TRPC6 inhibitory compounds for treatment of sepsis

Abstract

The present invention relates to compounds of formula (I) wherein the groups Y, A and R1 to R7 have the meanings given in the claims and the description, for use in a method of treating patients suffering from disorders associated with bacterial or fungal severe sepsis and bacterial or fungal septic shock and the conditions resulting therefrom; pharmaceutical compositions containing such compounds and their use as medicaments for the treatment of bacterial or fungal severe sepsis and bacterial or fungal septic shock and conditions resulting therefrom. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202280067695.8, application date October 14, 2022, and invention name “TRPC6 inhibitory compounds for the treatment of sepsis”. Technical Field

[0002] The present invention relates to compounds for use in methods of treating patients suffering from systemic reactions to bacteria, fungi or circulating bacteria or fungal products and conditions caused by such systemic reactions using compounds of formula (I) or derivatives thereof

[0003]

[0004] wherein the groups Y, A and R1 to R7 have the meanings given in the claims and the specification; pharmaceutical compositions containing such compounds and their use as drugs for treating bacterial or fungal severe sepsis or bacterial or fungal septic shock and the conditions caused thereby. Background Art

[0005] In bacterial or fungal severe sepsis or bacterial or fungal septic shock, the increase in vascular permeability increases in several organs including, but not limited to, the lungs, kidneys, liver, and heart. Interstitial fluid accumulation in these organs impairs their normal function (e.g., leading to hypovolemia, hypotension, cardiac arrhythmias, disruption of glomerular filtration, or impaired metabolism) and leads to organ failure and subsequent death. Conventional antibiotics are not used for fungal infections because they are ineffective.

[0006] Sepsis, severe sepsis, and septic shock are disorders caused by a systemic inflammatory response to infection (see Mitchell M. Levy et al., Crit Care Med. 2003 April; 31(4): 1250-6.). Sepsis is a disorder that combines infection (e.g., bacterial, fungal, abdominal trauma, intestinal perforation) and a systemic inflammatory response. This leads to increased vascular permeability in several organs (such as the kidneys, liver, heart, and lungs). Severe sepsis (sepsis with organ dysfunction) refers to sepsis with acute organ dysfunction caused by sepsis. Septic shock refers to persistent hypotension that cannot be explained by other causes.

[0007] There is a need for compounds that can be used in methods for treating bacterial or fungal severe sepsis and bacterial or fungal septic shock. Summary of the invention

[0008] The present invention provides compounds for use in methods of treating patients suffering from bacterial or fungal severe sepsis and bacterial or fungal septic shock and conditions resulting therefrom, particularly conditions associated with bacterial or fungal parasitic infections.

[0009] In one embodiment, the invention relates to a pharmaceutical composition for use in a method for treating a patient suffering from a systemic inflammatory response to a bacterial or fungal infection (such as severe sepsis and bacterial or fungal septic shock caused thereby), the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I),

[0010]

[0011] in

[0012] Y is CH or N;

[0013] A is CH or N;

[0014] R1 is selected from methyl, ethyl and propyl, wherein the hydrogen atoms may be partially or completely replaced by fluorine,

[0015] or R1 is selected from halogen, C 3-6 -Cycloalkyl, OC 3-6 -Cycloalkyl and OC 1-6 -alkyl, wherein the alkyl may be optionally substituted by 1 to 3 halogens and C 3-6 -cycloalkyl substituted, the C 3-6 -cycloalkyl is optionally independently selected from halogen and C 1-6 - 1 to 3 groups substituted by alkyl,

[0016] R2 is selected from H, C 1-6 -alkyl, OCF3, C 3-6 -Cycloalkyl, OC 1-6 -Alkyl and OC 3-6 - cycloalkyl,

[0017] R3 is selected from H, C 1-6 -alkyl, C 3-6 -Cycloalkyl and OC 3-6 -cycloalkyl; wherein the C 1-6 -alkyl, C 3-6 -Cycloalkyl, OC 3-6 -cycloalkyl groups can each be optionally independently selected from halogen, OH, OC 1-6 -Alkyl, SC 1-6 -alkyl and N(C 1-6 -alkyl)2; and wherein the C1-6 -alkyl can be optionally selected from NH, N(C 1-6 -alkyl), one or two parts of O and S;

[0018] R4 and R5 are each independently selected from H and C 1-6 -alkyl;

[0019] R3 and R4 can be joined together with the atoms to which they are attached to form a 3- to 9-membered carbocyclic ring, which optionally can contain one to three heteroatoms selected from N, O and S, or

[0020] R3 and R5 can be joined together with the atoms to which they are attached to form a 3- to 9-membered bicyclic ring, which can optionally contain one to three heteroatoms selected from N, O and S;

[0021] R6 is selected from H, C 1-6 -alkyl, CN, CF3, OCF3, C 3-6 -Cycloalkyl, OC 1-6 -Alkyl and OC 3-6 -cycloalkyl, R7 is selected from H and OC 1-6 -alkyl,

[0022] or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0023] In a specific embodiment, the above invention relates to a pharmaceutical composition, wherein the patient's bacterial or fungal severe sepsis and septic shock is associated with ARDS (related to infection).

[0024] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from a systemic inflammatory response to a bacterial or fungal infection (such as severe sepsis and bacterial or fungal septic shock) and / or a condition caused by the systemic inflammatory response, wherein

[0025] R1 of formula (I) is selected from CF3, halogen, OC 3-6 -Cycloalkyl and OC 1-6 -alkyl, the OC 1-6 -alkyl optionally substituted with one to three halogens and optionally with 1 to 3 halogen groups 3-6 - cycloalkyl substituted,

[0026] R2 of formula (I) is OC 1-6 -alkyl,

[0027] R3 of formula (I) is selected from H and optionally OH or OC 1-6 -alkyl substituted C 1-6-alkyl,

[0028] R4 of formula (I) is H,

[0029] R5 of formula (I) is H,

[0030] R3 and R4 of formula (I) can be joined together with the atoms to which they are attached to form a 3- to 9-membered carbocyclic ring, which optionally can contain one to three heteroatoms selected from N and O; or

[0031] R3 and R5 of formula (I) can be joined together with the atoms to which they are attached to form a 3- to 9-membered bicyclic ring, which can optionally contain one to three heteroatoms selected from N and O;

[0032] R6 of formula (I) is selected from H, C 1-6 -Alkyl, OC 1-6 -Alkyl and OC 3-6 - cycloalkyl,

[0033] R7 of formula (I) is selected from H and OC 1-6 - alkyl groups, such as methoxy,

[0034] or a pharmaceutically acceptable salt thereof.

