LU101724B1 - Active ingredients for medical use - Google Patents

Abstract

The subject of the present invention relates to an amine (AM) according to the general formula (I); a carbonic acid adduct (KA) and a pharmaceutical composition (PZ) for use in the treatment of atypical pneumomy.

Description

New LU patent application | Applicant: inflamed pharma GmbH.

Our reference: JCL17054LU © LU101724 | Active ingredients for medical use É.

TECHNICAL AREA |

The subject of the present invention relates to an amine (AM) according to the | general formula (I); a carbonic acid adduct (KA) and a pharmaceutical | Composition (PZ) for use in the treatment of atypical pneumomy. . TECHNICAL BACKGROUND |

Procaine and structurally related compounds according to the general formula (I) | are used as local anesthetics. An oral application for the systematic | Pain reduction is not possible because procaine hydrochloride cannot pass through the intestinal wall due to its ionic structure. Procaine hydrochloride is only appreciably parenteral | used. The procaine is practically unchanged in the stomach when administered orally. The higher the pH, the higher the rate of adsorption of procaine in the intestine. ©

[003] Carbonic acid adducts of procaine and structurally related local anesthetics are. outwardly neutral, therefore permeable to the membrane and can also pass through the intestinal wall. a Due to the better penetration into the tissue, procaine is withdrawn in the form of carbonic acid | Adducts to the rapid breakdown by the pseudocholinesterase in the plasma. Therefore, | Carbonic acid adducts of procaine and structurally related local anesthetics more versatile | are used as procaine hydrochloride. |

WO2006 / 007835 A2 discloses ammonium salts and stable storable | Ammonium salt-mineral salt clathrates with acidic dibasic acid residues such as © hydrogen carbonate, processes for their production as well as pharmaceutical-medical and |. chemical synthetic applications for these compounds. The use of procaine and structurally related local anesthetics or of carbonic acid adducts thereof in the treatment of atypical pneumonia is not disclosed. .

The aim of the application DE 10 2013 015 035 A1, which refers directly to WO2006 / 007835 A2 | is taking some disadvantages of the Procainium carbonic acid described above. To improve mineral salt clusters by developing suitable formulations so that these | become suitable for medicinal products and thus meet higher demands in terms of stability, effectiveness and © acceptance. To this end, a process for the production of carbonic acid is used. Described mineral salt clusters of procaine, and its use in formulations | for parenteral application, inhalation solutions, ointments and tablets. Analogous to . WQ2006 / 007835 A2 discloses the document that in the production of the Procainium- | Carbonic acid mineral salt clusters both salt and CO, present in the reaction solution. are. DE 10 2013 015 035 A1 also does not disclose the use of procaine and structurally. related local anesthetics or carbonic acid adducts thereof in the treatment of P atypical pneumomy. È

[006] WOO2019048590 likewise discloses carbonic acid adducts based on amines, 0 in particular also on procaine and structurally related local anesthetics, and |. pharmaceutical preparations therefrom and processes for their manufacture. Aside from that . medical uses of the carbon adducts are disclosed, but not. Use in the treatment of atypical pneumonia. |

2.

Atypical pneumonia refers to inflammation of the alveolar space and / or the / 101724 | interstitial lung tissue, which can be triggered by viruses, bacteria or fungi, among others. When there is inflammation [1], adrenaline is released, which leads to | Narrowing of the arterioles and enlargement of venules results. Then the exudation takes place. The | The walls of the capillaries become more permeable for protein and neutrophils to pass through. It | an inflammatory swelling develops. The permeability of the vessel walls is determined by vessel | mediators such as histamine, prostaglandins, kinins and serotonin are increased so that blood congestion | arises. The nerve endings are irritated by the increased tissue pressure, peptides and lactic acid f, it hurts. Now the cellular reaction sets in, i.e. neutrophils emerge from the vessels and reach the location of the stimulus mainly through chemotaxis (acidic milieu) or damage. Phagocytosis occurs. The resulting decay products can |. Set off a fever and cause pus. Furthermore, mast cells are increased in the inflammatory | deten tissue washed ashore. |

An occasionally possible fatal complication, especially in connection with atypical pneumonia, is based on an excessive immune reaction that leads to. Development of acute respiratory distress syndrome (ARDS) [2]. Through the |. Increase in the permeability of the vessels and damage to the lungs in the course of inflammation |. interstitial pulmonary edema develops. Inflammatory factors such as TNF-α, | IL-6 and IL-8 trigger the immigration of neutrophils. These release free radicals such as O, H, O ,, OH and HOCI and Iytic enzymes that reduce the inflammation reaction | further strengthen. Under the influence of the inflammatory medidators there is a | pronounced “capillary leak”, which leads to the formation of an alveolar odor. This becomes | the surfactant on the surface of the alveoli is destroyed and microelectasis occurs. The | This disrupts gas exchange between the lungs and blood. |

S. Pecher et al. [3] discloses the local anesthetic such as lidocaine one. have anti-inflammatory effects. Pecher et al. cite studies by Mikawa et al. | on rabbits incubated with E. coli and given lidocaine. It turned out |. that the administration of lidocaine leads to an increase in p, O, and improved lung mechanics in the |. Leads to improved compliance and reduced resistance. In addition, it came to. a reduced degree of pulmonary edema compared to a comparison group. In the Ë bronchoalveolar lavage, fewer leukocytes and a lower albumin content in the lidocaine group were found. The formation of hemorrhages, alveolar septum thickening and the. Lidocaine visibly reduced the number of inflammatory cells in the alveolar space 1. However, S. Pecher does not disclose the use of procaine and structurally |. related local anesthetics or carbonic acid adducts thereof in the treatment of | atypical pneumomy, in particular virus or fungus-induced atypical | Pneumonia. |

In view of the recent pandemic triggered by the Sars-CoV-2 virus and the 2 sometimes fatal course, including the development of an acute respiratory distress syndrome. (ARDS), it becomes clear that there is still a need for therapeutics that help at least | a milder course of atypical pneumonia, especially that caused by viruses and. Fungus-triggered atypical pneumonia. |

SUMMARY OF THE INVENTION È

The invention relates to an amine (AM) according to the general formula (1) |

Ry 0 LU101724: Re Rs 0 oo ”| where in formula (I) © Ry is H, (C4-40) alkyl, (C240) alkenyl, (Cs-C44) aryl or (Cs-C, o) heteroaryl, preferably H or '(C1.10) alkyl, more preferably H: © Ra is H, (Ci.10 alkyl), (C210) alkenyl, (Cs-C4 + 4) aryl or (Cs-C, o) heteroaryl, preferably H or | (C1.10) alkyl, more preferably H; . Rs is (CH), NReRe: © n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, | Rg is (C + -10) alkyl, preferably (C4.2) alkyl; Rg is (C + -10) alkyl, preferably (C4.2) alkyl; | | Rs is H, halogen, (C4.40) alkyl, (Coo) alkenyl, (Cs-Cig) aryl, (Cs-Cio) heteroaryl or -O (C4-10) alkyl, preferably H, halogen, (C + +0) alkyl or —O (C + -40) alkyl, more preferably H or | Halogen; | Rs is H, halogen, (C4.40) alkyl, (Czso) alkenyl, (Cs-Ca) aryl, (Co-Co) heteroaryl or —O- (C4.10) É alkyl, preferably H, halogen, (C4 .0) alkyl or -O (C ++ 0) alkyl, more preferably H or. Halogen; a Rs is H, halogen, (C4.40) alkyl, (C2-10) alkenyl, (Cs-Cya) aryl, (Cs-C40) heteroaryl or -O (C + 40) | Alkyl, preferably H, halogen, (C + -10) alkyl or -O (C + 10) alkyl, more preferably H or -O (C | 10) alkyl; . Rz is H, halogen, (C4.10) alkyl, (C2-10) alkenyl, (Cs-C44) aryl, (Cs-C10) heteroaryl or —O (C + -40) É alkyl, preferably H, halogen, ( C + -10) alkyl or -O (G410) alkyl, more preferably H or -O- (C-. | 10) alkyl; | where the amine according to formula (1) can optionally also be used in the form of a salt, for use in the treatment of atypical pneumonia. ;

In a further aspect, the invention relates to a carbonic acid adduct (KA) É comprising at least one structural element according to the general formula (II), (III) and / or È (IV) É

Rs "Ro | Rg CH, | A) n - | e x mol (S) |.

R4 | Re ~ _ |, Ro.

+ 3 2- e x moles (S) | CO3 |! Rg Ry | Ra |, Ro.

