Diamidine derivatives for anti-inflammatory applications

Abstract

A pharmaceutical composition used for the prevention or treatment of inflammation in a subject comprises a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof. Furthermore, the method for preventing or treating inflammation in a subject is carried out by administering a therapeutically effective amount of the pharmaceutical composition to a subject requiring the treatment. TIFF2026512833000023.tif44130 (wherein R1 contains one or more cycloalkyl groups, and R2 contains one or more cycloalkyl groups.)

Description

Technical Field

[0001] This application claims priority based on U.S. Provisional Patent Application No. 63 / 492,661, filed on March 28, 2023, the content of which is incorporated herein by reference.

[0002] The present disclosure relates to the treatment and prevention of inflammatory diseases or disorders, and more specifically, to compounds that are diamidine derivatives, and to the treatment and prevention of inflammatory diseases or disorders using pharmaceutical compositions.

Background Art

[0003] Pentamidine has recently been studied to bind to lipopolysaccharide (LPS), as described in the 2022 paper in Frontiers in Pharmacology by Wu et al. (doi: 10.3389 / fphar.2022.835081). Lipopolysaccharide is a macromolecule containing lipids and polysaccharides. Lipopolysaccharide is a bacterial toxin present in the outer membrane of Gram-negative bacteria and causes an inflammatory response in the host. Long-term exposure to LPS can lead to inflammatory diseases and disorders.

[0004] For example, when LPS is present in the intestine (due to the presence of a large amount of Gram-negative bacteria), it may cause inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. LPS may also be present in the liver, and the resulting inflammation may cause fatty liver disease.

[0005] A 2022 paper by Wu et al. in Frontiers in Pharmacology (doi: 10.3389 / fphar.2022.835081) revealed that the ether skeleton of pentamidine is involved in binding to LPS and suppresses LPS-derived inflammation in subjects. Modification of the ether skeleton by adding an oxygen atom reduced the anti-inflammatory properties of pentamidine. However, despite its anti-inflammatory properties, pentamidine still exhibited a considerable level of toxicity in subjects. As a result, pentamidine was unsuitable for the treatment of inflammatory diseases or disorders due to its toxicity, as the harms outweighed the benefits, especially when pentamidine had to be taken long-term to treat or prevent inflammation caused by or associated with inflammatory diseases or disorders. [Overview of the Initiative]

[0006] This disclosure relates to a group of diamidine derivatives. At least some of these compounds may be suitable for the treatment of LPS-mediated anti-inflammatory disorders in subjects.

[0007] Furthermore, the toxicity of pentamidine in subjects has been found to be due to its affinity for endo-exonucleases. Endo-exonucleases can be involved in DNA repair and recombination. For example, U.S. Patent No. 5,324,830 by Resnick et al. describes the isolation of a DNA fragment encoding the endo-exonuclease RhoNuc from S. cerevisiae. Consequently, inhibiting endo-exonuclease function in healthy cells using pentamidine may result in toxicity to subjects.

[0008] This disclosure relates to a group of diamidine derivative compounds modified to reduce the toxicity to subjects caused by the ingestion of diamidine derivatives compared to pentamidine, by reducing binding to endo-exonucleases or inhibiting the binding of diamidine derivatives to endo-exonucleases.

[0009] The diamidine derivative compounds of this disclosure can reduce their binding activity to endo-exonucleases compared to pentamidine, thereby maintaining binding affinity to LPS while reducing toxicity upon administration to the subject. As a result of the reduced toxicity, these diamidine derivative compounds have significantly lower toxicity compared to pentamidine and can be used in the treatment of inflammatory diseases or disorders.

[0010] In a broad aspect of this disclosure, the diamidine derivative compounds have the following structure 1. TIFF2026512833000002.tif44130

[0011] R1 and R2 are substituted to reduce or prevent the diamidine derivative from binding to the endo-exonuclease. As shown in Chow's U.S. Patent No. 11,103,468, the introduction of specific substituents at the R1 and R2 positions may conversely increase the binding affinity to the endo-exonuclease, so appropriate substituent selection is necessary. Furthermore, the size and / or properties of R1 and R2 must not be such that these substituents prevent the compound from binding to LPS via the backbone.

[0012] As a result, R1 and R2, which contain at least five-membered cycloalkyl groups, appear to cause a sufficient change in the structure of pentamidine (presumably due to the bulkiness of substituents containing larger ring structures), thereby preventing the binding of diamidine derivatives to endo-exonucleases, reducing toxicity to the subject, while maintaining interaction with LPS, thereby removing LPS and consequently reducing inflammation.