[0035] In a further embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and bacterial or fungal septic shock and / or a condition resulting therefrom, wherein

[0036] A is CH and Y is N, or

[0037] A is CH and Y is CH, or

[0038] A is N and Y is CH,

[0039] or a pharmaceutically acceptable salt thereof.

[0040] In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method for treating a patient suffering from bacterial or fungal severe sepsis and bacterial or fungal septic shock and / or a condition caused thereby, wherein the compound of formula (I) has the following structure

[0041]

[0042] in

[0043] Y is CH or N,

[0044] R1 is selected from CF3, halogen, OC 3-6-Cycloalkyl and OC 1-6 -alkyl, the OC 1-6 -alkyl is optionally substituted with one to three halogens and unsubstituted cyclohexyl or cyclohexyl substituted with a group selected from the group consisting of fluorine (F), unsubstituted -CH3, -CH3 substituted with 1 to 3 fluorine atoms, unsubstituted -CH2CH3, -CH2CH3 substituted with 1 to 5 fluorine atoms, unsubstituted propyl and propyl substituted with 1 to 7 fluorine atoms;

[0045] R2 is selected from H, -CH3, -CH2CH3, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl and OC 1-6 -alkyl, such as -O-CH3, -O-CH2CH3, O-CF3, hydroxymethyl, hydroxyethyl and hydroxypropyl; and

[0046] R6 is selected from H (hydrogen), unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or methyl substituted by 1-3 fluorine atoms, ethyl substituted by 1-5 fluorine atoms and propyl substituted by 1-7 fluorine atoms;

[0047] R7 is selected from H and OC 1-6 -alkyl,

[0048] or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) having the structure

[0050]

[0051] The pharmaceutical composition is used in a method for treating patients suffering from bacterial or fungal severe sepsis and bacterial or fungal septic shock and / or conditions caused thereby, wherein

[0052] R1 is unsubstituted methyl, ethyl or propyl, or methyl, ethyl or propyl substituted by 1 to 7 fluorine atoms, or fluorine, R2 is OC 1-6 - alkyl, such as methoxy, ethoxy or propoxy,

[0053] R6 is selected from H, unsubstituted methyl, unsubstituted ethyl, and unsubstituted propyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, and propyl substituted by 1 to 7 fluorine atoms; methoxy, ethoxy, propoxy and cyclopropyloxy,

[0054] or a pharmaceutically acceptable salt thereof.

[0055] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) having the following structure, for use in the treatment of patients suffering from bacterial or fungal severe sepsis and bacterial or fungal septic shock and / or conditions caused thereby, wherein

[0056]

[0057] R1 is unsubstituted methyl, ethyl or propyl, or methyl, ethyl or propyl substituted by 1 to 7 fluorine atoms, or fluorine, R2 is selected from OC 1-6 - alkyl groups, such as methoxy, ethoxy and propoxy,

[0058] R6 is selected from H, unsubstituted methyl, unsubstituted ethyl, and unsubstituted propyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, and propyl substituted by 1 to 7 fluorine atoms; methoxy, ethoxy, propoxy and cyclopropyloxy,

[0059] or a pharmaceutically acceptable salt thereof.

[0060] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0061] Y is CH and A is N,

[0062] R1 represents Cl, F, methoxy, isopropoxy, trifluoromethyl, difluoromethoxy, cyclopropyloxy,

[0063] R2 is methoxy or ethoxy,

[0064] R3, R4 and R5 are each H,

[0065] R6 is H, methyl, methoxy or ethoxy,

[0066] R7 is H,

[0067] or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or conditions resulting therefrom, wherein

[0069] Y is CH and A is CH,

[0070] R1 is Cl, F, methoxy, trifluoromethyl,

[0071] R2 is methoxy or ethoxy,

[0072] R3, R4 and R5 are each H,

[0073] R6 is H, methyl, methoxy or ethoxy,

[0074] R7 is H,

[0075] or a pharmaceutically acceptable salt thereof.

[0076] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0077] Y is N and A is CH,

[0078] R1 represents H or fluorine,

[0079] R2 is a methoxy group,

[0080] R3 is selected from H, 2-hydroxymethyl and hydroxyethyl,

[0081] R4 is H,

[0082] R5 is H,

[0083] R3 and R4 can be combined to form a spiro ring,

[0084] or

[0085] R3 and R5 may be joined together with the atoms to which they are attached to form a bicyclic ring,

[0086] R6 is selected from H and methoxy,

[0087] R7 is H,

[0088] or a pharmaceutically acceptable salt thereof.

[0089] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0090] R1 is optionally independently selected from halogen and C 3-6 -Cycloalkyl substituted with 1 to 3 groups 1-6 -alkyl,

[0091] R2 is OC 1-6 -alkyl,

[0092] R3, R4 and R5 are each H,

[0093] R6 is selected from H, C 1-6 -Alkyl and OC 1-6 -alkyl,

[0094] R7 is H,

[0095] or a pharmaceutically acceptable salt thereof.

[0096] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0097] R1 represents a group selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl and 3,3,3-trifluoro-2-methyl-propyl;

[0098] R2 is a methoxy group,

[0099] R3, R4 and R5 are each H,

[0100] R6 is selected from H, methyl and methoxy,

[0101] R7 is H;

[0102] or a pharmaceutically acceptable salt thereof.

[0103] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0104] Y is CH and A is N;

[0105] R1 represents a group selected from the group consisting of propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-cyclopropylethyl, 2-cyclopropylethyl and cyclohexyl,

[0106] R2 is a methoxy group,

[0107] R3, R4 and R5 are each H,

[0108] R6 is selected from H, methyl and methoxy,

[0109] R7 is H,

[0110] or a pharmaceutically acceptable salt thereof.

