mM MgCl2, and 0.9 mM CaCl2 for 30 minutes, the cells were treated with influenza A / Puerto Rico / 8 / 34 (MOI 0.1) in PBS. INF (0.2% BSA, 1mM MgCl2, 0.9 CaCl 2、 100U ml -1 penicillin, and 0.1 mg ml -1 The cells were infected with a solution of 1000 ribosomal inhibitors (streptomycin) for 30 minutes. The cells were then washed and incubated in medium containing the inhibitor for up to 24 hours post-infection. Virus titers in the supernatants were determined by standard plaque assay on MDCK cells. Figure 1(A) shows two independent experiments with biological replicates.

[0156] Addition of carbonate adduct (KA) of Example 1 reduced the virus titer by up to 1 log level, or up to 90%, compared to untreated samples.

[0157] 4.2 Antiviral activity tests against SARS-CoV-2 Calu-3 cells were pretreated with the indicated concentrations of ProcCluster® (= carbonate adduct (KA) from Example 1) from Figure 1(B) or procaine HCl (Figure 1(C)) in DMEM (10% FCS) for 30 minutes, and then infected with a solution of SARS-CoV-2 (MOI 0.5) in DMEM (10% FCS) containing the corresponding inhibitor for 2 hours. The cells were washed and incubated in DMEM (10% FCS) containing the corresponding inhibitor for 24 hours post-infection. The cells were then washed and incubated in DMEM (10% FCS) containing the corresponding inhibitor at the indicated concentrations until 24 hours post-infection. Virus titers in the supernatants were determined by plaque assay on Vero-76 cells. Biological replicates are shown.

[0158] Addition of the carbonate adduct (KA) of Example 1 reduced the virus titer by up to 1 log level, i.e., up to 90%, compared to samples without the addition of the carbonate adduct (KA) of Example 1.

[0159] literature TIFF2025169345000012.tif51163

Claims

1. Amines (AM) of general formula (I) for use in the treatment of atypical pneumonia and in the therapy of viral diseases: 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 Ha-(CH 2 ) n NR 8 R 9 and; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 (C 1～10 ) alkyl, preferably (C 1～2 ) alkyl, R 9 (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; The amines of formula (I) herein may optionally be used in the form of salts.

2. Carbonate adducts (KA) comprising at least one structural element of general formula (II), (III) and / or (IV) for use in the treatment of atypical pneumonia and in the therapy of viral diseases: 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 Ha-(CH 2 ) n NR 8 R 9 and; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 (C 1～10 ) alkyl, preferably (C 1～2 ) alkyl, R 9 (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 between 0.5 and 30; (S) is salt.

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 atypical pneumonia and in the therapy of viral diseases, 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 Ha-(CH 2 ) n NR 8 R 9 and; n is 1 to 5, preferably 1 to 3, more preferably 1 to 2; R 8 (C 1～10 ) alkyl, preferably (C 1～2 ) alkyl, R 9 (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 said at least one amine of formula (I) may optionally be used in the form of a salt; The following steps: (a) at least one solvent and CO dissolved in the at least one solvent; 2 providing a solution (A) comprising: optionally, (b) dissolving a base (BA) other than the amine (AM) in the solution (A) to obtain a solution (A1); (c) dissolving said at least one amine (AM) in 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 more than 4 days; The carbonate adduct can be prepared by a method comprising the steps of:

4. A pharmaceutical composition (PZ) comprising an amine (AM) according to claim 1 or a carbonate adduct according to any one of claims 2 or 3 for use in the treatment of atypical pneumonia and in the therapy of viral diseases.

5. (i) the amine of general formula (I) and 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) Salt (S) is Na + , K. + , Li + , Mg 2+ , Zn 2+ , Fe 2+ , Fe 3+ , and Mn 2+ , preferably Na + and at least one cation selected from Cl - , Br - , J - , F - , SO 4 2- , SO 3 2- , HSO 4 - , HSO 3 - , HCO 3 - , CO 3 2- , P.O. 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 - , particularly preferably Cl - a salt composed of at least one anion selected from An amine for use according to claim 1, a carbonate adduct (KA) for use according to any one of claims 2 or 3, and a pharmaceutical composition (PZ) for use according to claim 4.

6. Step (a) comprises the following substeps: (a1) cooling the solvent, preferably water, to 3-8°C, preferably 5°C, and / or (a2) CO 2 is preferably added to a saturation concentration of 3 to 10 g / L, more preferably to a saturation concentration of 4.5 to 7.5 g / L. 2 into the solvent, preferably CO 2 the pH of the solution after saturation with is ≦3.0 to 6.0, more preferably ≦4.3 to 4.8; and / or (a3) storing solution (A) at 1-10°C, preferably for at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; up to 5 days (120 hours), preferably at 3-8°C, preferably for at least 30 minutes, more preferably at least 50 minutes, even more preferably at least 60 minutes; up to 5 days (120 hours); including at least one of the following: Preferably, step (a) comprises all substeps (a1), (a2) and (a3), Preferably, the partial steps (a1), (a2) and (a3) ​​are carried out in the following order: (a1) followed by (a2) and (a2) followed by (a3); 6. Carbonate (KA) for use according to any one of claims 3 and 5.

