Diazine and triazine compounds for the treatment of cytokine storm syndrome

Abstract

This invention provides compounds for use in the treatment of cytokine storm syndrome or cytokine release syndrome. [Solution] Diazine and triazine compounds having the following structure are provided, which have activity as interferon and interleukin inhibitors, particularly interferon-gamma, tumor necrosis factor (TNF) α, and interleukin 1β, 2, 4, 6, 8, 13, and 17 inhibitors. TIFF2026122986000016.tif30114

Description

Detailed description of the invention

[0001] Field of Invention The present invention relates to diazine and triazine compounds having activity as interferon and interleukin inhibitors, particularly interferon-gamma, tumor necrosis factor (TNF) α, and interleukin 1β, 2, 4, 6, 8, 13, and 17 inhibitors, as well as compounds for use in the treatment of cytokine storm syndrome or cytokine release syndrome.

[0002] Background of the Invention WO2009090431A discloses a triazine of the following formula, where ring A may be a sulfur-containing heterocycle such as optionally substituted thienyl and benzothienyl rings. [ka]

[0003] WO2009090431A further discloses a triazine with the following formula: [ka]

[0004] The compound WO2009090431A is described as having activity as a voltage-gated sodium channel blocker.

[0005] Cytokine storm syndrome (CSS) was defined in 2012 by Canna and Behrens as "a group of disorders representing diverse inflammatory etiologies with overwhelming systemic inflammation, hemodynamic instability, multiple organ failure, and the ultimate common outcome of potential death." See reference (Pediatr Clin North Am., April 2012, 59(2), pp. 329-344). Cytokine storm syndrome can be triggered by a variety of factors, including viral infections, septic infections (Chaudhry et al., In Vivo., 2013, 27(6), pp. 669-684), or treatment with certain drugs (Nebelsiek et al., Recent Pat Cardiovasc Drug Discov, July 2012, pp. 170-174). Cytokine release syndrome refers to an adverse systemic inflammatory response to monoclonal antibody treatment (Winkler et al., Blood, 1999, 94, pp. 2217-2224). Tisoncik et al. discussed the immunopathogenesis caused by cytokine storm syndrome induced by SARS-CoV, influenza virus, and dengue virus infections. Discussing (Microbiology and Molecular Biology) Reviews, March 2012, Vol. 76, No. 1, pp. 16-32). Tisoncik et al. further discuss the pathophysiology of cytokine storms, stating that interferon-gamma, interleukin (IL) 1 beta, 6, 8, and 17 are all associated with cytokine storms along with IL-6 and IL-17, and are identified as important cytokine storm mediators in gene knockout mouse studies. Russell et al. re-examine clinical trials of interferon inhibitors and interleukin (IL) 1, 2, and 6 inhibitors (ecancer, 2020 14:1022). They report that increased serum expression of IL-2R and IL-6 appears to predict the severity of 2019-nCoV pneumonia and the prognosis of patients, and that COVID-19 is observed to induce high levels of IL-6 for at least two weeks after the onset of symptoms. The authors further conclude that IL-1 is elevated in patients infected with the coronavirus.

[0006] Rider et al. and Lin et al. have discussed compensatory mechanisms observed when specific cytokine activity or mechanisms are blocked. Rider et al. (International Journal of Cell Biology, Volume 2016, Article ID 9259646, page 11) state that "the drawbacks of cytokine therapy are due to the basic properties of cytokines. (i) Cytokines are pleiotropic, meaning they affect multiple processes in parallel. (ii) Cytokines are also known to have redundancy, meaning that the effects achieved by blocking one specific cytokine activity can be compensated by other cytokine activities", whereas Lin et al. (Acta Biomaterialia, 10 (2014), pages 3747 - 3755) discuss research on the alleviation of wear particle-induced osteolysis and state that "although blocking individual cytokines showed promising effects..., in human clinical studies, blocking of TNF-α by neutralizing antibodies has been shown not to alleviate osteolysis. This could be explained by compensatory upregulation of other inflammation-inducing factors" (emphasis added).

[0007] Summary The present invention relates to a compound of formula (I), or a salt, tautomer or solvate thereof, for use in the treatment of cytokine storm syndrome or cytokine release syndrome

Chemical formula

Chemical formula

[0008] The present invention further provides a method for treating cytokine storm syndrome or cytokine release syndrome, comprising the step of administering a therapeutically effective amount of a compound of formula (I) as defined above, or a salt, tautomer, or solvate thereof, to a subject in need thereof.

[0009] The present invention further provides the use of a compound of formula (I) as defined above, or a salt thereof, tautomer, or solvate thereof, in the manufacture of a pharmaceutical product for use in the treatment of cytokine storm syndrome or cytokine release syndrome.

[0010] The present invention further provides a pharmaceutical composition for use in the treatment of cytokine storm syndrome or cytokine release syndrome, comprising a compound of formula (I) as defined above or a salt thereof, a tautomer or solvate thereof, and one or more pharmaceutically acceptable excipients. [Brief explanation of the drawing]

[0011] [Figure 1] A figure showing the effect of compound 1 on cytokine production from stimulated human peripheral blood mononuclear cells. [Figure 2] A diagram showing the inhibitory effect of compound 1 on interleukin (IL) 1 beta. [Figure 3] A diagram showing the inhibitory effect of compound 1 on interleukin (IL) 6. [Figure 4] A diagram showing the inhibitory effect of compound 1 on interleukin (IL) 8. [Figure 5] A diagram showing the inhibitory effect of compound 1 on tumor necrosis factor (TNF) α. [Figure 6] A diagram showing the inhibitory effect of compound 1 on interferon-gamma (IFN-γ). [Figure 7]A diagram showing the inhibitory effect of compound 1 on interleukin (IL) 17A. [Figure 8] A diagram showing the inhibitory effect of compound 2 on interleukin (IL) 17A. [Figure 9] A diagram showing the inhibitory effect of compound 2 on tumor necrosis factor (TNF) α. [Figure 10] A diagram showing the inhibitory effect of compound 2 on interferon-gamma (IFN-γ). [Figure 11] A diagram showing the inhibitory effect of compound 2 on interleukin (IL) 8. [Figure 12] Compound 2 exhibits an inhibitory effect on interleukin (IL) 6.