[0013] Since diamidine derivatives are ingestible, they can be administered orally. Compared to the known properties and mechanism of action of pentamidine, the structure of the diamidine derivative compounds is remarkably maintained as they pass through the subject's digestive system and are absorbed, at least partially, into the subject's liver. As a result, diamidine derivatives react with LPS present in the digestive system and / or liver, reducing inflammation by removing toxins in the digestive system and / or liver, and thus treating or preventing related diseases or disorders.

[0014] A first broad embodiment is the compound of formula 1. TIFF2026512833000003.tif44130 (wherein R1 contains one or more cycloalkyl groups, and R2 contains one or more cycloalkyl groups.)

[0015] In some embodiments, R1 and R2 are identical.

[0016] In some embodiments, one or more cycloalkyl groups of R1 are a single cycloalkyl group, and one or more cycloalkyl groups of R2 are a single cycloalkyl group.

[0017] In some embodiments, one or more cycloalkyl rings of R1 include ring atoms selected from C and N, and one or more cycloalkyl rings of R2 include ring atoms selected from C and N.

[0018] In some embodiments, one or more cycloalkyl rings of R1 are partially substituted, and one or more cycloalkyl rings of R2 are partially substituted.

[0019] In some embodiments, one or more cycloalkyl rings of R1 are aromatic, and one or more cycloalkyl rings of R2 are aromatic.

[0020] In some embodiments, one or more cycloalkyl groups of R1 contain imidazole, and one or more cycloalkyl groups of R2 contain imidazole.

[0021] In some embodiments, the compound has the following structure. TIFF2026512833000004.tif34129

[0022] In some embodiments, the compound has the following structure. TIFF2026512833000005.tif29129

[0023] In some embodiments, the compound has the following structure. TIFF2026512833000006.tif25129(wherein, A1 is C1-C7 alkyl or OH-C1-C7 alkyl, and A2 is C1-C7 alkyl or OH-C1-C7 alkyl.)

[0024] In some embodiments, A1 and A2 are the same.

[0025] In some embodiments, A1 is OH-C1-C7 alkyl and A2 is OH-C1-C7 alkyl.

[0026] In some embodiments, the compound has the following structure. TIFF2026512833000007.tif31129(wherein, A1 is C1-C7 alkyl or OH-C1-C7 alkyl, A2 is C1-C7 alkyl or OH-C1-C7 alkyl, A3 is C1-C7 alkyl, OH-C1-C7 alkyl, or hydrogen, and A4 is C1-C7 alkyl, OH-C1-C7 alkyl, or hydrogen.)

[0027] In some embodiments, A1 and A2 are the same.

[0028] In some embodiments, A1 is an OH-C1~C7 alkyl group, and A2 is an OH-C1~C7 alkyl group.

[0029] In some embodiments, A1 and A2 are each selected from the group consisting of ethanol, propanol, methanol, and isopropanol.

[0030] In some embodiments, A3 and A4 are selected from the group consisting of ethanol, propanol, methanol, and isopropanol, respectively.

[0031] In some embodiments, A3 and A4 are identical.

[0032] In some embodiments, A3 and A4 are hydrogen atoms, respectively.

[0033] In some embodiments, R1 contains at least two N atoms within the monocyclic or polycyclic ring of at least one cycloalkyl group from among one or more cycloalkyl groups, and R2 contains at least two N atoms within the monocyclic or polycyclic ring of at least one cycloalkyl group from among one or more cycloalkyl groups.

[0034] Another broad embodiment is a pharmaceutical composition used for the prevention or treatment of inflammation in a subject, comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof. TIFF2026512833000008.tif44130 (wherein R1 contains one or more cycloalkyl groups, and R2 contains one or more cycloalkyl groups.)

[0035] In some embodiments, R1 and R2 are identical.

[0036] In some embodiments, one or more cycloalkyl groups of R1 are a single cycloalkyl group, and one or more cycloalkyl groups of R2 are a single cycloalkyl group.

[0037] In some embodiments, one or more cycloalkyl rings of R1 include ring atoms selected from C and N, and one or more cycloalkyl rings of R2 include ring atoms selected from C and N.

[0038] In some embodiments, one or more cycloalkyl rings of R1 are partially substituted, and one or more cycloalkyl rings of R2 are partially substituted.

[0039] In some embodiments, one or more cycloalkyl rings of R1 are aromatic, and one or more cycloalkyl rings of R2 are aromatic.

[0040] In some embodiments, one or more cycloalkyl groups of R1 include imidazole, and one or more cycloalkyl groups of R2 include imidazole.