[0111] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0112] Y is CH and A is CH,

[0113] R1 represents a group selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, 2,2-dimethylpropyl, 1-methylcyclopropylmethyl, 1-fluoromethylcyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclobutylmethyl, 3,3-difluorocyclobutylmethyl, 3-(trifluoromethyl)cyclobutylmethyl and 3,3,3-trifluoro-2-methyl-propyl,

[0114] R2 is a methoxy group,

[0115] R3, R4 and R5 are each H,

[0116] R6 is selected from H, methyl and methoxy,

[0117] R7 is H,

[0118] or a pharmaceutically acceptable salt thereof.

[0119] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0120] R3 and R4, together with the atoms to which they are attached, are joined to form a 3-membered carbon ring,

[0121] or a pharmaceutically acceptable salt thereof.

[0122] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0123] R3 and R5, together with the atoms to which they are attached, join to form a 3- to 9-membered bicyclic ring, which optionally can contain one to two heteroatoms independently selected from N and O, and

[0124] or a pharmaceutically acceptable salt thereof.

[0125] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0126] Y is CH,

[0127] A is N,

[0128] R2 is OCH3; and

[0129] R3, R4, R5 and R7 are each H,

[0130] or a pharmaceutically acceptable salt thereof.

[0131] In another embodiment, the invention relates to a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or conditions resulting therefrom, wherein

[0132] R1 is phenyl optionally substituted by 1 to 3 groups independently selected from the group consisting of methyl, ethyl or propyl, or methyl, ethyl or propyl substituted by 1 to 7 fluorine atoms, CF3, halogen, C 3-6 -Cycloalkyl, OC 3-6 -cycloalkyl and optionally substituted by one to three halogens 1-6 -alkyl; and

[0133] R6 is H or OCH3,

[0134] or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0136] R1 is selected from unsubstituted phenyl or phenyl substituted by 1 to 3 groups independently selected from the following: unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, and propyl substituted by 1 to 7 fluorine atoms, halogen, OC 3-6 -cycloalkyl and optionally substituted by one to three halogens 1-6 -alkyl;

[0137] R2 is OCH3 or OCH2CH3,

[0138] R3, R4, R5, R6 and R7 are each H; and

[0139] or a pharmaceutically acceptable salt thereof.

[0140] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method of treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition resulting therefrom, wherein

[0141] R1 is selected from unsubstituted phenyl or phenyl substituted by 1 to 3 groups independently selected from the following: CF3, halogen, OC 3-6 -Cycloalkyl, unsubstituted OC 1-6 -alkyl and OC substituted by one to three halogens in the alkyl moiety 1-6 -alkyl;

[0142] R2 is OCH3 or OCH2CH3,

[0143] R3, R4, R5 and R7 are each H,

[0144] R6 is CH3 or OCH3,

[0145] Y is CH; and

[0146] A is N,

[0147] or a pharmaceutically acceptable salt thereof.

[0148] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method for treating a patient suffering from bacterial or fungal severe sepsis and septic shock and / or a condition caused thereby

[0149] or a pharmaceutically acceptable salt thereof.

[0150] In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in a method for treating patients suffering from bacterial or fungal severe sepsis and bacterial or fungal septic shock and / or conditions caused thereby, wherein the compound is selected from compounds 1-95 shown in Table 1 below or a pharmaceutically acceptable salt thereof.

[0151] The pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable excipient, and the pharmaceutical composition is used in a method for treating patients suffering from bacterial or fungal severe sepsis and septic shock and / or conditions caused thereby.

[0152] Table 1 below shows specific compounds that can be used in the pharmaceutical compositions described herein.

[0153] Table 1: Specific compounds for use in treating bacterial or fungal severe sepsis and septic shock and / or conditions resulting therefrom

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] BRIEF DESCRIPTION OF THE DRAWINGS

[0169] Figure 1 : Effects of compound 2 of WO 2019 / 161010 in Example 1 on pulmonary stem tissue in the mouse CLP model.

[0170] Figure 2 : Effects of compound 2 of WO 2019 / 161010 in Example 1 on liver stem tissue in the mouse CLP model.

[0171] Figure 3 : Effects of compound 2 of WO 2019 / 161010 in Example 1 on renal stem tissue in the mouse CLP model.

[0172] Figure 4 : Effects of compound 2 of WO 2019 / 161010 in Example 1 on cardiac stem tissue in the mouse CLP model.

[0173] Figure 5 : Effects of compound 17 in Example 2 on lung stem tissue in the mouse CLP model.

[0174] Figure 6 : Effects of compound 17 in Example 2 on liver stem tissue in the mouse CLP model.

[0175] Figure 7 : Effects of compound 17 in Example 2 on renal stem tissue in the mouse CLP model.

[0176] Figure 8 : Effects of compound 17 in Example 2 on cardiac stem tissue in the mouse CLP model.

[0177] Fig. 9 : The amount of total protein in BALF after LPS treatment in Example 3 without (+) Compound 17 or after pretreatment with (+) Compound 17 (first experiment).

[0178] Fig.10 : The amount of total protein in BALF after LPS treatment in Example 3 without (+) Compound 17 or after pretreatment with (+) Compound 17 (second experiment).

[0179] Fig.11 : Percentage of total protein in BALF after LPS treatment in Example 3 without (+) Compound 17 or after pretreatment with (+) Compound 17.

[0180] Fig.12 : Effect of compound 2 of WO 2019 / 161010 in Example 4 on survival rate in the mouse CLP model.

[0181] Fig.13 : Effect of compound 17 in Example 4 on the survival rate in the mouse CLP model. DETAILED DESCRIPTION

[0182] The compounds shown in Table 1 can be prepared according to the procedures described in WO 2019 / 081637 and WO 2019 / 161010.

