Compounds and their use in treating non-viral and infectious diseases - Patents.com

Abstract

The present invention relates to compounds having a structure according to general formula I, II, or III for use in the treatment of non-viral infections or diseases caused by non-viral infections. The present invention relates to compounds having a structure according to general formula III, and pharmaceutical compositions comprising at least one of said compounds. The present invention further relates to methods of treating non-viral infections or diseases caused by non-viral infections.

Description

[Technical Field]

[0001] The present invention relates to compounds having a structure according to general formula I or II or III for use in the treatment of non-viral infections or diseases caused by non-viral infections. The present invention further relates to methods of treating non-viral infections or diseases caused by non-viral infections. The present invention relates to compounds having a structure according to general formula III, and pharmaceutical compositions comprising at least one of said compounds. [Background technology]

[0002] At the 2017 G20 Summit, world leaders deemed the spread of antimicrobial resistance one of the greatest challenges facing humanity (G20 Leaders Declaration: Shaping an interconnected world. (2017)). "No time to wait" - In 2019, the World Health Organization (WHO) issued an urgent warning about antimicrobial resistance, a global crisis that threatens 100 years of progress (Interagency Coordination Group on Antimicrobial Resistance: No time to wait: securing the future from drug-resistant infections, World Health Organization (2019)). The challenges associated with antimicrobial resistance are complex and multifaceted, but if we act now, it is not too late to overcome the threat of drug-resistant infections. The emergence of drug-resistant bacteria is primarily due to widespread overuse and misuse of drugs, which places continuous selective pressure on bacteria (Davies and Davies, 2010; CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: USDapartment of Health and Human Services, CDC (2019)). Surprisingly, for several antibiotics in clinical use, there is a lack of scientific data regarding the precise mechanism of action and protein targets involved. This hinders our understanding of resistance development and the identification of novel antibiotics for the development of next-generation drugs (Bandow et al., 2003; Ang et al., 2017).

[0003] One example of a poorly understood mechanism of action is that of the commonly used antibiotic metronidazole. Metronidazole has been the standard treatment for several infectious diseases for over 45 years (primarily due to a lack of alternatives) against several protozoal infections, anaerobic bacteria (e.g., Clostridioides difficile), and microaerophilic bacteria (e.g., Helicobacter pylori) (Loefmark et al., 2010). However, despite its widespread application in the treatment of H. pylori and C. difficile, its exact mechanism of action remains poorly understood, and alternative drugs with improved efficacy, particularly against metronidazole-resistant strains, are urgently needed.

[0004] Helicobacter pylori infection is characterized by increasing antibiotic resistance, which is impacting the effectiveness of current treatment options (Vakil et al., 2007; Megraud et al., 2004). In Europe, H. pylori resistance rates among adults are as high as 18% for clarithromycin, 14% for levofloxacin, and 35% for metronidazole, making resistance a major cause of treatment failure (Ang et al., 2017). H. pylori is a Gram-negative, microaerophilic bacterium implicated in numerous gastrointestinal disorders, including gastritis, peptic ulcer disease, and even gastric cancer (Perez-Perez et al., 2004; Megraud et al., 2004). Furthermore, unless treated, colonization of the human stomach persists for life (Lehours et al., 2007). It is the first officially recognized bacterial carcinogen and a widely recognized human pathogen, with 50% of the world's population infected. In developing countries, the prevalence of infection reaches 80%. Of those infected, 15% develop gastritis and 1% develop cancer (Ang et al., 2017). Therefore, the development of new or improved drugs, improved treatment options, and monitoring of antibiotic resistance in H. pylori are essential for infection management in clinical practice (Ang et al., 2017; Boucher et al., 2009; Zagari et al., 2018).

[0005] Jamshidi et al. (2022) described triazole / quinoline hybrid compounds with antifungal activity against Saccharomyces cerevisiae and Candida albicans, as well as activity against aerobic bacteria such as E. coli and Staphylococcus aureus. Li et al. (2019) described an indole-nitroimidazole conjugate that reduces gene expression in methicillin-resistant Staphylococcus aureus. Foroumadi et al. (2004) described the in vitro antituberculosis activity of two thiadiazole derivatives.

[0006] Thus, there is a great need for new compounds with antibacterial activity for the treatment of non-viral and infectious diseases, especially bacterial diseases caused by bacteria that are resistant to commonly used antibiotics.

[0007] It is an object of the present invention to provide novel compounds and their use in the treatment of non-viral infections or diseases caused by non-viral infections. Summary of the Invention

[0008] According to the present invention, the object is to provide a compound of general formula I or II or III for use in the treatment of non-viral infections or diseases caused by non-viral infections.