O n 2HCO; | © * Mol (S) | | ON Rs | Ra R7.

wherein in formula (11), (III), and (IV) |

Rı is H, (C + 10) alkyl, (C2.40) alkenyl, (Cs-C44) aryl or (Cs-C4o) heteroaryl, preferably H or 101724 | (C + -10) alkyl, more preferably H; | Ra is H, (C4.10 alkyl), (Co.0) alkenyl, (Cs-C, 4) aryl or (Cs-C + 0) heteroaryl, preferably H or fi (C + -10) alkyl, more preferably H. ; . Rs is - (CHa) ANReRe: 3 n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, | Rs is (C1.10) alkyl, preferably (C-2) alkyl; Rg is (C1.10) alkyl, preferably (C42) alkyl; © Rs is H, halogen, (C4.40) alkyl, (Coo) alkenyl, (Cs-Cya) aryl, (Cs-C, o) heteroaryl or -O (C4. | 10) alkyl, preferably H, halogen, (Ci.10) alkyl or —O (C + 10) alkyl, more preferably H or | Halogen; . Rs is H, halogen, (Crso) alkyl, (Czso) alkenyl, (Cs-C: a) aryl, (Cs-C10) heteroaryl or —O- (C410) È alkyl, preferably H, halogen, (Ci.10 ) Alkyl or -O (C4.10) alkyl, more preferably H or. Halogen; | Re is H, halogen, (Ci.10) alkyl, (Gz-40) alkenyl, (Cs-Cis) aryl, (Cs-C, o) heteroaryl or -O (C4.40) | Alkyl, preferably H, halogen, (C + -40) alkyl or -O (C1.10) alkyl, more preferably H or -O (C,. | Rz is H, halogen, (Ci.10) alkyl, (Co40) Alkenyl, (Cs-Cig) aryl, (Cs-Cig) heteroaryl or —O (C4-40) | alkyl, preferably H, halogen, (C + -40) alkyl or -O (Cy.10) alkyl, more preferably H. or -O (C4. É. Alkyl. x is 0.5 to 30; L for use in the treatment of atypical pneumonia.;

In a further aspect, the invention relates to a carbonic acid adduct (KA). comprising carbonic acid, at least one amine (AM) according to the general formula (I) and | at least one salt (S), | R4 O È Re Ra | O7 | > Re | where in formula (I) LU101724 0 Ry is H, (C; .10) alkyl, (Coo) alkenyl, (Cs-C, a) aryl or (Cs-C, o) heteroaryl, preferably H or. (C1.10) alkyl, more preferably H; = Ra is H, (C + -10 alkyl), (Cz10) alkenyl, (Cs-C44) aryl or (Cs-C40) heteroaryl, preferably H or; (C1.10) alkyl, more preferably H; | n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, É Rg is (C410) alkyl, preferably (C..2) alkyl, x Rg is (C1.10) alkyl, preferably (C4.2) Alkyl; | R4 is H, halogen, (Cii0) alkyl, (Caio) alkenyl, (Cs-Cis) aryl, (Cs-Cig) heteroaryl or -O (C, A 10) alkyl, preferably H, halogen, (C + -10 ) Alkyl or —O (C-.10) alkyl, more preferably H or | Halogen; | Rs is H, halogen, (Ci.10) alkyl, (Cz-10) alkenyl, {Cs-Cig) aryl, (Cs-Cio) heteroaryl or —O- (C4-40) | Alkyl, preferably H, halogen, (C + 4o) alkyl or -O (C + 40) alkyl, more preferably H or halogen; | Rs is H, halogen, (Ci10) alkyl, (Co.o) alkenyl, (Cs-C44) aryl, (Cs-C40) heteroaryl or -O (C410) | Alkyl, preferably H, halogen, (C + - + 0) alkyl or -O (C + -10) alkyl, more preferably H or -O (C,. © 0) alkyl: | Rz is H, halogen, (Ci.10) alkyl, (Co.40) alkenyl, (Cs-Cya) aryl, (Cs-C + 0) heteroaryl or —O (C4.10) | Alkyl, preferably H, halogen, (C + -10) alkyl or -O (C4-10) alkyl, more preferably H or -O (C,. | Ay: a where the at least one amine according to formula (I) optionally also in Form of a salt; can be used; can be produced by a process comprising the steps: | a) providing a solution (A) which contains at least one solvent and in which at least | CO dissolved in a solvent comprises | optionally b) dissolving a base (BA) which does not correspond to the amine (AM) in the solution (A) | with receipt of the solution (A1), | c) Dissolving the at least one amine (AM) in the solution (A) or (A1), while obtaining the | Solution (B), d) freezing the solution obtained after completion of step c), | e) Storage of the solution frozen in step d) at -100 to 0 ° C for no longer than 4 days; | for use in the treatment of atypical pneumonia. |

The invention further relates to a pharmaceutical composition-V101724 | comprising the amine, or carbonic acid adduct for use in the treatment of | atypical pneumonia. . Detailed description of the invention |

The invention is directed to an amine (AM) according to the general formula (I). | Ra 0 É 7 | N Rs.

where in formula (I) | R4 is H, (C ++ 4o) alkyl, (C2-10) alkenyl, (Cs-C44) aryl or (Cs-C40) heteroaryl, preferably H or; (C1-10) alkyl, more preferably H; | Ro is H, (C + -10 alkyl), (Cs.10) alkenyl, (Cs-Ci4) aryl or (Cs-C40) heteroaryl, preferably H or. (C + -10) alkyl, more preferably H; . n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, | Rg is (Cy.10) alkyl, preferably (C42) alkyl,. | Ro is (C + -40) alkyl, preferably (C + 2) alkyl; a R. is H, halogen, (Ci.i0) alkyl, (Coo) alkenyl, (Cs-C44) aryl, (Cs-Cio) heteroaryl or -O (C4. | 10) alkyl, preferably H, halogen, ( C; .4o) alkyl or —O (C + 40) alkyl, more preferably H or. Halogen; | Rs is H, halogen, (C + -4o) alkyl, (Cz-40) alkenyl, (Cs-C1a) aryl, (Cs-C10) heteroaryl or -O- (C ++ 0) 0 alkyl, preferably H, halogen , (Ciig) alkyl or -O (C4.40) alkyl, more preferably H or © halogen; | Re is H, halogen, (C ++ o) alkyl, (C2410) alkenyl, (Cs-C44) aryl, (Cs-Cy0) heteroaryl or -O (C4-40). Alkyl, preferably H, halogen, (C + -40) alkyl or -O (C + 10) alkyl, more preferably H or -O (C,. © 1) alkyl; |

Rz is H, halogen, (C4.40) alkyl, (Czso) alkenyl, (Cs-Cia) aryl, (Cs-Cro) heteroaryl or —O (C, .40} 4101724 | alkyl, preferably H, halogen, ( C + -10) alkyl or -O (C410) alkyl, more preferably H or -O- (C4. | Where the amine according to formula (1) can optionally also be used in the form of a salt, | for use in the treatment of atypical Pneumonia. 0

In one embodiment in formula (I) Ry, Ra, Rs, Ra, Rs, rice H; © Ra is - (CH2) uNRgRe; © n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, | Re is (C1.10) alkyl, preferably (C4.2) alkyl,. Rg is (C4.10) alkyl, preferably (C4.2) alkyl; .

In the present invention, definitions such as (C4.10) alkyl, such as | for the remainder R; defined by formula (I) that this substituent (radical) is a saturated alkyl radical> with a carbon number of 1 to 10. The alkyl radical can be either linear or branched and possibly be cyclical. Alkyl radicals that have both a cyclic and a linear | Have components also fall under this definition. The same applies to other | Alkyl radicals such as, for example, a Ci, alkyl radical. If appropriate, alkyl radicals can also start with | functional groups such as amino, hydroxy, halogen, aryl or heteroaryl simple or. be substituted several times. Unless otherwise indicated, alkyl radicals are preferred. does not have any functional groups as substituents. Examples of alkyl radicals are methyl, ethyl, n- © propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, iso-propyl (also 2-propyl or 1- | methylethyl called), iso-butyl, tert-butyl, sec-pentyl, neo-pentyl, 1,2-dimethylpropyl, iso-amyl, | iso-hexyl, iso-heptyl. |

In the present invention, definitions such as Cz4 mean alkenyl such as | defined for example for the radical R4 of formula (I) that this substituent (radical) is a | Is an alkenyl radical with a carbon number of 2 to 10 which has at least one unsaturated | Has carbon-carbon bond. The alkenyl radical can be either linear or branched L and optionally cyclic. Alkenyl radicals that have both a cyclic and a | have linear components also fall under this definition. The same applies to other |. Alkenyl radicals such as, for example, a C2, alkenyl radical. If appropriate, alkenyl radicals can also be | be monosubstituted or multiply substituted by functional groups such as amino, hydroxy, halogen, aryl or heteroaryl. Alkenyl radicals preferably have no further functional | Groups as substituents. Examples of alkenyl radicals 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. |

In the present invention, the definition of aryl means that it is a | aromatic or heteroaromatic radical is. An aromatic residue is a. aromatic cyclic hydrocarbon consisting of a ring or a ring system of | may consist of several condensed rings. The aromatic radical can, for example, | be monocyclic, bicyclic or tricyclic. The monocyclic E aromatic radical preferably forms a 5- or 6-membered ring. Preferably the bicyclic forms | aromatic ring a 9- or 10-membered ring. Preferably the tricyclic © aromatic ring forms a 13- or 14-membered ring. A definition like (Cs-C44) aryl means U101724 | that the aryl group comprises 5 to 14 carbon atoms. The aryl group preferably contains 3. up to 14, more preferably 4 to 6 carbon atoms. If appropriate, aryl radicals can also be used with. functional groups such as alkyl, alkenyl, amino, cyano, -CF ;, hydroxy, halogen, aryl or | Heteroaryl be monosubstituted or polysubstituted, preferably the aryl radicals do not have any | further substituents. Examples of aromatic radicals are phenyl and naphthyl. .