[0183] The present invention relates to a pharmaceutical composition comprising any one of compounds 1 to 95 described in Table 1 and a pharmaceutically acceptable salt thereof, for use in a method for treating a patient suffering from a systemic inflammatory response to a bacterial or fungal infection (such as sepsis, bacterial or fungal severe sepsis or bacterial or fungal septic shock) or a condition caused by the systemic inflammatory response, the condition being selected from infection-related ARDS, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

[0184] In certain embodiments, any one of compounds 6, 16, 17, 29, 31, 33, 34, 40, 41, 44, 49, 54, 56, 57, 66, 80, 83, 85, 87, 88, and 90 depicted in Table 1, or a pharmaceutically acceptable salt thereof, is contained in a pharmaceutical composition administered to a patient.

[0185] A pharmaceutical composition comprising any compound for use in treatment with one or more of the compounds 1 to 95 of Table 1 disclosed above is understood to have the corresponding embodiment of the following European Second Medical Use Form: "a pharmaceutical composition comprising compound X for use in the treatment of disease Y",

[0186] wherein compound X represents a compound of formula (I) or one or more of compounds 1 to 95 disclosed above, and disease Y represents a disorder associated with bacterial or fungal sepsis, bacterial or fungal severe sepsis or bacterial or fungal septic shock.

[0187] In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above for use in the treatment of bacterial or fungal severe sepsis and septic shock and / or conditions resulting therefrom.

[0188] General Definition

[0189] Terms that are not clearly defined herein should be given the meanings given by those skilled in the art based on the present disclosure and context. However, unless otherwise indicated, the following terms used in the specification have the indicated meanings and comply with the following conventions.

[0190] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group, e.g. 1-6-alkyl means an alkyl group or free radical having 1 to 6 carbon atoms. In general, in groups like HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., the skilled person can see the one or more points of radical attachment to the molecule from the free valence of the group itself. For a composite group containing two or more subgroups, the last named subgroup is the point of radical attachment, e.g., the substituent "aryl-C 1-3 -alkyl" means a 1-3 -alkyl-bound aryl, the C 1-3 The -alkyl group is bound to the core or to the group to which the substituent is attached.

[0191] If a compound is described both by its chemical name and as a chemical formula, in the event of any inconsistency, the chemical formula shall prevail.

[0192] The term "substituted" as used herein means that any one or more hydrogens on the designated atom are replaced with the selection of a designated group, provided that the normal valency of the designated atom is not exceeded and that the substitution results in a stable compound.

[0193] Unless explicitly indicated otherwise, throughout the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures of any of the foregoing, wherein such isomers and enantiomers are present, as well as salts, including pharmaceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates, including solvates of the free compound or solvates of the salt of the compound.

[0194] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0195] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing its acid or base salts. Pharmaceutically acceptable salts include, but are not limited to, basic residues such as inorganic or organic acid salts of amines; acidic residues such as basic or organic salts of carboxylic acids; and the like.

[0196] For example, such salts include acetate, ascorbate, benzenesulfonate, benzoate, benzenesulfonate, bicarbonate, bitartrate, bromide / hydrobromide, edetate, camphorsulfonate, carbonate, chloride / hydrochloride, citrate, edisylate, ethanedisulfonate, propionate lauryl sulfate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothiosulfate, lactate, lactobionate , malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthenate, nitrate, oxalate, pamoate, pantothenate, phenylacetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfonamide, sulfate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, trifluoroacetate, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine and procaine. Additional pharmaceutically acceptable salts can be formed with cations from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc (see also pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 66 , 1-19), or can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0197] The term halogen generally refers to fluorine, chlorine, bromine and iodine.

[0198] The term "C 1-n -alkyl" (wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4 or 6) alone or in combination with another group represents an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5-Alkyl groups include the following groups: H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-C(CH3)2-, H3C-C(CH3)2-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0199] The term "C 3-n -cycloalkyl" (wherein n is an integer from 4 to n) alone or in combination with another group denotes a cyclic, saturated, unbranched hydrocarbon radical having 3 to n C atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0200] The term "halogen" added to an "alkyl", "alkylene" or "cycloalkyl" group (saturated or unsaturated) is an alkyl or cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine. Examples include: H2FC-, HF2C-, F3C-. Similarly, the term "halogen" added to an aryl group (e.g. phenyl) means that one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine.

[0201] The term "carbocyclyl" as used alone or in combination with another group means a monocyclic-, bicyclic- or tricyclic structure consisting of 3 to 9 carbon atoms and optionally heteroatoms selected from N, O and S. The term "carbocyclyl" refers to a fully saturated ring system, and encompasses fused, bridged and spiro ring systems.

[0202] Many of the terms given above may be used repeatedly in the definitions of formulae or radicals and have in each case, independently of one another, one of the meanings given above.

[0203] Unless otherwise indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass its tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures of any of the foregoing, wherein such isomers and enantiomers are present, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof, such as, for example, hydrates, including solvates of the free compound or solvates of the salt of the compound.

[0204] Some of the compounds in Table 1 may exist in more than one tautomeric form. The present invention includes methods for using all such tautomers.

[0205] In addition, the use of prodrugs of compounds of formula (I) for use in methods for treating patients with bacterial or fungal severe sepsis and septic shock is within the scope of the present invention. Prodrugs include those compounds that are modified by simple chemical transformations to produce the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. Specifically, when the prodrug is to be administered to a patient, the prodrug can be converted to the compounds disclosed herein above, thereby imparting the desired pharmacological effect.

[0206] For all compounds disclosed hereinabove in this application, if the nomenclature conflicts with the structure, it is understood that the compound is defined by the structure.

[0207] Methods of therapeutic use

[0208] The compounds disclosed herein are particularly effective for treating bacterial and fungal severe sepsis and septic shock.

[0209] In one embodiment, the invention provides a compound of formula (I) for use in a method of treating a patient suffering from bacterial and fungal severe sepsis and septic shock by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I) as defined above or a compound selected from compounds 1 to 95 of Table 1, but preferably selected from compounds 6, 16, 17, 29, 31, 33, 34, 40, 41, 44, 49, 54, 56, 57, 66, 80, 83, 85, 87, 88 and 90 depicted in Table 1, or a pharmaceutically acceptable salt thereof.