[0041] In some embodiments, the compound has the following structure. TIFF2026512833000009.tif37142

[0042] In some embodiments, the compound has the following structure. TIFF2026512833000010.tif37142

[0043] In some embodiments, inflammation occurs in the intestines, and the pharmaceutical composition is adapted for oral administration.

[0044] In some embodiments, inflammation is caused by inflammatory bowel disease.

[0045] In some embodiments, inflammation occurs in the liver, and the pharmaceutical composition is adapted for oral administration.

[0046] In some embodiments, the subject has a fatty liver disease associated with liver inflammation.

[0047] In some embodiments, the compound has the following structure. TIFF2026512833000011.tif38142 (in the formula, B1, B2, B3, B4, B5, B6, B7, B8, B9, B 10 Each of these is selected from the group consisting of C1-C7 alkyl, OH-C1-C7 alkyl, and hydrogen.

[0048] In some embodiments, one of the B1-B5 groups is C1-C7 alkyl or OH-C1-C7 alkyl, and the other groups of the B1-B5 group are H, and B6-B 10 One of the groups is C1-C7 alkyl or OH-C1-C7 alkyl, and B6-B 10 The other group in the group is H.

[0049] Another broad embodiment is a method for treating or preventing inflammation in at least one of the intestines and liver of a subject, comprising administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject in need.

[0050] In some embodiments, administration is performed orally.

[0051] In some embodiments, the compound is encapsulated in a sustained-release capsule to delay its release after oral administration.

[0052] In some embodiments, administration is performed parenterally.

[0053] In some embodiments, the inflammation to be treated or prevented occurs in the intestines.

[0054] In some embodiments, inflammation is caused by or associated with inflammatory bowel disease.

[0055] In some embodiments, inflammatory bowel disease is ulcerative colitis.

[0056] In some embodiments, inflammatory bowel disease is Crohn's disease.

[0057] In some embodiments, the inflammation to be treated or prevented occurs in the liver.

[0058] In some embodiments, inflammation is caused by or associated with fatty liver disease.

[0059] Another broad embodiment is a method of using the compounds of the present disclosure to treat or prevent inflammation in a subject.

[0060] In some embodiments, the inflammation being treated or prevented is located in the intestines.

[0061] In some embodiments, inflammation is caused by or associated with inflammatory bowel disease.

[0062] In some embodiments, inflammatory bowel disease is ulcerative colitis.

[0063] In some embodiments, inflammatory bowel disease is Crohn's disease.

[0064] In some embodiments, the inflammation being treated or prevented is in the liver.

[0065] In some embodiments, inflammation is caused by or associated with fatty liver disease.

[0066] Another broad embodiment is a method for treating or preventing inflammatory bowel disease in a subject. The method comprises detecting inflammatory bowel disease in a subject and then administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject in need.

[0067] In some embodiments, detection is performed by measuring LPS in an intestinal sample taken from the subject.

[0068] In some embodiments, the method includes determining the effectiveness of the treatment by collecting a subsequent intestinal sample after administration and obtaining an indicator of inflammation in the subject's intestinal tract.

[0069] In some embodiments, the indicator of inflammation is determined by measuring LPS levels in an intestinal sample.

[0070] Another broad embodiment is a method for treating or preventing fatty liver disease in a subject. The method comprises detecting inflammatory bowel disease in a subject and then administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject in question.

[0071] In some embodiments, detection is performed by measuring LPS in an intestinal sample taken from the subject.

[0072] In some embodiments, the method includes determining the effectiveness of a treatment by obtaining an indicator of inflammation in the liver of a subject.

[0073] In some embodiments, an indicator of inflammation is determined by measuring the level of LPS in the liver. [Modes for carrying out the invention]

[0074] This disclosure relates to a group of diamidine derivative compounds that exhibit reduced toxicity to subjects compared to pentamidine, while being suitable for treating or preventing inflammatory diseases or disorders in subjects by binding to LPS (inflammatory substances). As a result of the reduced toxicity of the diamidine derivative compounds, these compounds are suitable for treating or preventing inflammatory diseases or disorders.

[0075] Diamidine derivative compounds retain the ether skeleton of pentamidine, which has been shown to confer the ability to target and bind to LPS, thereby inactivating or removing LPS and reducing LPS-induced inflammation in subjects. However, diamidine derivative compounds contain cycloalkyl groups as terminal substituents, and these cycloalkyl groups reduce or inhibit the binding of the diamidine derivative to endo-exonucleases, thereby reducing the associated toxicity.