In the present invention, the definition heteroaryl means that it is a | heteroaromatic residue is. Heteroaromatic ring means that in one. aromatic radical, as defined above, the ring system of which is formed by carbon atoms ©, one or more of these carbon atoms by heteroatoms such as O, N or S. are replaced. A definition like (Cs-C, 0) heteroaryl is based on the corresponding definition for | / the aryl group, and means that the heteroaryl group has 5 to 10 atoms in the ring. . However, as defined above, 1 or more carbon atoms are replaced by heteroatoms. | This means that the (C; -C + 0) heteroaryl group has 5 to 10 atoms in the ring, but of which | not all are carbon atoms. Hence, for example, furanyl would be a Cs-heteroaryl group. ; If appropriate, heteroaryl radicals can also be mono- or polysubstituted with functional groups such as alkyl, alkenyl, amino, cyano, -CF ,, hydroxy, halogen, aryl or heteroaryl be, the heteroaryl radicals preferably have no further substituents. Examples of | heteroaromatic radicals which fall under the definition of aryl in the present invention are furanyl, thienyl, oxazolyl, pyrazolyl, pyridyl and indolyl. .

In the present invention, the definition means halogen such as. defined above for the radical R4 for formula (I) that it is a chlorine, bromine, iodine © or fluorine substituent. It is preferably a chlorine or fluorine substituent. |

The amine (AM) according to the general formula (I) is preferably selected from the group consisting of 2- (N, N-diethylamino) ethyl 4-aminobenzoate (procaine) and ethyl 4- (aminobenzoate (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).

The amines (AM) according to the general formula (I) and those specifically designated above | are in medical use as local anesthetics and are correspondingly commercial. available. .

As already stated above, atypical pneumonia, in particular. within this invention pneumonia caused by viruses, bacteria or fungi, | preferably by viruses. As already mentioned above, atypical pneumonia with the development of acute respiratory distress syndrome (ARDS) can result in | hyperinflammation in the lungs associated with atypical pneumonia. |

In one embodiment, the atypical pneumonia is caused by bacteria. | The bacteria are preferably selected from the group consisting of mycoplasmas, | Legionella, and Clamydia. |

A.

In a further embodiment, the atypical pneumonia is caused by fungi / 101724. The mushrooms are preferably selected from a group consisting of | Aspergillus, Pneumocystis, and Candida. |

In a further embodiment, the atypical pneumonia is caused by viruses. 4 The pneumonia is, preferably caused by a virus selected from coronaviruses, | Influenza Viruses, Adenoviruses, and Respiratory Syncytial Virus. The virus | is more preferred SARS-CoV-2. .

The invention further relates to a carbonic acid adduct (KA) comprising | at least one structural element according to the general formula | (I), (111) and / or (IV) | Ry 0 LS 2 O N - | e x mol (S) | R4 = N Rs | Rg Re; Re fer,) | 0 n 2- e x moles (S) | Ro R; |

Ra Rg |

Ra 0 hd | oO n 2HCO; | © * Mol (S) |

Ro R7 0 where in formula (11), (111), and (IV), R, is H, (C4.40) alkyl, (C2-40) alkenyl, (Cs-C44) aryl or (Cs-C + 0) heteroaryl, preferably H or | (C4.10) alkyl, more preferably H; | Ra is H, (C4.40 alkyl), (C2-10) alkenyl, (Cs-Cy4) aryl or (Cs-C, 0) heteroaryl, preferably H or |] (C + -10) alkyl, more preferably H; | Ra is - (CH) -NReRs; | n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, Rs is (C4.10) alkyl, preferably (C: 2) alkyl, | Rg is (C4.40) alkyl, preferably (C4.2) alkyl; . Rs is H, halogen, (Ci.0) alkyl, (Coo) alkenyl, (Cs-Cig) aryl, (Cs-C; 0) heteroaryl or -O (C4. | 10) alkyl, preferably H, halogen, ( C + 10) alkyl or —O (C1-40) alkyl, more preferably H or |. Halogen; É Rs is H, halogen, (Cr.10) alkyl, (Ca1o) alkenyl, (Cs-Cya) aryl, (Co-Cro) heteroaryl or —O- (© + .10) | Alkyl, preferably H, halogen, (C + 40) alkyl or -O (C; -40) alkyl, more preferably H or. Halogen; © Re is H, halogen, (C1-ao) alkyl, (Cz-40) alkenyl, (Cs-Cya) aryl, (Cs-Cig) heteroaryl or -O (C + -40) | Alkyl, preferably H, halogen, (C + -10) alkyl or -O (C4.0) alkyl, more preferably H or -O (C ;. | 10) alkyl; ; R; is H, halogen, (Ci.10) alkyl, (Cz-4o) alkenyl, (Cs-Cis) aryl, (Cs-Cio) heteroaryl or —O (C1-10) | Alkyl, preferably H, halogen, (Ci.10) alkyl or -O (C440) alkyl, more preferably H or -O (C4. | Alkyl: | x is 0.5 to 30; "| (S) is a salt ;. for use in the treatment of atypical pneumonia as defined above. |

In one embodiment in formula (1) Ry, Ra, Ra, Ra, Rs, Re is H; LU101724 É Rs is - (CH2) ANRaRs; | n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, A Rs is (C4-10) alkyl, preferably (C4.2) alkyl, |. Rg is (C4.40) alkyl, preferably (C4.2) alkyl; ©

The salt (S) comprises at least one cation selected from Na *, K *, Li ”, Mg” *, Zn ”,. Fe? *, Fe ** and Mn **, preferably Na *. Furthermore, this includes Salt (S) at least one anion | selected from CI, Br, J, F, 80,%, SOz ", HSO, HSO5," HCOz, COs ", PO", HPO, H, POy, | SIO, *, AIO, SiO5 and / or [AIO ») 12 (SiO2) a] ″, preferably CI and Br, particularly preferably |

The production of the carbonic acid adduct (KA) is also disclosed in WO2006 / 007835, | DE 10 2013 015 035 A1 and WO2019 / 048590 to which reference should be made here. ©

The invention further relates to a carbonic acid adduct (KA) comprising carbonic acid. at least one amine (AM) according to the general formula (I) and at least one salt (S), Ry 0 * Rs] where in formula (1). R4 is H, (C440) alkyl, (Cz40) alkenyl, (Cs-C44) aryl or (Cs-C40) heteroaryl, preferably H or; (C + -10) alkyl, more preferably H; | Ro is H, (C + -10 alkyl), (Cz40} alkenyl, (Cs-C44) aryl or (Cs-C10) heteroaryl, preferably H or (C1-10) alkyl, more preferably H; | Ra is (CHa ) NRgRg; | n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, | Rg is (C + -10) alkyl, preferably (C4.2) alkyl, | Rg is (Cq.10) alkyl, preferably (Cy2) alkyl; | Rs is H, halogen, (C4.40) alkyl, (Co.0) alkenyl, (Cs-Cya) aryl, (Cs-C, o) heteroaryl or -O (C-. | 10 ) Alkyl, preferably H, halogen, (C + -0) alkyl or —O (Cy.10) alkyl, more preferably H or | halogen; |

Rs is H, halogen, (Ci.10) alkyl, (C2.10) alkenyl, (Cs-C44) aryl, (Cs-C, o) heteroaryl or —O- (C, -16) U101724 1) alkyl, preferably H, halogen, (Ci.1) alkyl or -O (Ci.) alkyl, more preferably H or | Halogen; | Rs is H, halogen, (Ci.10) alkyl, (Cai0) alkenyl, (Cs-Cya) aryl, (Cs-Cyo) heteroaryl or -O (C4.40) | Alkyl, preferably H, halogen, (C + -10) alkyl or -O (G410) alkyl, more preferably H or -O (C + | Ry is H, halogen, (C4.40) alkyl, (Cz2-10) alkenyl, (Cs-Cis) aryl, (Cs-C10) heteroaryl or —O (Cy.10) | alkyl, preferably H, halogen, (C + -10) alkyl or -O (Ci.10) alkyl, more preferably H or - O (C + | where the at least one amine according to formula (I) can optionally also be used in the form of a salt /; E.g. for use in the treatment of atypical pneumonia, as defined above. EF

In one embodiment in formula (1) Ra, Ra, Rs, Ra, Rs, Rp is H; | Rs is - (CH2) NReRe; | n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,. Rg is (C1-10) alkyl, preferably (Cq.2) alkyl, © Rg is (C4-10) alkyl, preferably (C-4-2) alkyl; .

The salt (S) can be formed, for example, by an acid-base reaction of the base (BA) when carrying out step b) with the acid added to the amine (AM), if a | Acid addition salt of amine (AM) is used. The salt (S) can also be added directly to one of the. Steps a), b) and / or c) are added. The direct addition of the salt (S) is preferred, | if the amine (AM) is not used in salt form and / or step b) is not carried out | will. |

The carbonic acid adduct (KA) preferably remains at one temperature when stored from 2 to 10 ° C for at least 12 months, more preferably for at least 13 months, still | more preferably for at least 20 months, particularly preferably for at least 23 months, | and very particularly preferably stable for at least 27 months. |

The carbonic acid adduct (KA) is no longer considered stable when using IR spectroscopy, | especially in the solid of the carbonic acid adduct (KA), the specific bands of the | at least one amine (AM) can be detected. The specific IR bands of the | Amines are those bands which are also found in the infrared spectroscopic examination of the pure | Amine (AM) can be detected. As long as the amine (AM) is bound in the stable carbonic acid | Adduct (KA) is present, the specific IR bands of the amine (AM) are not detected. |

The loss of stability can in individual embodiments also with an increase | the pH value, or with the measurement of two melting / decomposition areas, i.e. one | Area that corresponds to the amine (KA) and a region that corresponds to the carbonic acid adduct (KA) | corresponds to go hand in hand. In the case of the carbonic acid adduct, which is at least partially | Decomposition into the amine (AM) and CO, and / or water, has become unstable, it can also lead to | a change in the solution behavior. The carbonic acid adduct that has become unstable |

14 | (KA) can prove to be more difficult to solve or at least partially incompletely solved | LU101724 | will. .