[0210] In the context of treating sepsis, the most common cause of acute respiratory distress syndrome (ARDS), pulmonary inflammation and / or pulmonary edema characterized by increased pulmonary vascular permeability, the present invention also provides a compound of formula (I) for use in a method of treating a patient suffering from ARDS by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I) as defined above or a compound selected from compounds 1 to 95, but preferably selected from compounds 6, 16, 17, 29, 31, 33, 34, 40, 41, 44, 49, 54, 56, 57, 66, 80, 83, 85, 87, 88 and 90 depicted in Table 1, or a pharmaceutically acceptable salt thereof.

[0211] In another embodiment, the invention relates to the treatment of a respiratory disorder or condition caused by a bacterial infection, wherein the respiratory disorder or condition is selected from pulmonary vascular hyperpermeability, pulmonary (pulmonary) edema, pulmonary ischemia-reperfusion, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and severe acute respiratory syndrome (SARS), by administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I) as defined above or a compound selected from compounds 1 to 95, but preferably selected from compounds 6, 16, 17, 29, 31, 33, 34, 40, 41, 44, 49, 54, 56, 57, 66, 80, 83, 85, 87, 88 and 90 depicted in Table 1, or a pharmaceutically acceptable salt thereof.

[0212] For use in the treatment of bacterial or fungal severe sepsis and bacterial or fungal septic shock, the compounds of the present invention can be administered in any conventional manner via a pharmaceutical composition in any conventional pharmaceutical dosage form, such as a composition comprising a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof, the compound being in the range of 0.1 wt% to 90 wt% of the composition as a whole, preferably in the range of 0.5 wt% to 50 wt% of the composition as a whole. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable for the particular dosage form selected. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, by infusion, sublingual, transdermal, oral, topical or by inhalation. Preferred modes of administration are oral and intravenous.

[0213] The compounds of the present invention may be administered alone or in combination with adjuvants (including other active ingredients) that enhance the stability of the compounds of formula (I), promote the administration of pharmaceutical compositions containing them, provide increased dissolution or dispersion, increase inhibitory activity, provide adjuvant therapy, etc. in certain embodiments. In one embodiment, for example, a variety of compounds of the present invention may be administered. Advantageously, such combination therapies use lower doses of conventional therapeutic agents, thereby avoiding toxicity and adverse side effects that may be caused when those conventional therapeutic agents are used as monotherapy. The compounds of the present invention may be physically combined with conventional therapeutic agents or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of the compounds of the present invention (w / w) or a combination thereof. The optimal percentage (w / w) of the compounds of the present invention may vary and is within the purview of those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants may be administered separately (continuously or in parallel). Separate administration allows for greater flexibility in dosing regimens.

[0214] As described above, the dosage form of the compounds of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablets, capsules, capsules, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstructible powders, granules, suppositories, and transdermal patches. The method for preparing such dosage forms is known (see, for example, HC Ansel and NG Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th edition, Lea and Febiger (1990)). Those of ordinary skill in the art can select the dosage level and demand of the compounds of the present invention according to the available methods and techniques applicable to specific patients. In some embodiments, for 70kg patients, the dosage level range is about 1-1000mg / agent. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000mg / day may be required. As will be appreciated by the skilled artisan, lower or higher doses may be required depending on particular factors. For example, the specific dose and treatment regimen will depend on factors such as the patient's overall health, the severity and course of the patient's disorder or the treatment of the disorder, and the judgment of the treating physician.

[0215] The compounds of the present invention may be used alone or in combination with one or more additional therapeutic agents. Non-limiting examples of additional therapeutic agents may include:

[0216] Antimalarials, such as hydroxychloroquine or chloroquine, with or without azithromycin,

[0217] angiotensin II receptor antagonists (angiotensin receptor blockers (ARBs)), such as candesartan, eprosartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, azilsartan, and olmesartan methoate,

[0218] Angiotensin-converting enzyme inhibitors (for example, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, and perindopril),

[0219] Anticoagulants (for example, dabigatran, actylise, warfarin, heparin, and acetylsalicylic acid),

[0220] Antidiabetic agents, such as alpha-glucosidase inhibitors (e.g., miglitol and acarbose), amylin analogs (e.g., pramlintide), dipeptidyl peptidase 4 inhibitors (e.g., alogliptin, sitagliptin, saxagliptin, and linagliptin), incretin mimetics (e.g., liraglutide, exenatide, liraglutide, exenatide, dulaglutide, albiglutide, and lixisenatide), insulin, meglitinides (e.g., repaglinide and nateglinide), biguanides (e.g., metformin); SGLT-2 inhibitors (e.g., canagliflozin, empagliflozin, and dapagliflozin), sulfonylureas (e.g., chlorpropamide, glimepiride, glyburide, glipizide, glyburide, tolazamide, and tolbutamide), and thiazolidinediones (e.g., rosiglitazone and pioglitazone); CGRP antagonists (e.g., olcegepant, vaczegepant, or zavegepant),

[0221] Bronchodilators, including short- and long-acting beta agonists (e.g., albuterol, levalbuterol, salmeterol, formoterol, arformoterol, vilanterol, indacaterol, and olodaterol) and short- and long-acting anticholinergics (ipratropium, tiotropium, umeclidinium, glycopyrrolate, and aclidinium),

[0222] steroids, such as fluticasone and budesonide; and

[0223] Corticosteroids, such as dexamethasone (Dex), prednisone, methylprednisolone, and hydrocortisone.

[0224] In yet another embodiment, the compounds of the present invention can be used in combination with various kinase inhibitors that provide immunomodulatory effects, such as TKIs approved for the treatment of hematological malignancies or in late-stage development (APKater et al., Blood Adv. 2021 Feb 9;5(3):913-925).

[0225] In a further embodiment, the compounds of the invention may be used in combination with an anti-fibrotic agent such as nintedanib or pirfenidone, since patients requiring mechanical ventilation often develop pulmonary fibrosis.

[0226] When used as a combination therapy of a drug combination, the compound of the invention and one or more additional agents may be administered in the same dosage form or in different dosage forms. The compound of the invention and one or more additional agents may be administered simultaneously or separately as part of a regimen.