[0012] Detailed explanation Compounds of formula (I) have been found to exhibit inhibitory activity against interferon-gamma, tumor necrosis factor (TNF) α, and interleukin-1 beta, 2, 4, 6, 8, 13, or 17, and are therefore useful in the treatment of cytokine storm syndrome and cytokine release syndrome. The activity mediated by the compounds of formula (I) through multiple mechanisms is thought to address the compensatory upregulation of other pro-inflammatory factors observed when one factor is inhibited.

[0013] Embodiment 1 of the present invention relates to a compound of formula (I), or a salt, tautomer, or solvate thereof, for use in the treatment of cytokine storm syndrome or cytokine release syndrome. [ka] (In the formula, X is N and Y is C, or X is C and Y is N, or Both X and Y are N. A is a substituted 3- to 10-membered heterocycle containing 1, 2, or 3 sulfur atoms, wherein the heterocycle is (i) a halogen, or (ii) all optionally substituted with one or more halogens, hydroxyls, and aryls. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, or C 1-6 Alkoxy, as well as (iii) amino, monosubstituted or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and C 1-6 Having two or more substituents selected from alkylthio groups, or A is the basis of the following equation [ka] (In the formula, · indicates a bonding point) And, R1 is hydrogen, or C 1-10 Alkyl, C 2-10 Alkenyl, benzyl, piperidine-methyl, thienyl-methyl, furyl-methyl, or C 3-10 The substituents are selected from cycloalkyl groups, and these are all hydroxy, halogen, carboxamide, and halo C groups. 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Can it be arbitrarily substituted with an alkoxy? , or Y is N and is non-substitutable, R2 is amino, C 1-10 Alkyl or phenyl, R3 is phenyl, xanthyal, or naphthyl, each optionally substituted with 1 to 5 substituents selected from halogens or C1-C6 alkoxy groups. R4 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, xanthyal, or naphthyl, and the phenyl or naphthyl may be optionally substituted with 2 to 5 substituents selected from halogens or C1-C6 alkoxy groups. R5 is hydrogen, N *When R1 is hydrogen or a substituent, it is either =NH or N * The group is NRaRb, and Ra and Rb are independently either H or an alkyl group, or N * (This is a piperazinyl ring optionally substituted with one or more halogens or C1-C6 alkoxy groups.) To provide.

[0014] As Embodiment 2, the present invention provides a compound of formula (I) as defined in Embodiment 1, or a salt, tautomer, or solvate thereof, for use in the treatment of infection-induced cytokine storm syndrome.

[0015] As Embodiment 3, the present invention provides a compound of formula (I) as defined in Embodiment 1, or a salt, tautomer, or solvate thereof, for use in the treatment of cytokine storm syndrome induced by infection selected from sepsis, influenza virus, coronavirus, and dengue virus.

[0016] As Embodiment 4, the present invention provides a compound of formula (I) as defined in Embodiment 1, or a salt, tautomer, or solvate thereof, for use in the treatment of coronavirus-induced cytokine storm syndrome.

[0017] As Embodiment 5, the present invention provides a compound of formula (I), or a salt, tautomer, or solvate thereof, for use as defined in any of the prior embodiments, where both X and Y are N.

[0018] As Embodiment 6, the present invention provides a compound of formula (I), or a salt, tautomer, or solvate thereof, for use as defined in any of the prior embodiments, wherein R1 is hydrogen.

[0019] As Embodiment 7, the present invention provides a compound of formula (I), or a salt, tautomer, or solvate thereof, for use as defined in any of the prior embodiments, wherein R2 is an amino acid.

[0020] As Embodiment 8, the present invention provides a substituted 3- to 10-membered heterocycle in which A contains 1, 2, or 3 sulfur atoms, wherein the heterocycle is (i) halogen, and (ii) all optionally substituted with one or more halogens, hydroxyls, and aryls. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, or C 1-6 Alkoxy, as well as (iii) amino, monosubstituted or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and C 1-6 The present invention provides a compound of formula (I) for use as defined in any of the preceding embodiments, having two or more substituents selected from alkylthio groups, or a salt, tautomer, or solvate thereof.

[0021] As Embodiment 9, the present invention relates to a prior embodiment in which A is thienyl or benzothienyl The present invention provides a compound of formula (I), or a salt thereof, a tautomer, or a solvate thereof, for use as defined by any of the application forms.

[0022] In Embodiment 10, the present invention provides a system where A is a halogen, and C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 alkyl and halo C 1-6 The present invention provides compounds of formula (I), or salts, tautomers, or solvates thereof, for use as defined in Embodiment 8 or 9, which are substituted with one or more substituents selected from alkoxys.

[0023] As Embodiment 11, the present invention provides a compound of formula (I), or a salt, tautomer, or solvate thereof, for use as defined in any one of Embodiments 8 to 10, in which A is substituted with one, two, or three chlorine or bromine atoms.