The carbonic acid adduct (KA) can be produced by a process comprising steps a), optionally b), c), d) and 6). 2

In step a) a solution (A) is provided which contains at least one solvent and in | the at least one solvent comprises dissolved CO. |

The solution (A) comprises at least one solvent and CO, in dissolved form. In the context of this invention, 0 CO is understood to mean carbon dioxide. Under CO, in dissolved form | are understood in the context of this invention, all forms of CO, which this when dissolving | comes in. For example, it is known for aqueous solutions that the dissolved CO in the | Solution among other things in equilibrium as CO ,, as carbonic acid, as single or double |. deprotonated carbonic acid, i.e. as hydrogen carbonate or carbonate. a

The solution (A) is obtained in the CO, in the at least one solvent | is introduced. The CO, can be in all suitable forms known to the person skilled in the art and introduced into the solvent. Preferably gaseous or frozen CO, in the form of dry ice, more preferably gaseous CO, is added to the solvent | brought in. Preferably the gaseous CO, or frozen CO, has at least | Food grade, more preferably a grade suitable for pharmaceutical use | is. The gaseous and / or frozen CO 2 used preferably has a degree of purity. of at least 99.5%, more preferably 99.9%. ©

In the context of this invention, food quality preferably means that the | relevant provisions of German and European food law are met. © These preferably include the vo (EG) | No. 852/2004 and Regulation (EC) No. 178/2002 as well as Regulation (EC) No. 1333/2008 and Regulation (EU) | 231/2012. |

Preferably, pharmaceutical quality means that the relevant regulations. of the European Pharmacopoeia (Ph. Eur.). |

The CO, can also be introduced under pressure, especially if it is gaseous CO, is introduced into the solution. Bringing in under pressure means in this | Relation that a pressure greater than atmospheric pressure, preferably greater than 1.01325 | bar, is used. For this purpose, the introduction of the CO; into the solvent in | take place in a container that isolates the solvent from the environment in such a way that in | a pressure can be generated in the container, in particular by supplying the CO 2, the | above atmospheric pressure, preferably above 1.01325 bar. The introduction of the | CO, in the solution, especially in gaseous form, can be carried out in one step or at intervals | take place. |

The person skilled in the art can use any suitable solvent in step a). | A polar protic solvent is preferably used as the solvent, more | the solvent is preferably water. The solvent can be used depending on the intended use Purpose of the carbonic acid adduct (KA) in various degrees of purity | can be used. For example, water with the degree of purity “Aqua ad iniectabilig‘ / 101724 | be used if the carbonic acid adduct (KA) for pharmaceutical-medical | Purposes to be used. |

Step a) can comprise the substep a1), wherein the solvent, preferably before | the introduction of the CO », is cooled to 3 to 8 ° C, preferably to 5 ° C. The cooling can take place by means of all methods known to the person skilled in the art and identified as suitable. | For example, the cooling by storing the solvent for one can be sufficient. in a refrigerator for a long time until the solvent reaches the target temperature. External cooling can also be used, for example. ©

Step a) can comprise the substep a2), wherein the CO, in the solvent | is introduced, preferably up to a saturation concentration of 3 to 10 © g / l, more preferably up to a saturation concentration of 4.5 to 7.5 g / l based on the | Total volume of the solution. The pH of the solution after saturation with CO is preferably <3.0 to <6.0, even more preferably <4.3 to = 4.8. Preferably the CO, in | Substep a2) solved under pressure, the pressure being 1.5 to 10 bar, more preferably 1.9 to 7 bar, E even more preferably 2 to 5 bar. |

Step a) can comprise substep a3), the preferably in substep a2) | obtained solution (A) at 1 to 10 ° C, preferably for at least 30 min, more preferably for | at least 50 minutes, more preferably for at least 60 minutes; up to a maximum of 5d (120h) | is stored. The solution (A) preferably obtained in sub-step a2) is preferably used at 3. to 8 ° C for at least 30 minutes, more preferably for at least 50 minutes, even more preferably | for at least 60 min; stored up to a maximum of 5d (120h). |

Preferably, step a) comprises all substeps a1), a2) and a3). |

The substeps a1), a2) and a3) are preferably followed in the order a2). a1) and a3) follows a2). |

Optionally, step b) can be carried out, wherein the base (BA), which is not the. Amine (AM) corresponds to, in the solution (A), is dissolved to obtain the solution (A1). | The base (BA) is preferably a hydrogen carbonate or a carbonate, more preferably a hydrogen carbonate, even more preferably sodium hydrogen carbonate. |

In step c) the at least one amine (AM) is dissolved in solution (A) or (A1) to obtain solution (B). |

The at least one amine (AM), as defined above, can in step c) both in | neutral form as well as in the form of a salt can be used. Optionally, the | at least one amine (AM) also as a mixture of the neutral form of the amine (AM) with the | Salt form of the amine (AM) can be used. Therefore, the at least one amine (AM), the | neutral amine (AM) and / or the salt form of the at least one amine (AM). | The salt form of the at least one amine (AM) is preferably a | Acid addition salt, preferably the acid addition salt is a hydrochloride, hydrobromide, | Hydroiodide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, hydrotosylate, | Hydroacetate, hydroformate, hydropropanoate, hydromalonate, hydrosuccinate, hydrofumarate, |

16 \ Hydroxalate, hydrotartrate, hydrocitrate, hydromaleate, more preferably a hydrochloride or 101724 a hydrobromide, even more preferably a hydrochloride of the at least one amine (AM). Ë

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

Step c) can comprise the substep c2), wherein the at least one amine (AM) in | Solution (A), or if step b) is carried out, in solution (A1) to obtain solution (B) | is resolved. |

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

In a further possible embodiment, the molar ratio of the amine © (AM) to the base equivalents of the base (BA) when performing step b) in solution (B) 2 is 0.8: 1 to 1.5: 1, preferably 1.2: 1, more preferably 1: 1. Base equivalents means in this. Context that when using a monovalent base, such as NaHCO; the molar ratio of the base (BA) to the amine (AM corresponds to the ratio given above. When using a divalent base (BA), such as Na: CO4, | based on the amount of substance in moles of the base (BA) is relative To use a monovalent | base, only half the amount of base is required to introduce the same amount of base equivalents. For example, with a ratio of 1: 1, when using 10 | mmol amine (AM), 10 mmol NaHCO; but only 5 mmol Na; COs. |

In a further embodiment, step b) is carried out and in substep c1) the | Amine (AM) added in the form of the acid addition salt, the amine (AM) with the on it. bound acid, is added in such an amount that the amine (AM) | Bound acid that is able to neutralize the base (BA) to such an extent that the solution (B) has a | Adopts a pH value of 6 to 8. |

Step ¢) can comprise the substep c2), solution (A) being added to solution (B) while obtaining solution (B1). |

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

Step c) can comprise the substep [3), where the solution (B) or when carried out | of substep c2), the solution (B1) is enriched with CO. Preferably the solution |. (B) with 2.5 g / l to 9 g / l, more preferably with 5 to 7.5 g / l CO; enriched. .

Step c) can comprise substep c4), where solution (B) or, if substep c2) is carried out, solution (B1) at 1 to 10 ° C, preferably 3 to 8 ° C, for | is stored for at least 1 hour, preferably 24 to 120 hours, more preferably 24 to 72 hours. |

Step c) can comprise substep c5), the solution (B) or, when performing substep b2), the solution (B1) with CO, preferably to a total concentration of | at least 6 g / l, more preferably at least 10 g / l, even more preferably at least 12 g / l, | very particularly preferably at least 14 g / l and most preferably at least 15 d / V101724. is enriched. In sub-step c5), a further 0.4 to 4.7 g / l, more preferably 1 to 3.5 g / l CO, are preferably introduced or added to the solution (B) or © (B1) until the required total concentration is reached . solved. .

The term “Total Concentration®” here refers to the total concentration of | dissolved CO, in solution (B) or (B1), including the CO ,, that in the carbonic acid adduct. (KA) is bound. The total concentration results additively from the increase in weight of the. Solution by the added CO, in all previous enrichment steps a2) | and / or c3), if stated, and c5), without taking CO »into account, which is optionally in the form | of hydrogen carbonate or carbonate as base (BA) is added to the solution. |

The enrichment of the solution (B) or the solution (B1) in sub-step [5) with CO, to the | The total concentration required can be at a pressure of 2.5 to 10 bar, preferably 4 | up to 10 bar, more preferably from 5 to 10 bar, even more preferably at 6 to 10 bar, very particularly preferably at 6.5 to 10 bar. Preferably the solution has | (B) or (B1), when enriching with CO; in sub-step c5) a temperature of 3 to 8 ° C, more | preferably from 5 ° C. |

The enrichment of solution (B) or (B1) in sub-steps c3) and c5) can take place in the same way as described for step a). .

Preferably, the pH of the solution (B) or, when carrying out the | Sub-step c2), the solution (B1) after performing step c5) <7.0. ©

Step c) preferably comprises all substeps c1), c2), [3), c4) and c5). E.