[0227] It has been found that compounds of formula (I) in which the radicals R1 to R7 have the meanings given above can surprisingly be used to treat patients suffering from systemic reactions to bacteria, fungi or circulating bacteria or fungal products (bacterial or fungal sepsis). Thus, the compounds according to the invention can be used to treat bacterial or fungal severe sepsis.

[0228] Example

[0229] CLP-induced polymicrobial sepsis in mice

[0230] Cecal ligation and puncture (CLP) is a model of polymicrobial sepsis that consists of expressing fecal contents from the abdominal cavity of animals under anesthesia.

[0231] Two models were conducted:

[0232] - Acute model of CLP lasting 24h to measure vascular hyperpermeability in lung, liver, kidney and heart tissues. Vascular hyperpermeability is followed by extravasation of intravenously injected Evans blue and diffusion and accumulation into tissues. Vascular hyperpermeability is expressed as Evans blue (μg) in 100mg dry tissue.

[0233] - Chronic model of CLP lasting 8 days. CLP was performed on day 0 and the survival rate was followed for 8 consecutive days.

[0234] CLP acute model: vascular hyperpermeability

[0235] Ketamine (80 mg kg -1 , intraperitoneally) and xylazine (10 mg kg -1, intraperitoneally) anesthetized mice. A 1-1.5 cm midline abdominal incision was made, and the cecum was located and tightly ligated with 4-0 silk suture (mild) at half the distance between the distal end and the base of the cecum. After the middle ligation, the cecum was punctured once with a 21-gauge needle. A small amount of feces was squeezed out to ensure that the wound was open. The cecum was then returned to its original position in the abdomen and closed with layered sutures. For negative control animals, a sham operation was performed: animals undergoing a sham operation underwent the same laparotomy, but without cecal ligation or puncture. Immediately after the operation, the animals were revived with 1 mL of subcutaneous saline and returned to their cages. The experiment was terminated 24 hours after CLP.

[0236] Example 1: Effect of Compound 2 of WO 2019 / 161010 on the CLP Acute Model

[0237] Oral administration (5 ml / kg) WO 2019 / 161010 Compound 2 or its vehicle (0.5% natrosol, 0.010% Tween 80) was administered prophylactically at 30 mg / kg 2 h before CLP and 8 h after CLP, or therapeutically at 10 or 30 mg / kg 2 h and 8 h after CLP. Dexamethasone was orally administered at 10 mg / kg 1 h before CLP. Ten mice were included in each group.

[0238] Evans blue dye (0.1 mL, 40 mg / kg) was injected through each tail vein 24 hours after CLP and 30 minutes before euthanasia. Lung, kidney, liver and heart tissues were collected and Evans blue was extracted in formamide. The concentration of Evans blue dye was calculated from the standard curve and expressed as μg / 100 mg lung stem tissue. Data were analyzed by using commercially available software (Prism, Version 8.3.0; GraphPad Software Inc., San Diego, California). Different groups (e.g., CLP group compared to treatment group) were compared using one-way analysis of variance (ANOVA) and subsequent Dunnett's test. All data are expressed as mean ± SEM. The limit of significance was taken as a p value less than 0.05 (p < 0.05).

[0239] In the lung, the Evans blue concentration in the CLP vehicle-treated group (37 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (15 μg / 100 mg dry tissue) ( Figure 1 Compound 2 of WO 2019 / 161010 significantly (p<0.05) reduced Evans blue concentrations in either the preventive mode (87% inhibition at 30 mg / kg) or the therapeutic mode (87% inhibition at 10 mg / kg, and 100% inhibition at 30 mg / kg). Figure 1 In this model, dexamethasone failed to reduce pulmonary vascular permeability ( Figures 1 to 4 ).

[0240] In the liver, the Evans blue concentration in the CLP vehicle-treated group (106 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (52 μg / 100 mg dry tissue) ( Figure 2 Compound 2 of WO 2019 / 161010 significantly (p<0.05) reduced Evans blue concentrations in the prevention mode (71% inhibition at 30 mg / kg) or in the treatment mode (88% inhibition at 30 mg / kg). Figure 2 In this model, dexamethasone failed to reduce pulmonary vascular permeability ( Figure 1 ).

[0241] In the kidney, the Evans blue concentration in the CLP vehicle-treated group (97 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (53 μg / 100 mg dry tissue) ( Figure 3 Compound 2 of WO 2019 / 161010 significantly (p<0.05) reduced Evans blue concentrations in the prevention mode (84% inhibition at 30 mg / kg) or in the treatment mode (98% inhibition at 30 mg / kg). Figure 3 In this model, dexamethasone failed to reduce pulmonary vascular permeability ( Figure 3 ).

[0242] In the heart, the Evans blue concentration in the CLP vehicle-treated group (39 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (22 μg / 100 mg dry tissue) ( Figure 4 Compound 2 of WO 2019 / 161010 significantly (p<0.05) reduced Evans blue concentrations in the treatment mode (94% inhibition at 30 mg / kg). Figure 4 In this model, dexamethasone (Dex) fails to reduce pulmonary vascular permeability ( Figure 4 ).

[0243] Example 2: Effect of Compound 17 on Acute CLP Model

[0244] Compound 17 was also tested in a mouse model of CLP under the same experimental conditions used for compound 2 of WO 2019 / 161010. In this experiment, compound 17 and compound 2 of WO 2019 / 161010 were orally administered in a therapeutic mode 2h and 8h after CLP.

[0245] In the lung, the Evans blue concentration in the CLP vehicle-treated group (61 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (15 μg / 100 mg dry tissue) ( Figure 5 Compound 17 significantly (p<0.05) dose-dependently reduced Evans blue concentration (65% inhibition at 1 mg / kg, 90% inhibition at 3 mg / kg and 100% inhibition at 10 mg / kg) ( Figure 5 ). Compound 2 of WO 2019 / 161010 significantly reduced the concentration of Evans blue in lung tissue by 94% at 30 mg / kg ( Figure 5 ).

[0246] In the liver, the Evans blue concentration in the CLP vehicle-treated group (11 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (4 μg / 100 mg dry tissue) ( Figure 6 Compound 17 significantly (p<0.05) reduced Evans blue concentration by 48% at 10 mg / kg. Compound 2 of WO 2019 / 161010 significantly reduced Evans blue concentration by 58% at 30 mg / kg ( Figure 6 ).