[0009] [ka]

[0010] (In the formula, R 1 is C1-C6 alkyl or C1-C6 haloalkyl, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl; The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl may optionally be halogen, OR 3 , or SR 3 and R 3 is hydrogen or C1-C6 alkyl) The problem is solved by providing a compound having a structure according to the following formula: or a pharmaceutically acceptable salt thereof, However, for compounds of general formula II or III, R 1 When is methyl, R 2 is not ethyl or C1-C4 alkyl substituted with halogen, OH, OMe, NH2, NH(CH3)2, or NH(CH2-CH3)2; R 1 When is CF3, R 2 is not a C1-C4 alkyl substituted with halogen, R 1 When is isopropyl, R 2 is not a C1-C4 alkyl substituted with halogen, However, with respect to general formula III, R 1 and R 2 cannot both be methyl.

[0011] According to the invention, the object is to Administering the compound having the general formula I, II or III according to the present invention or the pharmaceutical composition of the present invention to a subject in need thereof. The problem is solved by providing a method for treating a non-viral infection or a disease caused by a non-viral infection, comprising:

[0012] According to the invention, this object is to provide compounds of the general formula III

[0013] [ka]

[0014] (In the formula, R 1is C1-C6 alkyl or C1-C6 haloalkyl, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl; The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl may optionally be halogen, OR 3 , or SR 3 and R 3 is hydrogen or C1-C6 alkyl) The problem is solved by providing a compound having a structure according to the following formula: or a pharmaceutically acceptable salt thereof, however R 1 and R 2 Both of the groups cannot be methyl. R 1 When is methyl, R 2 is not ethyl or C1-C4 alkyl substituted with halogen, OH, OMe, NH2, or NH(CH3)2; R 1 When is CF3, R 2 is not a C1-C4 alkyl substituted with halogen, R 1 When is isopropyl, R 2 is not C1-C4 alkyl substituted with halogen.

[0015] According to the invention, the object is to (i) at least one compound having a structure according to general formula III of the present invention; (ii) optionally, pharmaceutical excipient(s) and / or carrier(s); The problem is solved by a pharmaceutical composition comprising:

[0016] According to the present invention, this object is solved by providing compounds having a structure according to general formula III of the present invention for use in medicine. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows compounds of the present invention. [Figure 2] Figure 2 shows exemplary results of an MTT assay for determining IC50 values ​​of compounds of the invention in HeLa cells. Values ​​obtained after MTT readout of nitroimidazole compounds are normalized to the DMSO control (DMSO control = 100% cell viability after 24 h incubation). The MTT assay was performed within a concentration range of 10 µM to 1 mM. [Figure 3] FIG. 3 shows the in vitro stability of compounds of the invention in mouse plasma. [Figure 4] Figure 4 shows the modification of recombinantly expressed H. pylori thiol peroxidase (HpTpx) by metronidazole or Metro-P3, as identified via intact protein mass spectrometry after protein purification. H. pylori thiol peroxidase was overexpressed in E. coli in the presence of 500 μM metronidazole or Metro-P3, then purified via affinity chromatography, analyzed via IP-MS, and compared to the unmodified HpTpx enzyme. [Figure 5] Figure 5 shows the results of a peroxidase assay using the thiol peroxidase HpTpx, showing that increasing the degree of modification with metro or metro-P3 decreases activity. [Figure 6] Figure 6 shows IP-MS studies of the enhanced efficacy of Metro-P3. Metro-P3 binds to HpTpx more readily (approximately 8-fold) than metronidazole, demonstrating the enhanced affinity of Metro-P3 over metronidazole. [Figure 7] Figure 7 shows the different binding modes of metronidazole versus metro-P3 in crystallography studies with HpTpx. Metro-P3 binds to the reduced state of HpTpx, which is a more stable and more abundant form of HpTpx in the cytoplasm. [Figure 8] FIG. 8 shows pharmacokinetic data for various nitroimidazole compounds of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0018] Before describing the present invention in more detail below, it is understood that this invention is not limited to the particular methodology, protocols, and reagents described herein, as these may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For purposes of the present invention, all references cited herein are incorporated herein by reference in their entirety.

[0019] Concentrations, amounts, and other numerical data may be expressed or presented in range format herein. It is understood that such range format is used merely for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. By way of example, a numerical range of "1 to 20" should be interpreted to include not only the explicitly recited 1 to 20 value, but also each individual value and subrange within the specified range. Thus, included within this numerical range are individual values ​​such as 1, 2, 3, 4, 5...17, 18, 19, 20, etc., and subranges such as 2 to 10, 8 to 15, etc. This same principle applies to ranges reciting only one numerical value, such as "more than 150 mg / day." Furthermore, such interpretation should apply regardless of the breadth of the range or the characteristics recited.