The substeps c1), c2), c3), c4) and c5) are preferably in the order c2) a follows c1), c3) follows c2), c4) follows c3), c5) follows c4) carried out. |

In step d) the solution obtained after completion of step c) is frozen. | Preferably in step d) the solution B) or after carrying out the substep c2), the. Solution (B1) frozen. ||

The solution, preferably solution (B) or (B1), which is subjected 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 very particularly preferred. at least 15 g / l. |

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

The freezing of the solution obtained after the completion of step c), preferably | Solution (B) or (B1) can in principle after all known to the person skilled in the art and as | appropriately identified methods. For example, the freezing caused by the. Transferring the solution obtained in step c) into a suitable vessel that takes place in a |

18 | Coolant is immersed. The vessel is preferably in the shape of a piston. Preferably datU101724 appears. Vessel in which the solution obtained in step c) is at an angle of 40 ° into the. Cooling medium. The cooling medium can, for example, from a solvent such as methanol. Ethanol or acetone are made up by adding dry ice, or suitable | Cooling equipment, such as cryostats, is brought to the desired temperature. .

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

Preferably, the solution obtained after the completion of step c), preferably | Solution (B) or (B1), within 0.3 to 60 minutes, more preferably within 1 to 30 minutes Minutes, even more preferably within 1.1 to 10 minutes, particularly preferably | Frozen within 1.5 to 5 minutes. |

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

Preferably, the vessel in which the | Solution, preferably solution (B) or (B1), is located in the freezing process. Cool medium, with 10 to 1000 rpm, more preferably with 50 to 600 rpm, even more preferably with. Rotates 100 to 400 rpm and particularly preferably at 200 to 300 rpm. |

The freezing can be carried out according to the shell freeze process. |

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

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

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

Storage at the defined temperature can in principle be carried out in any of the person skilled in the art; known cooling device take place. For example, storage can be carried out in a P freezer or a freezer room. |.

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

Preferably, in step f) the water from the solution stored in step e), 3 preferably solution (B) or (B1) up to a residual content of <0.8% by weight, is more preferred removed up to a residual content of <0.1% by weight based on the total weight of the dried 101724] carbonic acid adduct (KA). A.

Preferably, in step f), CO which is not bound in the carbonic acid adduct (KA) is removed. of the solution stored in step e), preferably (B) or (B1), up to a residual content of <© 0.8% by weight, more preferably up to a residual content of <0.1% by weight, based on the . Total weight of the dried carbonic acid adduct (KA) removed. |

The drying can be carried out using all methods known to the person skilled in the art and identified as being suitable. Drying is preferably carried out by means of freeze drying, | also called lyophilization. If the © freeze-drying process is used, step d) represents the freezing step and step e) represents the ripening step. |

The pressure during drying is preferably from 0.01 to 30 mbar, preferably from 0.02 to 20 mbar, more preferably from 0.03 to 10 mbar, even more preferably from 0.03 mbar up to 0.5 mbar and very particularly preferably 0.05 to 0.1 mbar. Preferably the pressure. Maintained throughout the drying process. Preferably, the above | defined pressure during drying within 7 hours, more preferably within 5 hours. and particularly preferably achieved within 4 hours from the start of evacuation. |

The person skilled in the art can determine the end point of drying from the temperature profile records. The total drying time is preferably É. in step f) 10 to 60 hours, more preferably 30 to 55 hours, particularly preferably 41 to 52 hours. The | Total drying time is defined as the time between the completion of storage in. Step e) and the termination of the drying in step f). |

The temperature is preferably 0 | during the entire drying in step f) to 20 ° C, preferably 4 to 18 ° C, more preferably 8 to 16 ° C. .

The invention further comprises a pharmaceutical composition (PZ) | comprising the amine (AM), or the carbonic acid adduct (KA) as described above for | Use in the treatment of atypical pneumonia. .

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

The pharmaceutical preparation (PZ) in the context of this invention is basically understood to mean a composition which contains the amine (AM) or carbonic acid adduct. (KA) and, in addition, may include other auxiliaries or additives that are necessary for a | pharmaceutical-medical use are suitable. |

In addition, the pharmaceutical preparation (PZ) can comprise further bases which | do not correspond to the amine (AM) and can be different from the base (BA). Of the . In principle, the person skilled in the art can use the additives depending on the intended use choose. He will take into account the desired form of application. |

The pharmaceutical preparation (PZ) can in principle be in any suitable | In the form of administration. For example, the pharmaceutical preparation (PZ) can be written in L

| Capsule form, as a tablet, as a solution, as an ointment, cream, gel, paste, envelope paste or + U101724 | active substance-containing plaster are present. 8th

The pharmaceutical preparation (PZ) can in principle be in any suitable | Application form are applied. The person skilled in the art will select a suitable form of administration © according to the intended form of administration. For example, the pharmaceutical preparation (PZ) can be administered orally, inhalatively, by injection, as a plaster, cutaneously comprising | at least dermal application, application to the eye, nasal application, the | rectal use and vaginal use; administered. |

When preparing the pharmaceutical preparation (PZ), the person skilled in the art can. basically use the methods known in the prior art. |

The temperature of the mixture of the carbonic acid adduct (KA) © and the auxiliaries used and optionally further bases during the preparation is preferably | of the pharmaceutical preparation (PZ) less than 60 ° C, preferably less than 50 ° C, | more preferably 0 to 50 ° C. .

When preparing the pharmaceutical preparation (PZ), preferably in | Ointment form, dispersion can also be used, preferably by means of an ointment maker ©. A speed of <2000 rpm is preferably used here. |

The carbonic acid adduct (KA) can before processing to the following | described oral dosage forms such as tablets or capsules or semi-solid © dosage forms, alone or in the presence of other auxiliaries or bases to form a powder. be rubbed. The person skilled in the art can in principle make use of the technical means that are suitable and known for the respective purpose. So can for attrition steps. for example mortars or similar suitable devices can be used. Preferably at. the trituration steps a technical aid is used that the mechanical | Keep pollution of the carbonic acid adduct as low as possible. Preferably the rubbing takes place | with a mortar. |.

The powder obtained in this way can then, for example, be pressed into tablets or in | Commercially available capsules filled or mixed with suitable auxiliaries and turned into semi-solid | Dosage forms are processed. |

One embodiment of the pharmaceutical preparation (PZ) relates to a | pharmaceutical preparation (PZ) comprising the carbonic acid adduct (KA) and oral | is applied. In this embodiment, the pharmaceutical preparation (PZ). preferably in capsules, more preferably in hard gelatine or cellulose capsules, especially | preferably administered in hard gelatine capsules. The pharmaceutical preparation can likewise. (PZ) are administered in tablet form in this embodiment. |

The pharmaceutical preparation (PZ) preferably comprises in this. Embodiment at least one auxiliary (H), preferably selected from starch, | in particular corn starch and / or rice starch, dextran, cellulose ester and SiO ». |

In addition, the pharmaceutical preparation (PZ) in this AusfilhrungsforrhU101724 | comprise at least one base (BA1) which does not correspond to the amine (AM) and is identical or. is different from the base (BA). The base (BA1) is preferably selected from NaHCO; | or KHCO ;, more preferably NaHCO. L.

[00104] The above statements preferably also apply to this embodiment General information on the pharmaceutical preparation (PZ), especially for the | Preparation of the pharmaceutical preparation (PZ) as far as for this embodiment | technically applicable. ;

In this embodiment, the pharmaceutical preparation (PZ) preferably comprises | a) 1 to 99% by weight, more preferably 15 to 95% by weight of the carbonic acid 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 auxiliary (H) based on the total weight of the | pharmaceutical preparation. |

Another embodiment of the pharmaceutical preparation (PZ) relates to | a semi-solid pharmaceutical preparation (PZ) comprising the carbonic acid adduct (KA), | and is applied cutaneously. The pharmaceutical preparation (PZ) in this embodiment | can for example in ointment form, as a cream, as a gel, as a paste, envelope paste or. active ingredient-containing plaster are applied. |

[00107] The above statements preferably also apply to this embodiment General information on the pharmaceutical preparation (PZ), in particular also for the E. Manufacture of the pharmaceutical preparation (PZ) as far as for this embodiment. technically applicable. |.