[0024] In Embodiment 12, the present invention relates to a compound in which 3,5-diamino-6-(2-thienyl)-1,2,4-triazine; 3,5-diamino-6-(3-thienyl)-1,2,4-triazine; 5(3)-amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazinemethanesulfonate; 5(3)-amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazinemethanesulfonate; 3,5-diamino-6-(2-thienyl)-1,2,4-triazine; 3,5-diamino-6-(3-thienyl)-1,2,4-triazine; 3,5-diamino-6-[3-(2,5-dichlorothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine; 5(3)-amino-6-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine; 5(3)-amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine; 5(3)-amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine; 3,5-diamino-6-[2-(4,5-dibromothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(5-bromothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(3-bromothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(5-chlorothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(benzo[b]thienyl)]-1,2,4-triazine; and 3,5-diamino-6-[2-(3-chlorobenzo[b]thienyl)]-1,2,4-triazine; Alternatively, they may be selected from the group consisting of salts, tautomers, or solvates thereof. or compound 2,6-diamino-3-(2-thienyl)-pyrazine; 2,4-diamino-5-(2-thienyl)-pyrimidine; 2,6-diamino-3-(3-thienyl)-pyrazine; 2,4-diamino-5-(3-thienyl)-pyrimidine; 2,6-diamino-3-[3-(2,5-dichlorothienyl)]-pyrazine; 2,4-diamino-5-[3-(2,5-dichlorothienyl)]-pyrimidine; 2,6-diamino-3-[2-(3,4,5-trichlorothienyl)]-pyrazine; 2,4-diamino-5-[2-(3,4,5-trichlorothienyl)]-pyrimidine; 2(6)-amino-3-(2-thienyl)-2,3(2,5)-dihydro-6(2)-imino-5-methylpyrazine; 4(2)-amino-5-(2-thienyl)-2,3(2,5)-dihydro-2(4)-imino-1-methylpyrimidine; 2(6)-amino-3-(2-thienyl)-2,3(2,5)-dihydro-6(2)-imino-5-ethyl-pyrazine; 4(2)-amino-5-(2-thienyl)-2,3(2,5)-dihydro-2(4)-imino-1-ethylpyrimidine; 2(6)-amino-3-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-6(2)-imino-5-methylpyrazine; 4(2)-amino-5-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-2(4)-imino-2-methylpyrimidine; 2(6)-amino-3-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-6(2)-imino-5-methylpyrazine; 4(2)-amino-5-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-2(4)-imino-1-methylpyrimidine; 2(6)-amino-3-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-6(2)-imino-5-ethyl-pyrazine; 4(2)-amino-5-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-2(4)-imino-2-ethylpyrimidine; 2,6-diamino-3-[2-(4,5-dibromothienyl)]-pyrazine; 2,4-diamino-5-[2-(4,5-dibromothienyl)]-pyrimidine; 2,6-diamino-3-[2-(5-bromothienyl)]-pyrazine; 2,4-diamino-5-[2-(5-bromothienyl)]-pyrimidine; 2,6-diamino-3-[2-(3-bromothienyl)]-pyrazine; 2,4-diamino-5-[2-(3-bromothienyl)]-pyrimidine; 2,6-diamino-3-[2-(5-chlorothienyl)]-pyrazine; 2,4-diamino-5-[2-(5-chlorothienyl)]-pyrimidine; 2,6-diamino-3-[2-(benzo[b]thienyl)]-pyrazine; 2,4-diamino-5-[2-(benzo[b]thienyl)]-pyrimidine; 2,6-diamino-3-[2-(3-chlorobenzo[b]thienyl)]-pyrazine; and The present invention provides compounds of formula (I), or salts, tautomers, or solvates thereof, selected from the group consisting of 2,4-diamino-5-[2-(3-chlorobenzo[b]thienyl)]-pyrimidines or salts, tautomers, or solvates thereof, for use as defined in any one of Embodiments 8 to 11.

[0025] As Embodiment 13, the present invention is based on the following formula where A is the basis [ka] (In the formula, · indicates a bonding point) And, R3 is phenyl, xantyl, or naphthyl, each optionally substituted with one or more halogens or 1 to 5 substituents selected from C1-C6 alkoxy groups. R4 is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, xanthyal, or naphthyl, and the phenyl or naphthyl is a halogen or C It may be optionally substituted with 2 to 5 substituents selected from 1-C6 alkoxy groups. The present invention provides a compound of formula (I), or a salt thereof, a tautomer, or a solvate thereof, for use as defined in any one of Embodiments 1 to 7, wherein R5 is hydrogen.

[0026] In Embodiment 14, the present invention is a phenyl molecule in which R3 is optionally substituted with one or more halogens or two or three substituents selected from C1-C6 alkoxy groups. The present invention provides a compound of formula 1 or a salt, tautomer, or solvate thereof for use as defined in Embodiment 13, wherein R4 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, or phenyl, and the phenyl may be optionally substituted with 2-3 substituents selected from halogens or C1-C6 alkoxy groups.