[0076] The diamidine derivative compounds of this disclosure have the following structure (1). TIFF2026512833000012.tif44130

[0077] R1 and R2 are each one or more cycloalkyl groups, as they reduce the binding of the compound to the endo-exonuclease compared to pentamidine.

[0078] Pentamidine, and by extension the diamidine derivative compounds of this disclosure, can be administered orally and their integrity is remarkably maintained throughout the subject's digestive system; therefore, the diamidine derivative compounds of this disclosure are suitable for the treatment or prevention of inflammatory bowel diseases and / or disorders in the intestines (e.g., Crohn's disease, ulcerative colitis, and other inflammatory bowel diseases). Furthermore, since the diamidine derivative compounds reach the liver similarly to pentamidine, they are also applicable to the treatment and / or prevention of inflammatory diseases and / or disorders in the liver (e.g., fatty liver disease).

[0079] Unless otherwise specified, throughout the following specification and claims, “comprise” and its variations (such as “comprises” and “comprising”) shall be interpreted in an open and comprehensive sense, that is, “including but not limited to.”

[0080] In this specification, the expression "one embodiment" or "a particular embodiment" means that a specific function, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, expressions such as "in one embodiment" or "in a particular embodiment" found in various parts of this specification do not necessarily all refer to the same embodiment. Furthermore, specific functions, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0081] In this specification and the attached claims, the singular forms "a," "an," and "the" include the plural form unless otherwise clearly indicated by the context. Furthermore, it should be noted that the term "or" generally includes "and / or" unless otherwise clearly indicated by the context.

[0082] From the foregoing, it will be understood that although certain embodiments are described herein for illustrative purposes, various modifications are possible without departing from the spirit and scope of the teachings. Accordingly, the claims are not limited by the disclosed embodiments.

[0083] definition In this specification, "C1-C7 alkyl" refers to a linear or branched hydrocarbon group consisting of carbon atoms and hydrogen atoms, which does not contain unsaturated bonds, has 1 to 7 carbon atoms, and is bonded to the rest of the molecule by single bonds. Examples of C1-C7 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, and isobutyl.

[0084] In this specification, "C2-C7 alkenes" refers to linear or branched hydrocarbon groups consisting of carbon atoms and hydrogen atoms, containing one or more double bonds, having 2 to 7 carbon atoms, and being bonded to the rest of the molecule by single bonds. Examples of C1-C7 alkenes include, but are not limited to, ethylene, propylene, and butylene.

[0085] In this specification, "C2-C7 alkynes" refer to linear or branched hydrocarbon groups consisting of carbon atoms and hydrogen atoms, containing one or more triple bonds, having 2 to 7 carbon atoms, and being bonded to the rest of the molecule by single bonds. Examples of C1-C7 alkynes include, but are not limited to, acetylene and propyne.

[0086] In this specification, "cycloalkyl" refers to a monocyclic or polycyclic ring structure ranging from five-membered to ten-membered rings, which may be saturated, partially saturated, or unsaturated, and whose ring atoms are selected from N, O, S, and C. Examples of cycloalkyls include, but are not limited to, azetidinyl, tetrahydrofuran, dihydrofuran, dioxane, and morpholine. Cycloalkyls may be optionally substituted with one to five substituents independently selected from the group consisting of, for example, hydroxyl groups, thiol groups, cyano groups, nitro groups, linear or branched OH-C1~C7 alkyl groups, sulfonyl groups, halogen atoms, and amino groups.

[0087] In this specification, “intestinal sample” refers to a sample derived from the digestive tract of a subject. In some embodiments, the intestinal sample is specific to the large intestine. In other embodiments, the intestinal sample is specific to the ascending or descending colon. The intestinal sample may be a stool sample or other non-invasive sample derived from the intestinal tract of a subject. In some embodiments, the intestinal sample includes taking an intramucosal interface (MLI) sample from the subject. In some embodiments, the intestinal sample is a biopsy sample derived from the subject, for example, taken during a colonoscopy.

[0088] In this specification, "C1-C7 alkoxy" refers to a functional group represented by the formula -ORa, where Ra is the C1-C7 alkyl group as generally defined above. Examples of C1-C7 alkoxys include, but are not limited to, methoxy, propoxy, butoxy, and pentoxy.

[0089] In this specification, "OH-C1~C7 alkyl" refers to a C1~C7 alkyl group in which one or more hydrogen atoms in the C1~C7 alkyl group are substituted with "OH". Examples of OH-C1~C7 alkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, and 2-hydroxybutyl.