In this embodiment, the pharmaceutical preparation (PZ) comprises | preferably at least one auxiliary (H1) selected from paraffins, in particular thick and | low-viscosity paraffins, wool wax, wool wax alcohols, hydrophobic base gel, vegetable | Oils, animal fats, synthetic glycerides, liquid polyalkylsiloxanes, waxes, petrolatum and | Starch, especially corn starch, preferably petroleum jelly. |

Under viscous paraffins (Paraffinum subliquidum) are understood paraffins © which have a viscosity of 110 to 230 mPas, while thin paraffins |. Paraffins (Paraffinum perliquidum) have a viscosity of 25 to 80 mPas. |

The pharmaceutical preparation (PZ) in this preferably comprises | Embodiment: | a) 0.1 to 40 wt .-%, preferably 0.4 to 10 wt .-% of the carbonic acid adduct (KA) and. b) 60 to 99.9% by weight, preferably 80 to 96% by weight, of the auxiliary (H1) based on. comprises the total amount of the pharmaceutical preparation (PZ). |

Another embodiment of the pharmaceutical preparation (PZ), the dad / 101724 | Carbonic acid adduct (KA), relates to a pharmaceutical preparation that is parenteral, | is administered nasally and / or inhalatively. )

The general information on the pharmaceutical preparation (PZ) given above preferably also apply to this embodiment, in particular also to the © preparation of the pharmaceutical preparation (PZ) as far as for this embodiment; technically applicable. |

The pharmaceutical preparation (PZ) is preferably located in this | Embodiment as a solution (A2), comprising the carbonic acid adduct (KA), dissolved CO,. and at least one auxiliary substance (H2). ©

The auxiliary (H2) is preferably selected from an alkali halide or | Alkaline earth halide, more preferably NaCl and MgCl, even more preferably NaCl. The auxiliary. (H2) can be identical to the salt (S). Quantities related to the auxiliary substance (H2), if this is identical to the salt (S) in individual embodiments, relate in the context of this invention to additional amounts of the auxiliary substance (H2) that are not in the form of the © salt (S) as part of the carbonic acid adduct (KA) in the pharmaceutical preparation (PZ) È. |

The solution (A2) is preferably made by introducing CO, into a | Solvent obtained. Preferably the solvent is water. Preferably the | CO, for the preparation of the solution (A2) at a temperature of 0 to 8 ° C, more preferably at 0. Brought into the solvent up to 5 ° C. The CO »can be in the form of the gas as well as in solid form Form, for example as dry ice, can be introduced into the solvent. Preferably the | CO, introduced into the solvent in the form of the gas. The CO, even under pressure, can be up to | be introduced into the solution to achieve the desired concentration, as described above for sub-step a2). |

Preferably, the CO, to prepare the solution (A2), up to one; Concentration of at least 3 g / l, more preferably up to 4 g / l, even more preferably from 4 g / l to 8. g / l introduced into the solvent. |

Preferably, the CO »that is used to prepare the solution (A2) | a purity of at least 99.9%, more preferably a quality suitable for | pharmaceutical applications as defined above. |

In this embodiment, the pharmaceutical preparation (PZ) preferably comprises, insofar as it is produced by dissolving the carbonic acid adduct (KA) in the solution | (A2) is obtained, | a) 0.05 to 100 mg / ml, more preferably 0.08 to 50 mg / ml of the carbonic acid adduct (KA) | b) 0 to 20 mg / ml, more preferably 3 to 10 mg / ml of the excipient (H2) | based in each case on the total volume of the pharmaceutical preparation (PZ). M.

23 | EXAMPLES OF THE INVENTION LU101724:

1. Embodiment 1, production of the carbonic acid adduct (KA) |

1.1 Materials: | ® Amine (AM): 68.8 to 110.1 g procaine hydrochloride (e.g. pure, for use as a pharmaceutical active ingredient; Ph. Eur. Or in a quality that is suitable for this purpose) ® Base (BA): 22, 2 to 33.9 g sodium hydrogen carbonate (eg pure or in a quality | which is suitable for this purpose), | © Solvent: 630 to 900 ml water (Aqua ad iniectiabilia) © CO ,: at least 12.0 g / l carbon dioxide from pressurized gas cylinders (CO, of suitable quality). © Dry ice for the preparation of cold mixtures and for cooling: ® Methanol, techn. for the preparation of cold mixtures;

1.2 Step a) / A cleaned plastic pressure bottle is filled with water (e.g. Aqua ad iniectiabilia) up to the / mark (approx. 800 to 900 ml) and for at least 1 hour in the refrigerator (3 to 8 ° C) | or precooled to 5 ° C using external cooling. | A carbonic acid solution saturated with carbon dioxide is prepared. For this, CO,; Intermittently introduced into the pre-cooled water under pressure (1.6 to 8 bar). The hissing (gas escaping through the pressure relief valve) indicates that the solution is saturated with CO. The ; Saturation is controlled by weight, up to 4.0 to 6.0 g CO, (corresponding to 4.5 to 7.5 g / l); are resolved. The saturated solution has a pH of = 4.3 to 4.8. This / carbonated water is immediately closed and for at least 1 hour in the | Stored in the refrigerator. |

1.3 Step b) | 21.2 g of sodium hydrogen carbonate are placed in a second plastic pressure bottle, with | 320 ml of chilled water containing CO are added and dissolved while swirling. |

1.4 Step c) | The equivalent amount of solid procaine hydrochloride is added to this solution at | given a constant temperature, whereby an almost neutral solution is formed, which after | Add another 320 ml of cold carbonated water a clear, weakly acidic | Solution results. The solution is enriched with CO. The solution prepared in this way is used for | stored in the refrigerator for at least 1 hour. The solution is then conditioned again with CO, until a CO, concentration of 12g / l is reached in the solution. The pH value is checked using the pH indicator sticks. The pH value is <6.6.

1.5 Step d) Round-bottom flasks are pre-cooled. For freezing, the reaction solution is measured in a precooled measuring cylinder, transferred in portions into round-bottom flasks and immersed in a dry ice / methanol cold mixture (<-60 ° C) according to the shell freezing process within - Trg RE of 1.5-3, Frozen for 5 min per flask (~ 200 rpm). The angle of immersion of the piston ak} 101724 | Rotary evaporator is set to approx. 40 °. ;

1.6 Step e) | The flasks with the goods frozen in this way are closed with a ground-joint stopper and | Intermediate storage in a freezer at -15 to -20 ° C for 2 to 4 days. |

1.7 Step f) | The flasks, which are heated in this way, are encased in styrofoam containers that are pre-cooled and | immediately individually to an evacuated (0.060 + 0.01 mbar, approx. -46 ° C, leak test) | Freeze-drying system, connected via a flexible rubber cone. The valve taps É are carefully opened and the individual flasks are placed under vacuum. Finally, all pistons must be evacuated. | To monitor the process, temperature sensors are placed at the bottom of the styrofoam jacket, | which record the entire temperature profile during the entire drying process. Before the | At the start of the lyophilization, the temperature sensors show temperatures of <-5 ° C. | During the lyophilization the pressure is 0.07 + 0.02 mbar. This sublimation pressure is reached within 4 hours and maintained during the entire lyophilization time. The | The cooling chamber is kept at 9 to 15 ° C during the entire drying process. The endpoint | the lyophilization is determined graphically from the temperature history records. The | Total drying time was a maximum of 52 hours. The dry lyophilizate is in a; Brown glass jar with twist-off lid transferred, provided with a desiccant bag and stored in the refrigerator at 0 to 15 ° C. |

2. Examples for pharmaceutical preparations (PZ))

2.1 Capsules and tablets | The following is an example of the composition of the inventive | pharmaceutical preparation (PZ) in the embodiment as a capsule or tablet fir | Procaine described as an amine (AM). Commercially available | Push-fit capsules in the commercially available sizes (5 to 000), which are marked with the | Powder containing carbonic acid adduct (KA), comprising procaine as amine (AM) (trituration of the 'active ingredient carbonic acid adduct (KA), comprising procaine as amine (AM) if necessary with additives,' fillers, and flow regulators). The carbonic acid adduct (KA) became | produced according to example 1. It has been shown that hard gelatin capsules compared to | Cellulose capsules are more suitable in terms of stability. The filled hard gelatine capsules, for example for hard gelatine capsules with 60 and 100 mg of active ingredient according to | Table 1, even after 12 months of storage in the refrigerator, there are no changes and are | thus stable (Figure 2). The stability was examined by means of IR spectroscopy. So in the case of | of the hard gelatine capsules within the 12 month period no procaine by IR spectroscopy; detected, while for cellulose capsules a procaine band in the | IR spectrum was measured. The content was determined at room temperature using UV / VIS spectroscopy. According to Pharmacopoeia Europaea point |

2.9.6 based on the total content including by-products, a tolerance range of +15% | required. |

The applicable and generally accepted pharmaceutical rules for the manufacturer / 191724 | of (prescription) drugs used (for example Pharmacopoea Europaea, Deutscher 'Arzneimittel-Codex). | Table 1: Example composition of capsules with NaHCO3z addition and carbonic acid adduct (KA) as active ingredient ’produced according to embodiment 1. | Filler, e.g. corn starch 120 120 'Table 2: Example composition of tablets with NaHCO4 addition and carbonic acid adduct (KA) as active ingredient | produced according to embodiment 1. | Filler, e.g. corn starch 2.5 5 85 10, including SiO; |

2.2 Ointments | The following is the composition of the pharmaceuticals according to the invention. Preparation (PZ) in the embodiment as an ointment, for example procaine as an amine (AM) in the | Carbonic acid adduct (KA) explained. When preparing the ointment, the applicable and 2 generally accepted pharmaceutical rules for the production of (prescription) drugs © are applied (for example Pharmacopoea Europaea, German Pharmaceutical Codex). In the . In the manufacture of the ointment, greater shear forces are avoided. In addition, the temperature | Also kept locally below 60 ° C during preparation. This is how the ground carbonic acid | Adduct (KA) comprising procaine as amine (AM) in a mortar or a fancy bowl, which are temperature-controlled by means of a water bath at 40 to 45 ° C, into the | Ointment base, for example Vaseline, introduced. Alternatively, you can also use | electrical mixed systems possible, as they are in the context of normal pharmacy operations for the | Use. | Table 3: Example composition of ointment and carbonic acid adduct (KA) as active ingredient prepared according to. Embodiment 1. | Ointment base ig] {e.g. 5 5 5 5 5 | Vaseline) |