[0027] In Embodiment 15, the present invention relates to a compound in which 3,5-diamino-6-[1,1-bis-(4-chlorophenyl)methyl]-1,2,4-triazine; 3,5-diamino-6-[1,1-bis-(4-fluorophenyl)methyl]-1,2,4-triazine; 3,5-diamino-6-(diphenylmethyl)-1,2,4-triazine; 3,5-diamino-6-(1-cyclopentyl-1-phenyl-methyl)-1,2,4-triazine; 3,5-diamino-6-[1-(6-methoxynaphthalene)methyl]-1,2,4-triazine; 3,5-diamino-6-[1-(6-methoxynaphthalene)ethyl]-1,2,4-triazine; 3,5-diamino-6-(1-isopropyl-1-phenylmethyl)-1,2,4-triazine 3,5-diamino-6-(9-xantyl)-1,2,4-triazine; and 3,5-diamino-6-{1-(4-chlorophenoxy)-1-methyl}ethyl-1,2,4-triazine; Alternatively, they may be selected from the group consisting of salts, tautomers, or solvates thereof. Or the compound, 2,6-diamino-3-(diphenylmethyl)-pyrazine; 2,4-diamino-5-(diphenylmethyl)-pyrimidine; 2,6-diamino-3-(1-cyclopentyl-1-phenyl-methyl)pyrazine; 2,4-diamino-5-(1-cyclopentyl-1-phenyl-methyl)-pyrimidine; 2,6-diamino-3-[1-(6-methoxynaphthalene)methyl]pyrazine; 2,4-diamino-5-[1-(6-methoxynaphthalene)methyl]pyrimidine; 2,6-diamino-3-[1-(6-methoxynaphthalene)ethyl]-pyrazine; 2,4-diamino-5-[1-(6-methoxynaphthalene)ethyl]pyrimidine; 2,6-diamino-3-(1-isopropyl-1-phenylmethyl)pyrazine; 2,4-diamino-5-(1-isopropyl-1-phenylmethyl)pyrimidine; 2,6-diamino-3-(9-xantyl)-pyrazine; 2,4-diamino-5-(9-xantyl)-pyrimidine; 2,6-diamino-3-[1,1-bis-(4-chlorophenyl)methyl]pyrazine; 2,4-diamino-5-[1,1-bis-(4-chlorophenyl)methyl]pyrimidine; 2,6-diamino-3-[1,1-bis-(4-fluorophenyl)methyl]pyrazine; 2,4-diamino-5-[1,1-bis-(4-fluorophenyl)methyl]pyrim gin; 2,6-diamino-3-{1-(4-chlorophenoxy)-1-methyl}ethylpyrazine; and 2,4-diamino-5-{1-(4-chlorophenoxy)-1-methyl}ethylpyrimidine; Alternatively, the present invention provides a compound of Formula 1 or a salt, tautomer, or solvate thereof, selected from the group consisting of salts, tautomers, or solvates thereof, for use as defined in Embodiment 14.

[0028] Embodiment 16 provides a method for treating cytokine storm syndrome or cytokine release syndrome, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a salt, tautomer, or solvate thereof to a subject in need thereof, wherein the compound of formula (I) is as defined in any of the preceding embodiments.

[0029] Embodiment 17 provides the use of a compound of formula (I) as defined above or a salt, tautomer, or solvate thereof in the manufacture of a pharmaceutical product for use in the treatment of cytokine storm syndrome or cytokine release syndrome, wherein the compound of formula (I) is as defined in any one of Embodiments 1 to 15.

[0030] As Embodiment 18, the present invention further provides a pharmaceutical composition for use in the treatment of cytokine storm syndrome or cytokine release syndrome, comprising a compound of formula (I) or a salt thereof, a tautomer or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the compound of formula (I) is as defined in any one of Embodiments 1 to 15.

[0031] The use of salts of the compound of formula (I) forms one aspect of the present invention. Preferred salts are pharmaceutically acceptable acid addition salts. Suitable pharmaceutically acceptable acid addition salts include those formed using organic and inorganic acids from both organic and inorganic acids, such as hydrochloric acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, malonic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, oxaloacetate, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, glutamic acid, naphthoic acid, and isethionic acid. Ethanolonates, malates, mandalates, benzoates, and salicylates are also suitable. Base addition salts also form one aspect of the present invention.

[0032] In the preparation of the compound of formula (I), the compound or a salt thereof can be obtained as a reaction solvent, a crystallization solvent, or a solvate of their components. The use of such solvates forms another aspect of the present invention. Suitable pharmaceutically acceptable solvates include hydrates.

[0033] Certain compounds of structure (I) have a chiral center and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers. All such isomers are included in the present invention. All geometric isomers of compounds of formula (I), whether individual isomers or mixtures thereof, are also included in the scope of the present invention. Thus, compounds of structure (I) in trans and cis configurations form further embodiments of the present invention, as well as all other tautomeristic forms of structure (I), including mixtures thereof. Furthermore, some crystalline forms of compounds of structure (I) may exist as polymorphs, all of which are included in the present invention.

[0034] The diazine compound of formula (I) can be prepared by a procedure similar to the one described in EP-0372934A. Formulas (II) and (I) disclosed in EP-0372934A The reaction products of (V) and (V) can be replaced with corresponding sulfur-containing heterocyclic analogs to prepare compounds useful in the present invention.

[0035] Alternatively, the compound of formula (I) can be prepared according to the procedure described in WO2009090431A.

[0036] The preparation of the specific compounds described above will be described later in this specification. Related compounds within the scope of the present invention can be prepared by obvious or routine modifications of the disclosed process, using appropriate starting materials to introduce desired substituents and parts of compounds within the scope of formula (I).

[0037] Salts of the compound of formula (I) can be obtained by the presence of residual acid in the preparation process. Alternatively, the salt can be prepared by mixing the compound of formula (I) as a free base with a pharmaceutically acceptable acid in a suitable solvent, removing the solvent and recovering the salt, or by crystallizing the salt from the solvent.