7. (i) the base (BA) in step (b) is a bicarbonate or a carbonate, more preferably a bicarbonate, even more preferably sodium bicarbonate; and / or (ii) CO in the solution 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 very particularly preferably at least 15 g / l, and the amine (AM) may be used in the form of a salt, 7. The carbonate adduct (KA) for use according to any one of claims 3, 5 and 6.

8. Step (c) comprises the following substeps: (c1) dissolving 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) CO in solution (B) or (B1) 2 and / or concentrating (c4) storing solution (B) or (B1) at 1 to 10°C, preferably 3 to 8°C, for at least 1 hour, preferably 24 to 120 hours, more preferably 24 to 72 hours; and / or (c5) CO in solution (B) or (B1) 2 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, very particularly preferably at least 15 g / l including at least one of the following: Here, optionally, (i) the concentration of amine (AM) in solution (B) or in solution (B1) if substep (c2) is carried out is between 0.01 and 0.25 g / ml, preferably between 0.03 and 0.20 g / ml, more preferably between 0.08 and 0.15 g / ml; and / or (ii) the pH of solution (B) or (B1) after step (c5) is ≦7.0, and / or (iii) when carrying out step (b), the ratio of amine (AM) to base (BA) in solution (B) is from 2 to 5, more preferably from 3 to 4, even more preferably from 3.23 to 3.26 [g / g]; and / or (iv) in step (c1), the at least one amine (AM) is present as an acid addition salt, preferably as a hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydrogen mesylate, hydrogen tosylate, hydrogen acetate, hydrogen formate, hydrogen propanoate, hydrogen malonate, hydrogen succinate, hydrogen fumarate, hydrogen oxalate, hydrogen tartrate, hydrogen citrate, hydrogen maleate, more preferably as a hydrochloride or hydrobromide; Preferably, step (c) comprises all substeps (c1), (c2), (c3), (c4) and (c5), Preferably, the substeps (c1), (c2), (c3), (c4) and (c5) are carried out in the following order: (c1) followed by (c2), (c2) followed by (c3), (c3) followed by (c4), (c4) followed by (c5), Carbonate (KA) for use according to any one of claims 3 and 5 to 7.

9. In step (d), (i) freezing solution (B) or (B1) at a temperature between −100° C. and −20° C., preferably between −90° C. and −30° C., more preferably between −80° C. and −40° C., and very particularly preferably between −70° C. and −50° C., and / or (ii) freezing solution (B) or (B1) 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) rotating the container in which solution (B) or (B1) is located during the freezing process, preferably in a cooling medium, at a speed of 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) freezing solution (B) or (B1) 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 (KA) for use according to any one of claims 3 and 5 to 8.

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

11. The method further comprises the step (f) carried out after step (e): (f) drying the solution stored in step (e) to obtain a dry carbonate adduct (KA); Includes; In step (f), optionally, (i) removing water from solution (B) or (B1) to a residual content of <0.8% by weight, preferably <0.1% by weight, relative to the total weight of the dried product (C); and / or (ii) CO unbound in the carbonate adduct (KA) from solution (B) or (B1). 2 to a residual content of <0.8% by weight, preferably <0.1% by weight, relative to the total weight of the dry product (C), and / or (iii) drying is by freeze-drying; and / or (iv) during drying, a pressure of 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, very particularly preferably 0.05 to 0.1 mbar, is preferably maintained throughout the drying process; and / or (v) the pressure during drying according to (iv) is reached 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 throughout the drying in step (f) is between 0 and 20°C, preferably between 4 and 18°C, more preferably between 8 and 16°C; and / or (vii) the total drying time is 10 to 60 hours, preferably 30 to 55 hours, more preferably 41 to 52 hours; Carbonate (KA) for use according to any one of claims 3 and 5 to 10.

12. The amine (AM) according to claim 1, and 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, wherein the atypical pneumonia is bacterial or viral atypical pneumonia, or atypical pneumonia caused by a fungus, preferably viral atypical pneumonia.

13. Atypical pneumonia (i) bacterial atypical pneumonia, preferably caused by a bacterium selected from Mycoplasma, Legionella, and Chlamydia; or (ii) viral atypical pneumonia, preferably caused by a virus selected from coronaviruses, influenza viruses, adenoviruses, and respiratory syncytial viruses, more preferably coronaviruses, in particular SARS CoV-2; or (iii) Atypical pneumonia caused by a fungus, preferably caused by a fungus selected from Aspergillus, Pneumocystis, and Candida. That is, An amine according to claim 12, and a carbonate adduct (KA) for the use according to claim 12, and a pharmaceutical composition for the use according to claim 12.

14. (i) the treatment of viral diseases relates to diseases caused by RNA viruses, preferably coronaviruses, influenza viruses, adenoviruses and respiratory syncytial viruses, more preferably influenza viruses and coronaviruses, particularly preferably coronaviruses, very particularly preferably SARS CoV-2; and / or (ii) in the treatment of viral diseases, patients who do not require intensive medical treatment are treated; An amine (AM) according to claim 1, and a carbonate adduct (KA) for use according to any one of claims 2, 3 and 5 to 11, and a pharmaceutical composition (PZ) for use according to claim 4.

15. The amine (AM) according to claim 1, and the carbonate adduct (KA) for use according to any one of claims 2, 3, and 5 to 14, and the pharmaceutical composition (PZ) for use according to any one of claims 4 and 12 to 14, wherein the administration is oral, buccal, parenteral, nasal, inhalation, or dermal.

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