26 |

2.3 Parenteral solutions | For the preparation of a parenteral solution comprising the carbonic acid adduct (KA) | Procaine containing amine (AM) is poured into a suitable vessel with a stir bar or | Similarly, the required amount of water (Aqua ad iniectabilia) is cooled to approx. 5 +3 ° C and | leave at this temperature. The water is filled with gaseous carbon dioxide. required quality enriched to approx. 3.2 g / l. In this CO, -containing water the | Corresponding amount of carbonic acid adduct (KA) comprising procaine as amine (AM) and 1 sodium chloride dissolved for an isotonic content. |

Alternatively, water heated to approx. 5 + 3 ° C is used under pressure in a | closed system with CO, enriched in such a way that there is a significant excess | (4.5 to 7.5 g / l). The corresponding amounts of carbonic acid adduct (KA) including procaine as amine (AM) and sodium chloride are also added to this carbonated water. given. /

This cold with the carbonic acid adduct (KA) comprising procaine as amine (AM) | and sodium chloride provided solution is provided under suitable spatial conditions. sterile-filtered and filled into appropriate vials. The applicable and generally customary pharmaceutical rules for the production of (prescription) drugs are applied à (for example Pharmacopoea Europaea). Ë Table 4: Example compositions for parenteral preparations with added NaCl and carbonic acid adduct | (KA) produced as an active ingredient according to embodiment 1. | | I - ee T i pom eee 7}

3. Solubility in octanol |

There solubility tests were carried out in octanol and the content in the; organic phase UV / VIS spectroscopy and the pH values examined. | Table 5: Solubility of different dosage forms | Carbonic acid adduct of 74% 7.5 | Procains |

LU101724 |

The pH values determined show that the carbonic acid adduct of procaine û as such and not converted into procaine and is soluble in this form in the organic phase | and is therefore permeable to the membrane. The UV / VIS spectroscopic © content measurement also shows that the carbonic acid adduct of procaine is lipophilic; is more similar to procaine than ProcHCI. So it behaves like the basic component | - the lipid-soluble base, which is formed depending on the pH value. The carbonic acid | Procaine adduct exhibits this property regardless of the pH value, i.e. it does not have to be converted into the lipophilic form by changing the pH value, as is the case with ProcHCI. | ProcHCI has a significantly lower value, which, at 8%, is of the order of magnitude for the. Protein binding of 6%. ;

LU101724 |.

REFERENCES |.

[1] E. Mutschier. G. Geisslinger, H.K. Kroemer, S. Menzel, P. Ruth; , Mutschler Medicinal Effects, Pharmacology, Pharmacological Effects, Toxicology “, Scientific | Publishing company, 10th edition, 2013 |

[2] https: // flexikon.doccheck.com/de/Acute respiratory _distress_syndrome, accessed on 23. March 2020.

[3] Pecher S., Bôttiger B.W., Graf B., Hollmann M.W .; Anesthesiologist 2004; 53; 316-325 ©

Claims (14)