[0090] In this specification, "amino C1-C7 alkyl" refers to a C1-C7 alkyl group in which one hydrogen atom is replaced by an amino group. Examples of amino C1-C7 alkyl groups include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, and 2-aminobutyl.

[0091] In this specification, "halogen" refers to bromine, chlorine, fluorine, or iodine.

[0092] In this specification, "halogenated C1-C7 alkyl" refers to a C1-C7 alkyl group in which one or more hydrogen atoms are substituted with halogens.

[0093] In this specification, “inflammatory bowel disease” refers to patients with ulcerative colitis (UC), Crohn’s disease (CD), and / or unclassified inflammatory bowel disease (IBD-U).

[0094] In this specification, “inhibit” means a reduction or suppression of a given condition, symptom, disease or disorder, or a decrease in the baseline activity of a biological activity or process.

[0095] In this specification, "measuring" a protein sample means analyzing the sample to determine the expression level of a protein (or the expression level of a related protein) using techniques such as immunoassays (e.g., ELISA), semi-quantitative immunoblotting, mass spectrometry, and other techniques well known in the art for quantitatively and / or qualitatively analyzing the composition of a sample obtained from a subject.

[0096] In this specification, “pharmaceutical composition” means a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a form suitable for oral or parenteral administration.

[0097] In this specification, "pharmaceutically acceptable carrier" refers to a substance useful for preparing a pharmaceutical composition, and includes, for example, one or more diluents, surfactants, preservatives, buffers, isotonic agents, salts, excipients, lubricants, wetting agents, flavorings, and the like.

[0098] In this specification, “prevent,” “preventing,” or “prevention” means the preventive treatment of a disease or disorder, or delaying the onset or progression of a disease or disorder.

[0099] In this specification, "subject" means a mammal such as a human. The term "subject" does not imply any restrictions regarding sex or age.

[0100] In this specification, “treat,” “treating,” or “treatment” means alleviating or improving the condition of a subject with respect to a particular disease or disorder, which can be quantified by improvement of at least one physical parameter, symptom, or biomarker in a subject having the disease or disorder.

[0101] Typical synthesis method: Reaction scheme 1 The diamidine derivative compounds of this disclosure can be prepared by organic synthesis methods well known in the art by referring to the following reaction scheme and examples.

[0102] The starting materials, constituent units, reagents, acids, bases, dehydrating agents, solvents, etc., used in the synthesis of this compound are commercially available or can be manufactured using well-known techniques of organic synthesis.

[0103] In this specification, “salt” or “salts” means an acid acid or base salt of the compound of this disclosure. “Medically acceptable salt” means a salt that retains the biological function and properties of the compound of this disclosure. For example, the compounds of this disclosure may form acid acid and / or base salts via an amino group and / or a carboxyl group (or a similar group).

[0104] Pharmaceutically acceptable salts can be formed using inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, etc.) and / or organic acids (e.g., acetic acid, oxalic acid, succinic acid, etc.).

[0105] pharmaceutically acceptable base salts can be formed using inorganic bases (e.g., sodium hydroxide, potassium hydroxide, magnesium hydroxide, etc.) and / or organic bases (e.g., isopropylamine, cholinate, lysine, etc.).

[0106] All chemical formulas described herein are intended to represent either the unlabeled or isotope-labeled form.

[0107] The intermediates and final products can be purified using well-known methods (e.g., chromatography, partitioning, recrystallization, etc.).

[0108] The synthesis method for the compound in Equation 1 is shown in Scheme 1 below. TIFF2026512833000013.tif59170 Scheme 1: Synthesis example of a compound of formula II where R2 is hydrogen

[0109] The synthetic strategy for preparing the compound of formula 1 involves using p-bromophenol, and compound 5 can be obtained by substituting the para-position nitrile group. Dinitrile compound 6 is obtained by reacting at least 2 equivalents of compound 5 with a suitable alkyl dibromide, alkyl dihalide, or alkyl reagent having two leaving groups in the presence of a base. The further reaction to convert dinitrile 6 to species 1 is carried out by treating with ethanol in the presence of hydrochloric acid, followed by treatment with 1 equivalent of a suitable amine (R2NH2), and then treatment with ammonia in ethanol.