[0038] In a further embodiment, the present invention provides pharmaceutical compositions for the treatment of disorders such as cytokine storm syndrome or cytokine release syndrome, or pharmaceutically acceptable salts, tautomers, or solvates thereof, as mixtures with one or more pharmaceutically acceptable excipients.

[0039] The compound of formula (I) is present in the composition of the present invention in an effective unit dosage form, i.e., in a sufficient amount to be effective against the disorder in vivo.

[0040] The pharmaceutically acceptable carriers present in the composition of the present invention may be substances conventionally used for the purpose of administering drugs. Otherwise, they may be inert or medically acceptable liquid or solid materials compatible with the active ingredient.

[0041] These pharmaceutical compositions can be administered orally or parenterally, for example, as suppositories, ointments, creams, powders, or transdermal patches. However, oral administration and intravenous injection of the compositions are preferred.

[0042] For oral administration, the fine powder or granules may be provided in the form of a liquid medicine, water or syrup, a dry capsule or sachet, or a non-aqueous suspension which may contain a diluent, a dispersant, and / or a surfactant, or in a suspension in water or syrup. Flavorings, preservatives, suspending agents, or thickeners may be included as desired or required. The dry powder or granules may be compressed to form tablets or placed in capsules.

[0043] Regarding injection, the compound may be present in a sterile aqueous injection solution that may contain antioxidants or buffers.

[0044] Free bases or their salts or solvates may also be administered in a pure form, unbound to other additives, in which case capsules or sachets are preferred carriers.

[0045] Alternatively, the active compound may be presented in its pure form as an effective unit dose, compressed, for example, as a tablet.

[0046] Other compounds that may be included are, for example, medically inert ingredients such as lactose, starch, or solid and liquid diluents such as calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules, and for suspensions or emulsions. The formulation contains water or vegetable oil, lubricants such as talc or magnesium stearate, gelling agents such as colloidal clay, thickeners such as tragacanth gum or sodium alginate, and other therapeutically acceptable auxiliary components such as humectants, preservatives, buffers, and antioxidants that are useful as carriers in such formulations.

[0047] Presentations of tablets or other forms provided in separate units may conveniently include units containing an amount of the compound of formula I, or a multiple thereof, that is effective in such doses, for example, 5 mg to 500 mg, usually about 10 mg to 250 mg.

[0048] The pharmaceutical compositions of the present invention can be prepared by mixing the compound of formula (I) with a pharmaceutically acceptable carrier. Conventional pharmaceutical excipients may be added as needed. Examples of suitable formulations are described in U.S. Patent No. 4,649,139.

[0049] As described above, compounds of formula (I) are generally useful for treating such disorders by oral administration or intravenous injection.

[0050] The compound of formula (I) is usually administered at a dose of 0.01 mg / kg to 20 mg / kg per day, preferably 0.1 to 5.0 mg / kg per day.

[0051] WO2016 / 198878A1 discloses the interferon-gamma (IFN-γ) inhibitory activity of specific compounds useful in the present invention. As detailed below, the diazine and triazine compounds of the present invention have also been found to possess inhibitory activity against TNF-α, as well as interleukins 1β, 2, 4, 6, 8, 13, and 17. Therefore, this combination of therapeutic activity makes these compounds useful in the treatment of cytokine storm syndrome and cytokine release syndrome. [Examples]

[0052] experiment The compound of formula (I) can be prepared using appropriate starting materials according to the method disclosed in WO2009 / 090431A1. Example 1: 2,4-diamino-5-(diphenylmethyl)-pyrimidine [ka] Formula: C 17 H 16 N4 Molecular weight: 276.34 LCMS: m / z = 277.20, protonated parent ion (M + H) + Match 1 H-NMR (DMSO-d6): 1 The H-NMR spectrum was found to be consistent with the structure described above. Purity: >99% by HPLC The compound of formula (I) can be investigated for its inhibition of the pro-inflammatory cytokines interleukin (IL) 1β, 6, 8, and 17A, interferon (IFN) gamma, and tumor necrosis factor (TNF) α in peripheral blood mononuclear cells (PBMCs) isolated from fresh human buffy coat by centrifugation using Lymphoprep® (Stemcell Technologies). All human cells were tested for 1% penicillin / sodium The cells are grown in RPMI-1640 cell culture medium supplemented with treptomycin and 5% heat-inactivated fetal bovine serum.

[0053] PBMCs stimulated with LPS (Salmonella enterica serotype tiphimurium), containing the compound under study, are incubated for 24 hours and reconstituted with dimethyl sulfoxide (DMSO). Levels of secreted interleukin-1β and interleukin-6 are measured in the cell culture supernatant using a cytometry bead array, and cell viability is quantified using trypan blue.

[0054] PBMCs stimulated with a mixture between TNF-α and IL-17A are incubated for 24 hours with the compound under study and reconstituted with DMSO. Levels of secreted interleukin-8 are measured in the cell culture supernatant using a cytometry bead array, and cell viability is quantified using trypan blue.

[0055] PBMCs stimulated with PMA / ionomycin containing the compound under investigation are incubated for 24 hours and reconstituted with DMSO. Interleukin-17A secretion levels are measured in the cell culture supernatant using a cytometry bead array, and cell viability is quantified using trypan blue.

[0056] PBMCs stimulated with PMA / ionomycin containing the compound under investigation are incubated for 24 hours and reconstituted with DMSO. Interferon-gamma and tumor necrosis factor α secretion levels in the cell culture supernatant are measured using the Human Quantikine ELISA Kit, and cell viability is quantified using trypan blue.