CLAIMS A 1. An amine (AM) according to the general formula (I): R4 0 | 07; N Rs | Ro Rs; wherein in formula (I); Ry is H, (C4-10) alkyl, (G2-10) alkenyl, (Cs-C14) aryl or (Cs-Cy0) heteroaryl, preferably H or (Ci. | 10) alkyl, more preferably H; | Ra is H, (C + -10 alkyl), (C240) alkenyl, (C5-C44) aryl or (Cs-C, o) heteroaryl, preferably H or (C-. 10) alkyl, more preferably H; . Rs is - (CHa) NReRe: | n is 1 to 5, preferably 1 to 3, more preferably 1 to 2, | Re is (Cr10) alkyl, preferably (C1.2) alkyl, | Re is (C + -10) alkyl, preferably (C4.2) alkyl; 8 R, is H, halogen, (C-10) alkyl, (Ca10) alkenyl, (Cs-Cia) aryl, (Cs-Cro) heteroaryl or -O (C + 10) alkyl, | preferably H, halogen, (C4.0) alkyl or —O (C410) alkyl, more preferably H or halogen; © Rs is H, halogen, (C + 10) AIKkyl, (C240) alkenyl, (Cs-C4a4) aryl, (Cs-C40) heteroaryl or —O- (C4.10) alkyl, [preferably H, halogen, ( © C1-10) alkyl or -O (C1.10) alkyl, more preferably H or halogen; , Re is H, halogen, (C + 10) alkyl, (C240) alkenyl, (Cs-Cys) aryl, (Cs-C + 0) heteroaryl or -O (C4.10) alkyl, 2 preferably H, halogen, (C; -40) alkyl or -O (C4.0) alkyl, more preferably H or -O (C-40) alkyl; | Ry is H, halogen, (C + 40) alkyl, (C240) alkenyl, (Cs-C4a) aryl, (Cs-C + 0) heteroaryl or -O (C + 40) alkyl, | preferably H, halogen, (C + -10) alkyl or -O (G440) alkyl, more preferably H or -O- (C.10) alkyl; | where the amine according to formula (I) can optionally also be used in the form of a salt; for use in the treatment of atypical pneumonia. ; 2. A carbonic acid adduct (KA) comprising at least one structural element according to the | general formula (II), (III) and / or (IV) | Ra |, Ro. R4 0 ~~ | A) n - | e x mol (S) | HCO; | a Rs; Res |, Ro | 0 n 2- e x mol (S) È COs | Ra Ry | Rs "Ro. Ra 0 ~~ 2 Re or,). 0 n 2HC07 e x mole (S) | > »Rs | where in formula (11), (111), and (IV) | Ry is H, (Cr.10) alkyl, (Ca0) alkenyl, (Cs-C1a) aryl or (Cs-Cro) heteroaryl, preferably H or k & 1.01724 | 10) alkyl, more preferably H; . Ra is H, (C4 + -10 alkyl), (C2-10) alkenyl, (Cs-C14) aryl or (Cs-C10) heteroaryl, preferably H or (C-. 10) alkyl, more preferably H; | Ry is (CH) NReRe A n is 1 to 5, preferably 1 to 3, more preferably 1 to 2.0 Ra is (C4.40) alkyl, preferably (C1.2) alkyl, | Ro is (C1.10) alkyl, preferably (C4.2) alkyl; | R, is H, halogen, (Ci.10) alkyl, (C240) alkenyl, (Cs-C4a) aryl, (Cs-C + 0) heteroaryl or -O (C + 40) alkyl, | preferably H, halogen, (C + 10) alkyl or —O (G440) alkyl, more preferably H or halogen; | Rs is H, halogen, (Cq.10) alkyl, (C210) alkenyl, (Cs-C, 4) aryl, (Cs-Cyg) heteroaryl or -O- (C10) alkyl, 2 preferably H, halogen, (C4 .0) alkyl or -O (C4.o) alkyl, more preferably H or halogen; Re is H, halogen, (Ci.10) alkyl, (Co.40) alkenyl, (Cs-C4a4) aryl, (Cs-C, o) heteroaryl or -O (C4.40) alkyl, preferably H, halogen , (C + .10) alkyl or -O (C4-40) alkyl, more preferably H or -O (C + 10) alkyl; | Ry is H, halogen, (C4.40) alkyl, (C240) alkenyl, (Cs-Cya) aryl, (Cs-C40) heteroaryl or -O (C + -10) alkyl, | preferably H, halogen, (C + .10) alkyl or -O (C + 10) alkyl, more preferably H or -O (C4.10) alkyl; | x is 0.5 to 30; . for use in the treatment of atypical pneumonia. ui 3. A carbonic acid adduct (KA) comprising carbonic acid, at least one amine (AM) according to A of the general formula (I) and at least one salt (S), || Re Ra | oo ”| where in formula (I) | R 1 is H, (C + -40) alkyl, (C240) alkenyl, (Cs-C + 4) aryl or (Cs-Cy0) heteroaryl, preferably H or (C-. | 10) alkyl, more preferably H; | Ra is H, (Cr.10 alkyl), (C2.10) alkenyl, (Cs-Cra) aryl or (Cs-Cio) heteroaryl, preferably H or 8101724 | 10) alkyl, more preferably H; . Ra is - (CH2) \ NRaRe: = n is 1 to 5, preferably 1 to 3, more preferably 1 to 2,) Rg is (C + 4-10) alkyl, preferably (C4.2) alkyl, 2 is Rg (C4.40) alkyl, preferably (C42) alkyl; | | R4 is H, halogen, (C + -40) alkyl, (Cz40) alkenyl, (Cs-C + s) aryl, (Cs-C10) heteroaryl or -O (C410) alkyl, L is preferably H, halogen, (C + 10) alkyl or —O (C + .10) alkyl, more preferably H or halogen; |. Rs is H, halogen, (Cq.10) alkyl, (C210) alkenyl, (C5-C4a) aryl, (Cs-C40) heteroaryl or —O- (C + .10) alkyl, à preferably H, halogen, (C + -10) alkyl or -O (C4.40) alkyl, more preferably H or halogen; |. Re is H, halogen, (C4.40) alkyl, (Ca-10) alkenyl, (Cs-Cia) aryl, (Cs-C, o) heteroaryl or -O (C + -40) alkyl,. preferably H, halogen, (C + -10) alkyl or -O (C410) alkyl, more preferably H or -O (C410) alkyl; . Ry is H, halogen, (C + 40) alkyl, (C240) alkenyl, (Cs-C44) aryl, (Cs-C + 0) heteroaryl or -O (C-.10) alkyl, | preferably H, halogen, (Cq.10) alky! or -O (C410) alkyl, more preferably H or -O (C + 10) alkyl; | where the at least one amine according to formula (1) is optionally also used in the form of a salt |! can be; 0 can be produced by a method comprising the steps: © a) Providing a solution (A) which contains at least one solvent and in which at least | CO dissolved in a solvent,. optionally b) dissolving a base (BA) which does not correspond to the amine (AM) in the solution (A) to obtain the solution (A1), | c) Dissolving the at least one amine (AM) in the solution (A) or (A1), while obtaining the solution | d) freezing the solution obtained after completion of step c); e) Storage of the solution frozen in step d) at -100 to 0 ° C for no longer than 4 days; © for use in the treatment of atypical pneumonia. | 4. A pharmaceutical composition (PZ) comprising the amine according to claim 1, N or the carbonic acid adduct according to one of claims 2 or 3 for use in the treatment of atypical pneumonia. . 5. The amine for use according to claim 1, the carbonic acid adduct (KA) for | Use according to one of claims 2 or 3, and the pharmaceutical composition | (PZ) for use according to claim 4, wherein | i) the amine according to the general formula (I) and in the general formulas (11), 491724; and (IV) is 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), 4-amino-3-butoxybenzoic acid-2-diethylaminoethyl ester (oxybuprocaine), (2- (dimethylamino) ethyl) -4- | (butylamino) benzoate (tetracaine), preferably 4-aminobenzoic acid 2- (N, N-diethylamino-. ethyl ester procaine and / or | ii) the salt (S) is a salt which is composed of at least one cation; selected from Na *, K *, Li *, Mg **, Zn ° *, Fe **, Fe ** and Mn ", preferably Na" and at least | an anion selected from CI, Br, J, F, SO4 ”, SOs *, HSO, HSOs, HCOs, COs”, PO,. HPO, 7, Hz2PO4, SiO4 ”, AlO, SiO; and / or [AlO2)> (SiO2) a] ″, preferably CI and Br, | particularly preferably CI. L 6. The carbonic acid adduct (KA) for use according to claim 3 and 5, wherein step a) comprises at least one of the following substeps: | a1) cooling the solvent, preferably water, to 3 to 8 ° C, preferably 5 ° C and / or | a2) Introduction of CO into the solvent, preferably up to a saturation concentration | from 3 to 10 g / l, more preferably up to a saturation concentration of 4.5 to 7.5 g / l, preferably E, the pH of the solution after saturation with CO, = 3.0 to 6.0, is still more preferred = | 4.3 to 4.8 and / or | a3) Storage of the solution (A) at 1 to 10 ° C., preferably for at least 30 minutes, more preferably. for at least 50 min, more preferably for at least 60 min; up to a maximum of 5d (120h); | storage is preferably at 3 to 8 ° C, preferably for at least 30 minutes, more | preferably for at least 50 min, even more preferably for at least 60 min; up to a maximum of 5d | step a) preferably comprises all sub-steps a1), a2) and a3), | preferably the substeps a1), a2) and a3) in the order a2) follows a1) and a3) | follows a2). | 7. The carbonic acid adduct (KA) for use according to one of claims 3, 5 and 6, | where | i) the base (BA) in step b) is a hydrogen carbonate or a carbonate, more preferably a | Is hydrogen carbonate, even more preferably sodium hydrogen carbonate and / or | ii) the CO content in the solution subjected to step d) is at least 6 g / l, | preferably at least 10 g / l, more preferably at least 12 g / l, even more preferably | is at least 14 g / l and very particularly preferably at least 15 g / l and the amine (AM) | can also be used in the form of a salt. | 8. The carbonic acid adduct (KA) for use according to one of claims 3 and 5 to 7, | wherein step c) comprises at least one of the following substeps:; 34 ı c1) Dissolve the at least one amine (AM) in solution (A) or (A1) while maintaining the LdsdHg! 724; (B) and / or 'c2) addition of solution (A) to solution (B) while maintaining solution (B1) and / or' c3) enrichment of solution (B) or (B1) with CO, and / or: c4) Storage of the solution (B) or (B1) at 1 to 10 ° C, preferably 3 to 8 ° C, for at least 1 h / preferably 24 h to 120 h, even more preferably 24 to 72 h, and / or ' c5) Enrichment of solution (B) or (B1) with CO 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 very particularly preferably at least 15 g / l: É where optionally 1 i) the concentration of the amine (AM) in solution (B) or when performing substep c2) in; Solution (B1) is 0.01 to 0.25 g / ml, preferably 0.03 to 0.20 g / ml, more preferably 0.08 to 0.15 cg / ml and / or) ii) the pH of solution (B) or (B1) after performing step c5) is <7.0 | and / or | iii) the ratio of the amine (AM) to the base (BA), when carrying out step b), in solution (B): 2 to 5, more preferably 3 to 4, even more preferably 3.23 to 3.26 [g / g] and / or iv) in step c1) the at least one amine (AM), the at least one amine (AM) as: acid addition salt, preferably as the hydrohalide, hydrogen sulfate, hydrogen sulfite, hydrogen phosphate, hydromesylate, hydrotosylate, hydroacetate, hydroformate , Hydropropanoate, | Hydromalonate, hydrosuccinate, hydrofumarate, hydroxalate, hydrotartrate, hydrocitrate, hydromaleate, | more preferably comprises than hydrochloride or hydrobromide. ] step c) preferably comprises all sub-steps c1), c2), c3), c4) and c5); | Preferably, the substeps c1), c2), c3), c4) and c5) in the order c2) follows c1), | c3) follows c2), C4) follows c3), c5) follows c4). | 9. The carbonic acid adduct (KA) for use according to one of claims 3 and 5 to 8, | where in step d): | i) the solution (B) or (B1) at -100 ° C to -20 ° C, preferably at -90 ° C to -30 ° C, even more | is preferably frozen at -80 to -40 ° C and very particularly preferably at -70 to -50 ° C | and / or | il) the 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 | is frozen for 1.5 to 5 minutes and / or | iii) the vessel in which the solution (B) or (B1) is located during the freezing process, | preferably in the cooling medium, with 10 to 1000 rpm, preferably with 50 to 600 rpm, more | is rotated preferably at 100 to 400 rpm and even more preferably at 200 to 300 rpm and / or iv) the solution (B) or (B1) with a cooling rate of 10 to 100 K / min, preferably at 201401724 0 80 K / min , more preferably at 30 to 70 K / min and particularly preferably at 40 to 60 K / min. is frozen. . 10. The carbonic acid adduct (KA) for use according to one of claims 3 and 5 to 8, | | where in step e): |. i) the frozen solution (B) or (B1) for 1.5 to 4 days, preferably for 2.5 to 4 days. is stored and / or. ii) the frozen solution (B) or (B1) preferably at -50 to 0 ° C, more preferably at -30 to | -5 ° C, even more preferably stored at -25 to -10 ° C, particularly preferably at -20 to -15 ° C | will. | 11. The carbonic acid adduct (KA) for use according to one of claims 3 and 5 to © 10, wherein the method comprises a further step f), which is carried out after step e), f) drying the stored in step e) Solution to obtain dried carbonic acid | Adduct (KA), | where in step f) optionally | i) the water from solution (B) or (B1) up to a residual content of <0.8% by weight, © preferably <0.1% by weight based on the total weight of the drying product (C) | is removed and / or. ii) CO not bound in the carbonic acid adduct (KA), from solution (B) or (B1) up to one | Residual content of <0.8% by weight, preferably <0.1% by weight based on the total weight of the | Drying product (C) is removed and / or L iii) drying is carried out by means of lyophilization and / or; iv) the pressure during drying 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. is preferably 0.05 to 0.1 mbar and preferably during the entire |. Drying process is maintained and / or | v) the pressure during drying according to iv) within 10 hours, preferably within 7 hours h, more preferably within 5 hours and particularly preferably within 4 hours from the start of evacuation, and / or. vi) the temperature during the entire drying in step f) 0 to 20 ° C, preferably 4 to | ; 18 ° C, more preferably 8 to 16 ° C and / or | vii) the total drying time 10 to 60, preferably 30 to 55 hours, more preferably 41 to 52 hours amounts to. 12. The amine (AM) according to claim 1 and the carbonic acid adduct (KA) for use according to 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 fungi, preferably. is a viral atypical pneumonia. | 36 | 13. The amine according to claim 12, and the carbonic acid adduct for use gemsäf01724 | Claim 12 and the pharmaceutical composition for use according to Claim 12, | with atypical pneumonia | i) bacterial atypical pneumonia is preferably caused by a bacterium; selected from mycoplasma, legionella, and clamydia or | ii) a viral atypical pneumonia is, preferably triggered by a virus selected - from coronoaviruses, influenza viruses, adenoviruses and respiratory syncytial virus, even more. preferably coronaviruses, especially SARS CoV-2 or | iii) is atypical pneumonia caused by fungi, preferably caused by a | Fungus selected from Aspergillus, Pneumocystis and Candida. : | 14. The amine (AM) according to claim 1, and the carbonic acid adduct (KA) for use É according to one of claims 2, 3 and 5 to 13 and the pharmaceutical composition for | Use according to claim 4 and 12 to 13, wherein the application is oral, parenteral, nasal,. by inhalation or cutaneous. |