[0110] Typical synthesis method: Reaction scheme 2 The synthetic strategy for preparing the compound of formula 1 involves converting dinitrile to species 1 using compound 6, which can be achieved by treating it with ethanol in the presence of hydrochloric acid, followed by treatment with 1 equivalent of a suitable amine (R1NH2) and 1 equivalent of a suitable amine (R2NH2). TIFF2026512833000014.tif32170 Scheme 2: Typical synthesis method of the compound in formula 1

[0111] Typical preparation methods for pharmaceutical compositions The pharmaceutical compositions of this disclosure can be prepared as pharmaceutically acceptable salts by reacting a compound in a basic form with a pharmaceutically acceptable acid. In some examples, instead, a compound in a free acid form is reacted with a base.

[0112] Compounds in basic or acidic form can be prepared from their corresponding basic or acidic salt form.

[0113] The chiral atoms (e.g., carbon) of the compounds of this disclosure can be prepared in racemic or enantiomerically enriched forms, e.g., in (R), (S), or (RS) configurations. In some embodiments, each enantiomer atom has an enantiomer excess of at least 50%. In some embodiments, each enantiomer atom has an enantiomer excess of at least 60%. In some embodiments, each enantiomer atom has an enantiomer excess of at least 70%. In some embodiments, each enantiomer atom has an enantiomer excess of at least 80%. In some embodiments, each enantiomer atom has an enantiomer excess of at least 90%. Substituents of the unsaturated bond may be present in cis or trans configurations.

[0114] The resulting stereoisomer mixture can be separated based on the physicochemical differences between its components, for example, by chromatography and / or fractionation crystallization.

[0115] This disclosure further includes variations of the process using intermediates that can be obtained at any stage of the process as starting materials. It is understood that the compounds and intermediates disclosed herein are interconvertible using arts well known in the art. Where a method for producing a particular material is not specifically described herein, it is understood that its synthesis can be carried out based on arts well known teachings.

[0116] The above scheme is merely one example of a method for producing the compound, and it should be understood that other suitable methods are available for synthesizing the compounds of this disclosure.

[0117] The following examples are provided to help those skilled in the art better understand the Disclosure. These are merely illustrative and illustrative examples and do not limit the scope of the Disclosure, but are added for illustrative and illustrative purposes only. It will be understood that the Disclosure can be further illustrated and illustrated by other examples without departing from this teaching.

[0118] Example 1 Endo-exonuclease inhibitory activity was measured using pentamidine and pentamidine derivatives in which the central part (carbon skeleton) of pentamidine was substituted. Endo-exonuclease inhibitory activity was tested in vitro. The results are shown in Table 1 below. TIFF2026512833000015.tif122169 Table 1: Inhibition of endo-exonuclease activity associated with modification of the central carbon skeleton.

[0119] The results shown in Table 1 indicate that modification of the central carbon skeleton of pentamidine does not eliminate endo-exonuclease activity. Since endo-exonuclease inhibitory activity is related to the cytotoxicity of a compound to patients, when this compound is administered to subjects for the treatment of inflammatory diseases, this modification of the central skeleton of pentamidine will not significantly reduce cytotoxicity. Rather, the inhibition of endo-exonuclease by pentamidine is related to the structure at both ends of the pentamidine molecule (which occurs by substituting nitrogen atoms that are single-bonded to adjacent carbon atoms at both ends of the pentamidine molecule (by substituting the hydrogen atoms bonded to those nitrogen atoms with other groups)). Furthermore, it has been found that substituting these R1 and R2 positions of pentamidine with cycloalkyl groups preferably containing one or more nitrogen atoms reduces the inhibition of endo-exonuclease activity by pentamidine derivatives while maintaining the binding affinity of the compound to LPS, compared to pentamidine. For example, suitable substituents at the R1 and R2 positions have been found to be 3a,4,5,6,7,7a-hexahydrobenzimidazole or N-hydroxyethylimidazole.

[0120] Consideration It was found that introducing bulky groups at the R1 and R2 positions of the following diamidine derivatives reduced or inhibited the binding of pentamidine to endo-exonucleases. TIFF2026512833000016.tif35129

[0121] For example, when both R1 and R2 contain 3a,4,5,6,7,7a-hexahydrobenzimidazole or N-hydroxyethylimidazole, it was found that binding to LPS could be maintained while inhibiting the binding of the diamidine derivative to endo-exonuclease. Therefore, these diamidine derivatives were shown to exert anti-inflammatory effects by binding to LPS, while their toxicity was significantly reduced by decreasing or inhibiting binding to endo-exonuclease (endo-exonuclease activity correlates with toxicity in humans).

[0122] However, it has been suggested that simply introducing bulky groups at the R1 and R2 positions may not be sufficient to reduce the binding of diamidine derivatives to endonucleases and consequently reduce toxicity. This is illustrated in U.S. Patent No. 11,103,468 by Cho, in which the binding affinity of diamidine derivatives to endo-exonucleases is actually increased compared to pentamidine when phenyl groups are substituted at R1 and R2.