[0247] In the kidney, the Evans blue concentration in the CLP vehicle-treated group (22 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (10 μg / 100 mg dry tissue) ( Figure 7 Compound 17 significantly (p<0.05) reduced the Evans blue concentration by 95% at 10 mg / kg ( Figure 7 ). Compound 2 of WO 2019 / 161010 significantly reduced the Evans blue concentration by 90% at 30 mg / kg ( Figure 7 ).

[0248] In the heart, the concentration of Evans blue in the CLP vehicle-treated group (18 μg / 100 mg dry tissue) was significantly (p<0.05) higher than that in the sham-operated group (8 μg / 100 mg dry tissue) ( Figure 8 Compound 17 significantly (p<0.05) reduced Evans blue concentration by 100% at 3 mg / kg and by 120% at 10 mg / kg ( Figure 8 ). Compound 2 of WO 2019 / 161010 significantly reduced the Evans blue concentration by 100% at 30 mg / kg ( Figure 8 ).

[0249] Figures 5 to 8It was shown that compound 17 significantly reduced vascular leakage, similar to compound 2 of WO / 2019 / 161010.

[0250] Example 3: Reduction of LPS-induced vascular leakage in a mouse model

[0251] Mice were placed in a chamber and exposed to lipopolysaccharide (LPS, known as endotoxin and found in the outer membrane of Gram-negative bacteria such as Escherichia Coli) aerosol (0.8 mg / ml) for 30 min (or phosphate buffered saline PBS as a vehicle). TRPC6 inhibitor compound 17 was orally administered 12 h and 2 h before LPS challenge. Mice were euthanized 4 h after the end of LPS aerosol exposure. Blood was collected for plasma exposure of the compound and the lungs were flushed with 0.8 ml PBS. The bronchoalveolar lavage fluid was centrifuged at 500 rpm for 10 min and the supernatant was collected for measurement of total protein according to the Lowry measurement method based on absorbance at 660 nm. The mouse LPS experiment was repeated twice, and for the first experiment, the data for each experiment were Fig. 9 , and for the second experiment, the data for each experiment are in Fig.10 Indicated in. Fig.11 The mean values ​​of two experiments are shown as a percentage of the LPS group. The plasma concentrations of the compounds measured at the end of the experiment are shown as multiples of the in vitro patch clamp IC50 (19 nM), IC75 (48 nM), IC90 (104 nM).

[0252] LPS aerosol-induced pulmonary edema is characterized by a significant accumulation of bronchoalveolar lavage fluid protein (BALF protein). The sources of these proteins are albumin from the blood due to vascular hyperpermeability and proteins from damaged alveolar cell membranes. In the LPS group, BALF protein (280-310 μg / ml BALF, Fig. 9 and Fig.10 ) was significantly higher than that in the PBS group (170-180 μg / ml BALF, Fig. 9 and Fig.10 Administration of compound 17 significantly reduced BALF protein concentration by 56% at 3 mg / kg p.o. and 62% at 10 mg / kg p.o. ( Fig.11 ).

[0253] Fig. 9 and Fig.10 The amount of total protein in BALF (bronchoalveolar lavage fluid) after LPS (lipopolysaccharide) treatment without (+) Compound 17 or after pretreatment with (+) Compound 17 as evaluated according to the following table scheme, and Fig.11The percentage of total protein is shown.

[0254]

[0255] Figures 9 to 11 It was shown that compound 17 significantly reduced vascular leakage, similar to compound 2 of WO / 2019 / 161010.

[0256] Example 4: Chronic Model of CLP: Survival Rate

[0257] On day 0, ketamine (80 mg kg -1 , intraperitoneally) and xylazine (10 mg kg -1 , intraperitoneally) anesthetized mice. A 1-1.5 cm midline abdominal incision was made, and the cecum was located and tightly ligated with 4-0 silk suture (mild) at half the distance between the distal end and the base of the cecum. After the middle ligation, the cecum was punctured once with a 21-gauge needle. A small amount of feces was squeezed out to ensure that the wound was open. The cecum was then returned to its original position in the abdomen and closed with layered sutures. For negative control animals, a sham operation was performed: animals undergoing a sham operation underwent the same laparotomy, but without cecal ligation or puncture. Immediately after the operation, the animals were revived with 1 mL of subcutaneous saline and returned to their cages.

[0258] Compound 2 of WO 2019 / 161010 or its vehicle (0.5% natrosol, 0.010% Tween 80) was orally administered (5 ml / kg) at 30 mg / kg 2 h after CLP and once daily from day 1 to day 6. Anti-adrenomedullin antibody adrecizumab was administered intravenously at 4 mg / kg 1 h before CLP, only once. Ten mice were included in each group.

[0259] No mortality was observed in the sham group within 8 days, whereas all mice in the CLP group were found dead on day 3. Compound 2 of WO 2019 / 161010 significantly reduced mortality on day 8, with a survival rate of 50% (5 out of 10 mice were still alive on day 8) ( Fig.12 ). Adezumab significantly reduced mortality on day 8, with a survival rate of 30% (3 of 10 mice were still alive on day 8). The survival rate of compound 2 of WO 2019 / 161010 was significantly better than that of Adezumab.

[0260] Fig.12 The effects of compound 2 of WO 2019 / 161010 on survival in the mouse CLP model were compared with those of the sham operation group and the effects of adezumab

[0261] In the second experiment, compound 17 or its vehicle (0.5% natrosol, 0.010% Tween 80) was orally administered (5 ml / kg). Compound 17 was administered at 10 mg / kg in both groups. In the first group, compound 17 was administered 2 h after CLP and twice daily from day 1 to day 6. In the second group, compound 17 was administered 24 h after CLP and twice daily from day 2 to day 6. Ten mice were included in each group.

[0262] No mortality was observed in the sham group within 8 days, while only 2 mice survived to day 8 in the CLP group. Compound 17 administered 2 h after CLP significantly reduced mortality on day 8, with a survival rate of 60% (6 of 10 mice were still alive on day 8) ( Fig.13 When the compound was administered 24 h after CLP, the survival rate was still 50% (5 mice out of 10 were still alive on day 8).