[0057] The compounds can be investigated for their inhibition of the pro-inflammatory cytokines interleukin-2, 4, and 13 in human CD4-positive T cells isolated from fresh isolated PBMCS using a CD4-positive T cell isolation kit.

[0058] CD4-positive T cells stimulated with beads coated with antibodies against CD2, CD3, and CD28, including the compound under study, are incubated for 48 hours and reconstituted with DMSO. Secretion levels of interleukin 2, 4, and 13 are measured in the cell culture supernatant using a cytometry bead array, and cell viability is measured using the MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay.

[0059] Secreted IL-4 levels can be measured using electrochemiluminescence (MSD kit, Meso Scale Discovery), while secreted IL-2 levels can be measured using near-field homogeneous time-resolved fluorescence (HTRF), and the amount of viable cells can be measured by adding resazurin (PrestoBlue®).

[0060] Compound 1, 3,5-diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine, and Compound 2, 3,5-diamino-6-(diphenylmethyl)-1,2,4-triazine, were studied using the method described above. Compound 1 was found to exhibit high inhibition of pro-inflammatory cytokines IL-1β, IL-8, IL-6, IFN-γ, and TNF-α, and moderate inhibition of IL-17, as shown in Figures 1-7. Compound 2 was found to exhibit high inhibition of IL-17A, IL-8, IFN-γ, and TNF-α (at the highest concentration), and moderate inhibition of IL-1β and IL-6, as shown in Figures 8-12.

[0061] Compound 1 has the following structure. [ka]

[0062] Compound 2 has the following structure. [ka]

[0063] Compounds 1 and 2 can be prepared by the process disclosed in WO2009 / 090431A1.

[0064] When tested in IL-2 and IL-4 inhibition assays, 3,5-diamino-6-(diphenylmethyl)-1,2,4-triazine was found to exhibit relative EC50s of 28.0 and 50.5 nM, respectively.

[0065] [Table 1]

[0066] These data demonstrate good levels of inhibition of both IL-2 and IL-4 by 3,5-diamino-6-(diphenylmethyl)-1,2,4-triazine without significant inhibition of T cell proliferation.

[0067] We also studied 3,5-diamino-6-(diphenylmethyl)-1,2,4-triazine for its IL-7A inhibition in a human PBMC model.

[0068] [Table 2]

[0069] Further data is shown in the figure. Figure 1 shows the effect of compound 1 on cytokine production from stimulated human peripheral blood mononuclear cells, with the bars representing the mean ± SEM for n=9–12 subjects.

[0070] Figure 2 shows the inhibitory effect of compound 1 on interleukin (IL) 1 beta, with the bars representing the mean ± SEM for n=9-10 subjects.

[0071] Figure 3 shows the inhibitory effect of compound 1 on interleukin (IL) 6, with the bars representing the mean ± SEM for n=9-10 subjects.

[0072] Figure 4 shows the inhibitory effect of compound 1 on interleukin (IL) 8, with the bars representing the mean ± SEM for n=8 to 12 subjects.

[0073] Figure 5 shows the inhibitory effect of compound 1 on tumor necrosis factor (TNF) α, with the bars representing the mean ± SEM for n=8 to 12 subjects.

[0074] Figure 6 shows the inhibitory effect of compound 1 on interferon-gamma (IFN-γ), with the bars representing the mean ± SEM for n=5 to 7 subjects.

[0075] Figure 7 shows the inhibitory effect of compound 1 on interleukin (IL) 17A, with the bars representing the mean ± SEM for n=5 to 7 subjects.

[0076] Figure 8 shows the inhibitory effect of compound 2 on interleukin (IL) 17A, with the bars representing the mean ± SEM for n=9 to 12 subjects.

[0077] Figure 9 shows the inhibitory effect of compound 2 on tumor necrosis factor (TNF) α, with the bars representing the mean ± SEM for n=9 to 12 subjects.

[0078] Figure 10 shows the inhibitory effect of compound 2 on interferon-gamma (IFN-γ), with the bars representing the mean ± SEM for n=5 to 8 subjects.

[0079] Figure 11 shows the inhibitory effect of compound 2 on interleukin (IL) 8, with the bars representing the mean ± SEM for n=5 to 8 subjects.

[0080] Figure 12 shows the inhibitory effect of compound 2 on interleukin (IL) 6, with the bars representing the mean ± SEM for n=9-10 subjects.

Claims

1. Compounds of formula (I), or salts, tautomers, or solvates thereof, for use in the treatment of cytokine storm syndrome or cytokine release syndrome. 【Chemistry 1】 (In the formula, X is N and Y is C, or X is C and Y is N, or Both X and Y are N, A is a substituted 3- to 10-membered heteroring containing 1, 2, or 3 sulfur atoms, wherein the heteroring is (i) a halogen, and (ii) all optionally substituted with one or more halogens, hydroxyls, and aryls. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, or C １－６ Alkoxy, as well as (iii) amino, monosubstituted or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and C １－６ Having two or more substituents selected from alkylthio groups, or A is the basis of the following equation 【Chemistry 2】 (In the formula, ・ indicates a connection point.) And, R1 is hydrogen, or C １－１０ alkyl, C ２－１０ alkenyl, benzyl, piperidin-methyl, thienyl-methyl, furyl-methyl or C ３－１０ cycloalkyl, and these are all optionally substituted with hydroxy, halogen, carboxamide, halo C １－６ alkyl, C １－６ alkyl or C １－６ alkoxy, or Y is N and unsubstituted, R2 is amino, C １－１０ Alkyl or phenyl, R3 is phenyl, xantyl, or naphthyl, each being a halogen or C １ -C ６ It is optionally substituted with 1 to 5 substituents selected from alkoxy groups. R4 is hydrogen, C １ -C ６ Alkyl, C ３ -C ８ Selected from cycloalkyl, phenyl, xantyl, or naphthyl, wherein the phenyl or naphthyl is a halogen or C １ -C ６ It may be optionally substituted with 2 to 5 substituents selected from alkoxy groups. R5 is hydrogen, N ＊ When R1 is hydrogen or a substituent, it is either =NH or N ＊ is the group NRaRb, where Ra and Rb are independently H or alkyl groups, or N ＊ This is one or more halogens or C １ -C ６ (A piperazinyl ring optionally substituted with an alkoxy group.)