[0123] Therefore, it is hypothesized that introducing a cycloalkyl group containing one or more nitrogen atoms or atoms belonging to the same periodic table column as nitrogen (such as phosphorus) at the R1 and R2 positions reduces the binding affinity of diamidine derivatives to endonucleases, thereby reducing toxicity to subjects after administration of diamidine derivatives.

[0124] A 2017 paper by Zhao E. et al. in Hepatology (66:922-935) showed that pentamidine reduces liver triglycerides, serum ALT, body weight, and food intake in mice. This study demonstrates that pentamidine can mitigate non-alcoholic fatty liver disease in mice. However, since the interaction between pentamidine and endonucleases can cause cytotoxicity in patients when treating fatty liver disease, reducing endonuclease inhibition by the administered compound is advantageous in reducing cytotoxicity. This can be achieved by introducing substituents at the R1 and R2 positions of pentamidine, more specifically, by including one or more ring structures in these substituents (in some examples, it is preferable to include at least one nitrogen atom within the ring structure). Substitution with cycloalkyl groups at the R1 and R2 positions of pentamidine has been shown to reduce endo-exonuclease activity while maintaining the compound's binding affinity to LPS.

[0125] Furthermore, it was found that substitutions at the R1 and R2 positions do not affect the binding affinity of diamidine derivatives to LPS, thus maintaining their anti-inflammatory properties regardless of R1 and R2 substitutions. However, it has been proven that maintaining the carbon-ether skeleton is important in order to maintain the LPS-binding ability of diamidine derivatives.

[0126] It was found that the aromaticity of the R1 and R2 rings is not necessary to reduce or eliminate the binding of diamidine derivatives to endo-exonucleases. However, the presence of one or more unsaturated bonds in the R1 and R2 rings of diamidine derivatives appears to contribute, at least to reducing the binding activity of diamidine derivatives to endo-exonucleases.

[0127] Exemplary treatments for inflammatory bowel disease Examples of the use of the diamidine derivative compounds disclosed herein include the treatment and / or prevention of inflammation caused by or associated with inflammatory bowel disease. Exemplary therapeutic approaches to inflammatory bowel disease using the diamidine derivative compounds described herein are described below.

[0128] The presence or absence of inflammatory bowel disease (IBD) in the subject can be determined. IBD can be detected in subjects by measuring one or more biomarkers (e.g., calprotectin, LPS, etc.) derived from one or more intestinal samples taken from the subject, as is well known in this field, or by observing the symptoms experienced by the subject.

[0129] If the presence of inflammatory bowel disease is detected or determined in a subject, one or more diamidine derivative compounds taught herein can be administered in therapeutically effective amounts. In some embodiments, the diamidine derivatives are administered orally. In some embodiments, the capsule containing one or more diamidine derivatives is a sustained-release capsule, for example, to delay the release of one or more diamidine derivative compounds until the capsule reaches the large intestine.

[0130] In some examples, the diamidine derivative compound is administered parenterally.

[0131] After administering one or more therapeutically effective doses of diamidine derivative compounds, intestinal samples can be taken from subjects to determine whether inflammatory bowel disease is being effectively treated (biomarkers are measured from these intestinal samples and compared to corresponding results obtained from initial intestinal samples).

[0132] Exemplary treatments for fatty liver disease Examples of uses for the diamidine derivative compounds of this disclosure include the treatment and / or prevention of inflammation caused by or associated with fatty liver disease. Exemplary therapeutic methods for fatty liver disease using the diamidine derivative compounds described herein are described below.

[0133] The presence or absence of fatty liver disease in a subject can be determined. Fatty liver disease can be detected by measuring one or more biomarkers (e.g., apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, LPS, ghrelin, tumor necrosis factor-α, etc.) from one or more samples taken from the subject, as is well known in this field for detecting fatty liver disease in subjects, or it can be determined from the symptoms reported by the subject.

[0134] If fatty liver disease is detected or determined in a subject, one or more diamidine derivative compounds of this instruction may be administered in a therapeutically effective amount. In some embodiments, the diamidine derivatives are administered orally. In some embodiments, the capsule containing one or more diamidine derivatives is, for example, a sustained-release capsule to delay the release of one or more diamidine derivative compounds.

[0135] In some examples, the diamidine derivative compound is administered parenterally.