[0263] Fig.13 The effect of compound 17 on survival in the mouse CLP model was compared with that of the sham-operated group.

Claims

1. A pharmaceutical composition for use in a method for treating a patient suffering from sepsis, severe sepsis or septic shock, the pharmaceutical composition comprising a compound of formula (I), in Y is CH or N, A is CH or N, R1 is selected from Methyl, ethyl and propyl, in which the hydrogen atoms may be partially or completely replaced by fluorine, or R1 is selected from halogen, C 3-6 -Cycloalkyl, OC 3-6 -Cycloalkyl and OC 1-6 -alkyl, wherein the alkyl can be optionally substituted by 1 to 3 halogens and C 3-6 -Cycloalkyl Substitution The C 3-6 -cycloalkyl is optionally independently selected from halogen and C 1-6 - 1 to 3 groups substituted by alkyl, R2 is selected from H, C 1-6 -alkyl groups such as -CH3 and -CH2CH3, OCF3, C 3-6 -Cycloalkyl, OC 1-6 -Alkyl and OC 3-6 - cycloalkyl, R3 is selected from H, C 1-6 -alkyl, C 3-6 -Cycloalkyl and OC 3-6 -cycloalkyl; wherein said R 3 Group C 1-6 -alkyl, C 3-6 -Cycloalkyl, OC 3-6 -cycloalkyl groups can each be optionally independently selected from halogen, OH, OC 1-6 Alkyl, SC 1-6 -alkyl and N(C 1-6 -alkyl)2; and wherein the C 1-6 -alkyl can be optionally selected from NH, N(C 1-6 -alkyl), one or two of O and S are substituted, R4 and R5 are each independently selected from H and C 1-6 -alkyl, R3 and R4 can be joined together with the atoms to which they are attached to form a 3- to 9-membered carbocyclic ring, which optionally can contain one to three heteroatoms selected from N, O and S, or R3 and R5 can be joined together with the atoms to which they are attached to form a 3- to 9-membered bicyclic ring, which can optionally contain one to three heteroatoms selected from N, O and S, R6 is selected from H, C 1-6 -alkyl, CN, CF3, OCF3, C 3-6 -Cycloalkyl, OC 1-6 -Alkyl and OC 3-6 -cycloalkyl, R7 is selected from H and OC 1-6 -alkyl, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

2. The pharmaceutical composition according to claim 1, wherein R1 of formula (I) is selected from CF3, OCF3, halogen, OC 3-6 -Cycloalkyl and OC 1-6 -alkyl, the OC 1-6 -alkyl is optionally substituted with one to three halogen and C optionally substituted by 1 to 3 halogen groups 3-6 - cycloalkyl substituted, R2 of formula (I) is OC 1-6 -alkyl, R3 of formula (I) is selected from H and optionally OH or OC 1-6 -alkyl substituted C 1-6 -alkyl, R4 of formula (I) is H, R5 of formula (I) is H, R3 and R4 of formula (I) can be joined together with the atoms to which they are attached to form a 3- to 9-membered carbocyclic ring, which optionally can contain one to three heteroatoms selected from N and O, or R3 and R5 of formula (I) can be joined together with the atoms to which they are attached to form a 3- to 9-membered bicyclic ring, which can optionally contain one to three heteroatoms selected from N and O, R6 of formula (I) is selected from H, C 1-6 -Alkyl, OC 1-6 -Alkyl and OC 3-6 - cycloalkyl, R7 of formula (I) is selected from H and OC 1-6 -alkyl.

3. The pharmaceutical composition according to claim 1, comprising a compound of formula (I) having the following structure, in Y is CH or N, R1 is selected from: CF3, halogen, OC 3-6 -Cycloalkyl and OC 1-6 -alkyl, the OC 1-6 -alkyl is optionally substituted with one to three halogen and unsubstituted cyclohexyl or cyclohexyl substituted by a group selected from the group consisting of fluorine (F), unsubstituted -CH3, -CH3 substituted by 1 to 3 fluorine atoms, unsubstituted -CH2CH3, -CH2CH3 substituted by 1 to 5 fluorine atoms, unsubstituted propyl and propyl substituted by 1 to 7 fluorine atoms, R2 is selected from H, -CH3, -CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and -OC 1-6 -alkyl, such as -O-CH3, -O-CH2CH3, -O-CF3, hydroxymethyl, hydroxyethyl and hydroxypropyl, and R6 is selected from hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms and propyl substituted by 1 to 7 fluorine atoms, or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 1, comprising a compound of formula (I) having the following structure, in R1 is unsubstituted methyl, ethyl or propyl, or methyl, ethyl or propyl substituted by 1 to 7 fluorine atoms, or fluorine, R2 is selected from OC 1-6 - alkyl groups, such as methoxy, ethoxy and propoxy, R6 is selected from H, unsubstituted methyl, unsubstituted ethyl, and unsubstituted propyl, methyl substituted by 1 to 3 fluorine atoms, ethyl substituted by 1 to 5 fluorine atoms, and propyl substituted by 1 to 7 fluorine atoms; methoxy, ethoxy, propoxy and cyclopropyloxy, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 1, comprising a compound of formula (I) selected from the group consisting of compounds 1 to 95 shown in Table 1 of this specification or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the patient's response is characterized by interstitial fluid accumulation and / or hypotension.

7. A medicament prepared using a compound of formula (I) or a salt thereof according to any one of claims 1 to 5, for use in a method of treating a patient suffering from a systemic inflammatory response to a bacterial or fungal infection.

8. The pharmaceutical composition according to any one of claims 1 to 5, for use in a method of treating a patient suffering from bacterial or fungal severe sepsis or bacterial or fungal septic shock.

9. A pharmaceutical composition according to any one of claims 1 to 5, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) as a whole is in the range of 0.1 wt% to 90 wt% of the composition.

10. The pharmaceutical composition according to claim 9, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) as a whole is in the range of 0.5 wt% to 50 wt% of the composition.

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