2. For use in the treatment of cytokine storm syndrome induced by infection, please The compound of formula (I) described in item 1, or its salt, tautomer, or solvate.

3. A compound of formula (I) according to claim 1 or 2, or a salt, tautomer or solvate thereof, for use in the treatment of cytokine storm syndrome induced by infection selected from sepsis, influenza virus, coronavirus, and dengue virus.

4. A compound of formula (I) according to any of the preceding claims, or a salt, tautomer, or solvate thereof, for use in the treatment of cytokine storm syndrome induced by coronavirus.

5. A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to any of the preceding claims, wherein both X and Y are N.

6. A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to any of the preceding claims, wherein R1 is hydrogen.

7. A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to any of the preceding claims, wherein R2 is an amino acid.

8. A is a substituted 3- to 10-membered heteroring containing 1, 2, or 3 sulfur atoms, wherein the heteroring is (i) a halogen, and (ii) all optionally substituted with one or more halogens, hydroxyls, and aryls. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, or C １－６ Alkoxy, as well as (iii) amino, monosubstituted or disubstituted amino, alkenyloxy, acyl, acyloxy, cyano, nitro, aryl and C １－６ A compound of formula (I), or a salt, tautomer, or solvate thereof, having two or more substituents selected from alkylthio groups, for use according to any of the preceding claims.

9. A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to any of the preceding claims, wherein A is thienyl or benzothienyl.

10. A is halogen, C １－６ Alkyl, C １－６ Alkoxy, Halo C １－６ Alkyl and Halo C １－６ A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to claim 8 or 9, substituted with one or more substituents selected from alkoxys.

11. A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to any one of claims 8 to 10, wherein A is substituted with one, two, or three chlorine or bromine atoms.

12. The aforementioned compound, 3,5-diamino-6-(2-thienyl)-1,2,4-triazine; 3,5-diamino-6-(3-thienyl)-1,2,4-triazine; 5(3)-amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazinemethanesulfonate; 5(3)-amino-6-(2-thienyl)-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazinemethanesulfonate; 3,5-diamino-6-(2-thienyl)-1,2,4-triazine; 3,5-diamino-6-(3-thienyl)-1,2,4-triazine; 3,5-diamino-6-[3-(2,5-dichlorothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine; 5(3)-amino-6-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine; 5(3)-amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine; 5(3)-amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine; 3,5-diamino-6-[2-(4,5-dibromothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(5-bromothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(3-bromothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(5-chlorothienyl)]-1,2,4-triazine; 3,5-diamino-6-[2-(benzo[b]thienyl)]-1,2,4-triazine; and 3,5-diamino-6-[2-(3-chlorobenzo[b]thienyl)]-1,2,4-triazine; Alternatively, they may be selected from the group consisting of salts, tautomers, or solvates thereof. or the compound 2,6-diamino-3-(2-thienyl)-pyrazine; 2,4-diamino-5-(2-thienyl)-pyrimidine; 2,6-diamino-3-(3-thienyl)-pyrazine; 2,4-diamino-5-(3-thienyl)-pyrimidine; 2,6-diamino-3-[3-(2,5-dichlorothienyl)]-pyrazine; 2,4-diamino-5-[3-(2,5-dichlorothienyl)]-pyrimidine; 2,6-diamino-3-[2-(3,4,5-trichlorothienyl)]-pyrazine; 2,4-diamino-5-[2-(3,4,5-trichlorothienyl)]-pyrimidine; 2(6)-amino-3-(2-thienyl)-2,3(2,5)-dihydro-6(2)-imino-5-methylpyrazine; 4(2)-amino-5-(2-thienyl)-2,3(2,5)-dihydro-2(4)-imino-1-methylpyrimidine; 2(6)-amino-3-(2-thienyl)-2,3(2,5)-dihydro-6(2)-imino-5-ethylpyrazine; 4(2)-amino-5-(2-thienyl)-2,3(2,5)-dihydro-2(4)-imino-1-ethylpyrimidine; 2(6)-amino-3-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-6(2)-imino-5-methylpyrazine; 4(2)-amino-5-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-2(4)-imino-2-methylpyrimidine; 2(6)-amino-3-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-6(2)-imino-5-methylpyrazine; 4(2)-amino-5-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-2(4)-imino-1-methylpyrimidine; 2(6)-amino-3-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-6(2)-imino-5-ethylpyrazine; 4(2)-amino-5-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-2(4)-imino-2-ethylpyrimidine; 2,6-diamino-3-[2-(4,5-dibromothienyl)]-pyrazine; 2,4-diamino-5-[2-(4,5-dibromothienyl)]-pyrimidine; 2,6-diamino-3-[2-(5-bromothienyl)]-pyrazine; 2,4-diamino-5-[2-(5-bromothienyl)]-pyrimidine; 2,6-diamino-3-[2-(3-bromothienyl)]-pyrazine; 2,4-diamino-5-[2-(3-bromothienyl)]-pyrimidine; 2,6-diamino-3-[2-(5-chlorothienyl)]-pyrazine; 2,4-diamino-5-[2-(5-chlorothienyl)]-pyrimidine; 2,6-diamino-3-[2-(benzo[b]thienyl)]-pyrazine; 2,4-diamino-5-[2-(benzo[b]thienyl)]-pyrimidine; 2,6-diamino-3-[2-(3-chlorobenzo[b]thienyl)]pyrazine; and Compounds of formula (I), or salts, tautomers, or solvates thereof, selected from the group consisting of 2,4-diamino-5-[2-(3-chlorobenzo[b]thienyl)]pyrimidines, or salts, tautomers, or solvates thereof, for use according to any of the preceding claims.