[0136] After administering one or more therapeutically effective doses of diamidine derivative compounds, it is possible to determine whether fatty liver disease is being effectively treated by taking samples from the subject (biomarkers are measured from these samples and compared to the results of the initial sample taken from the subject).

[0137] Exemplary and non-limiting embodiments of the present invention have been described in detail with reference to the accompanying drawings. This detailed description is intended to provide further details to those skilled in the art for carrying out preferred embodiments of the teachings and is not intended to limit the scope of the invention. Furthermore, each of the additional features and teachings disclosed above and below can be used alone or in combination with other features and teachings to provide useful amidine and diamidine compounds and methods for treating cancer using them.

[0138] Furthermore, the combinations of features and processes disclosed in the above detailed description and experimental examples are not necessarily required to carry out the invention in the broadest sense, but are merely taught to specifically illustrate representative embodiments of the invention. Moreover, the above exemplary embodiments and the various features of the various independent and dependent claims below can be combined in ways not specifically and explicitly described to provide additional useful embodiments of this teaching.

[0139] All features disclosed in the specification and / or claims are intended to be disclosed individually and independently, independently of the configuration of features in the embodiments and / or claims, for the purpose of limiting the purpose of the original written disclosure and the subject matter of the claims. Furthermore, all representations of ranges of values ​​or groups of elements are intended to disclose any possible intermediate values ​​or intermediate elements for the purpose of limiting the purpose of the original written disclosure and the subject matter of the claims.

Claims

1. The compound represented by formula 1 below. (In the formula, R1 contains one or more cycloalkyl groups, and R2 contains one or more cycloalkyl groups.)

2. The compound according to claim 1, A compound in which R1 and R2 are the same.

3. A compound according to claim 1 or 2, One or more cycloalkyl groups in R1 are single cycloalkyl groups. A compound in which one or more cycloalkyl groups of R2 are one cycloalkyl group.

4. A compound according to any one of claims 1 to 3, One or more cycloalkyl rings of R1 contain ring atoms selected from C and N. A compound in which one or more cycloalkyl rings of R2 contain ring atoms selected from C and N.

5. The compound according to claim 4, One or more cycloalkyl rings of R1 are partially substituted, A compound in which one or more cycloalkyl rings of R2 are partially substituted.

6. The compound according to claim 5, One or more cycloalkyl rings of R1 are aromatic, A compound in which one or more cycloalkyl rings of R2 are aromatic.

7. The compound according to claim 6, One or more cycloalkyl rings of R1 contain imidazole, A compound in which one or more cycloalkyl rings of R2 contain imidazole.

8. The compound according to claim 7, A compound represented by the following formula.

9. A compound according to any one of claims 1 to 5, A compound represented by the following formula.

10. A pharmaceutical composition used to prevent or treat inflammation in a subject, A pharmaceutical composition comprising a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof. (In the formula, R1 contains one or more cycloalkyl groups, and R2 contains one or more cycloalkyl groups.)

11. A pharmaceutical composition according to claim 10, One or more cycloalkyl groups in R1 are single cycloalkyl groups. A pharmaceutical composition in which one or more cycloalkyl groups of R2 are a single cycloalkyl group.

12. A pharmaceutical composition according to claim 10 or 11, One or more cycloalkyl rings of R1 contain ring atoms selected from C and N. A pharmaceutical composition in which one or more cycloalkyl rings of R2 contain ring atoms selected from C and N.

13. A pharmaceutical composition according to claim 12, One or more cycloalkyl rings of R1 are partially substituted, A pharmaceutical composition in which one or more cycloalkyl rings of R2 are partially substituted.

14. A pharmaceutical composition according to claim 13, One or more cycloalkyl rings of R1 are aromatic, A pharmaceutical composition in which one or more cycloalkyl rings of R2 are aromatic.

15. A pharmaceutical composition according to any one of claims 10 to 14, One or more cycloalkyl rings of R1 contain imidazole, A pharmaceutical composition in which one or more cycloalkyl rings of R2 contain imidazole.

16. A pharmaceutical composition according to claim 15, A pharmaceutical composition in which the compound is represented by the following formula.

17. A pharmaceutical composition according to any one of claims 10 to 15, A pharmaceutical composition in which the compound is represented by the following formula.

18. A pharmaceutical composition according to any one of claims 10 to 17, The inflammation is occurring in the intestines. A pharmaceutical composition that is suitable for oral administration.

19. A method of using a compound according to any one of claims 1 to 9 to prevent or treat inflammation in a subject.

20. The method according to claim 19, Inflammation is caused by or associated with fatty liver disease.

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