13. A is the basis of the following equation 【Transformation 3】 (In the formula, ・ indicates a connection point.) And, R3 is phenyl, xanthyal, or naphthyl, each containing one or more halogens or C １ -C ６ It is optionally substituted with 1 to 5 substituents selected from alkoxy groups. R4 is hydrogen, C １ -C ６ Alkyl, C ３ -C ８ Selected from cycloalkyl, phenyl, xantyl, or naphthyl, wherein the phenyl or naphthyl is a halogen or C １ -C ６ The alkoxy group may be optionally substituted with 2 to 5 substituents selected from the alkoxy group. R5 is hydrogen. A compound of formula (I), or a salt, tautomer, or solvate thereof, for use according to any one of claims 1 to 7.

14. R3 is either a 1-term halogen or C １ -C ６ A phenyl compound optionally substituted with two or three substituents selected from alkoxy groups, R4 is C １ -C ６ Alkyl, C ３ -C ８ Selected from cycloalkyl and phenyl, wherein the phenyl is a halogen or C １ -C ６ It may be optionally substituted with two or three substituents selected from the alkoxy group. A compound of formula 1 or a salt thereof, tautomer, or solvate for use according to claim 13.

15. The aforementioned compound, 3,5-diamino-6-[1,1-bis-(4-chlorophenyl)methyl]-1,2,4-triazine; 3,5-diamino-6-[1,1-bis-(4-fluorophenyl)methyl]-1,2,4-triazine; 3,5-diamino-6-(diphenylmethyl)-1,2,4-triazine; 3,5-diamino-6-(1-cyclopentyl-1-phenyl-methyl)-1,2,4-triazine; 3,5-diamino-6-[1-(6-methoxynaphthalene)methyl]-1,2,4-triazine; 3,5-diamino-6-[1-(6-methoxynaphthalene)ethyl]-1,2,4-triazine; 3,5-diamino-6-(1-isopropyl-1-phenylmethyl)-1,2,4-triazine 3,5-diamino-6-(9-xantyl)-1,2,4-triazine; 3,5-diamino-6-{1-(4-chlorophenoxy)-1-methyl}ethyl-1,2,4-triazine; and 2,4-diamino-5-(diphenylmethyl)-pyrimidine; Alternatively, they may be selected from the group consisting of salts, tautomers, or solvates thereof. or the compound 2,6-diamino-3-(diphenylmethyl)-pyrazine; 2,4-diamino-5-(diphenylmethyl)-pyrimidine; 2,6-diamino-3-(1-cyclopentyl-1-phenyl-methyl)pyrazine; 2,4-diamino-5-(1-cyclopentyl-1-phenyl-methyl)pyrimidine; 2,6-diamino-3-[1-(6-methoxynaphthalene)methyl]pyrazine; 2,4-diamino-5-[1-(6-methoxynaphthalene)methyl]pyrimidine; 2,6-diamino-3-[1-(6-methoxynaphthalene)ethyl]pyrazine; 2,4-diamino-5-[1-(6-methoxynaphthalene)ethyl]pyrimidine; 2,6-diamino-3-(1-isopropyl-1-phenylmethyl)pyrazine; 2,4-diamino-5-(1-isopropyl-1-phenylmethyl)pyrimidine; 2,6-diamino-3-(9-xanthyal)-pyrazine; 2,4-diamino-5-(9-xanthyal)-pyrimidine; 2,6-diamino-3-[1,1-bis-(4-chlorophenyl)methyl]pyrazine; 2,4-diamino-5-[1,1-bis-(4-chlorophenyl)methyl]pyrimidine; 2,6-diamino-3-[1,1-bis-(4-fluorophenyl)methyl]pyrazine; 2,4-diamino-5-[1,1-bis-(4-fluorophenyl)methyl]pyrimidine; 2,6-diamino-3-{1-(4-chlorophenoxy)-1-methyl}ethylpyrazine; and 2,4-diamino-5-{1-(4-chlorophenoxy)-1-methyl}ethylpyrimidine; Alternatively, a compound of formula 1 or a salt, tautomer, or solvate thereof, selected from the group consisting of salts, tautomers, or solvates thereof, for use according to claim 14.

16. A method for treating cytokine storm syndrome or cytokine release syndrome, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a salt, tautomer, or solvate thereof to a subject in need thereof, wherein the compound of formula (I) is as described in any of the preceding claims.

17. A pharmaceutical composition for use in the treatment of cytokine storm syndrome or cytokine release syndrome, comprising a compound of formula (I) or a salt thereof, a tautomer or solvate thereof, and one or more pharmaceutically acceptable excipients, wherein the compound of formula (I) is as described in any one of claims 1 to 15.

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