[0020] As used herein and throughout the specification, the term "alkyl" refers to a saturated, straight- or branched-chain hydrocarbon monoradical. Preferably, an alkyl group contains 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms, more preferably 1 to 4 carbon atoms. In some embodiments, alkyl groups employed in the present invention contain 1 to 6 carbon atoms (C 1-6In another embodiment, the alkyl group employed contains 1 to 5 carbon atoms (C 1-5 In another embodiment, the alkyl group employed contains 1 to 4 carbon atoms (C 1-4 In another embodiment, the alkyl group employed contains 1 to 3 carbon atoms (C 1-3 In another embodiment, the alkyl group employed contains 1 to 2 carbon atoms (C 1-2 (Alkyl). In another embodiment, the alkyl group employed is methyl. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-propyl, butyl, iso-butyl, n-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, and the like, which may bear one or more substituents. Substituents on alkyl groups include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety. In some embodiments, the alkyl chain is linear. In some embodiments, the alkyl chain is branched. In some embodiments, the alkyl chain is substituted. In some embodiments, the alkyl chain is unsubstituted. In some embodiments, the alkyl chain is linear, substituted or unsubstituted. In some embodiments, the alkyl chain is branched, substituted or unsubstituted.

[0021] As used herein and throughout the specification, the term "alkenyl" refers to a straight or branched chain hydrocarbon monoradical containing at least one double bond (-C=C-). Preferably, an alkenyl group contains 2 to 5 carbon atoms, i.e., 2, 3, 4, 5, or 6 carbon atoms, more preferably 1 to 4 carbon atoms. In some embodiments, alkenyl groups employed in the present invention contain 2 to 6 carbon atoms (C 2-6alkenyl). In another embodiment, the alkenyl group employed contains 2 to 5 carbon atoms (C 2-5 alkenyl). In another embodiment, the alkenyl group employed contains 2 to 4 carbon atoms (C 2-4 alkenyl). In another embodiment, the alkenyl group employed contains 2 to 3 carbon atoms (C 2-3 alkenyl). In another embodiment, the alkenyl group employed contains two carbon atoms (C2 alkenyl). Examples of alkenyl radicals include, but are not limited to, allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl, and the like, which may bear one or more substituents. Alkenyl group substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety. In some embodiments, the alkenyl chain is linear. In some embodiments, the alkenyl chain is branched. In some embodiments, the alkenyl chain is substituted. In some embodiments, the alkenyl chain is unsubstituted. In some embodiments, the alkenyl chain is linear, substituted or unsubstituted. In some embodiments, the alkenyl chain is branched, substituted or unsubstituted.

[0022] As used herein and throughout the specification, the term "alkynyl" refers to an alkyl group having at least one triple bond (-C = Alkynyl refers to a straight or branched chain hydrocarbon monoradical containing 3 to 6 carbon atoms (C-). Preferably, the alkynyl group contains 3 to 6 carbon atoms, i.e., 3, 4, 5, or 6 carbon atoms, more preferably 3 to 4 carbon atoms. In some embodiments, the alkynyl group employed in the present invention contains 3 to 6 carbon atoms (C 3-6 In another embodiment, the alkynyl group employed contains 3 to 5 carbon atoms (C 3-5 In another embodiment, the alkynyl group employed contains 3 to 4 carbon atoms (C2-4 alkynyl). In another embodiment, the alkynyl group employed contains four carbon atoms (C4 alkynyl). In another embodiment, the alkynyl group employed contains three carbon atoms (C3 alkynyl). Examples of alkenyl radicals include, but are not limited to, propargyl, but-1-yn, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, or 2-propynyl, and the like, which may bear one or more substituents. Alkynyl group substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety. In some embodiments, the alkynyl chain is straight-chained. In some embodiments, the alkynyl chain is branched-chained. In some embodiments, the alkynyl chain is substituted. In some embodiments, the alkynyl chain is unsubstituted. In some embodiments, the alkynyl chain is straight-chained, substituted or unsubstituted. In some embodiments, the alkynyl chain is branched-chained, substituted or unsubstituted.

[0023] As used herein and throughout the specification, the term "haloalkyl" refers to an alkyl group substituted with up to one halogen substituent per halo substitution. The halogen substituent is preferably fluorine. The haloalkyl is preferably perfluoroalkyl. In some embodiments, haloalkyl groups employed in the present invention contain 1 to 6 carbon atoms (C 1-6 In another embodiment, the haloalkyl group employed in the invention contains 1 to 5 carbon atoms (C 1-5 In another embodiment, the haloalkyl group employed in the invention contains 1 to 4 carbon atoms (C 1-4 In another embodiment, the haloalkyl group employed in the invention contains 1 to 3 carbon atoms (C 1-3 In another embodiment, the haloalkyl group employed in the invention contains 1 to 2 carbon atoms (C 1-2haloalkyl). In another embodiment, the haloalkyl group employed in the present invention contains one carbon atom (C1 haloalkyl). In another embodiment, the haloalkyl group employed in the present invention is trifluoromethyl. Exemplary fluoro-substituted C1-C2 alkyls include -CFH2, -CF2H, -CF3, CH2CH2F, -CH2CHF2, -CHFCH3, -CHFCH3, -CF2CHF2. Perfluoro-substituted C1-C2 haloalkyls include, for example, -CF3 and -CF2CF3. In some embodiments, the haloalkyl is C1 haloalkyl, particularly -CF3.

[0024] As used herein and throughout the specification, the term "substituted" refers to a group such as alkyl, alkenyl, or alkynyl, which may be substituted with one or more substituents, for example, halogen, OR, or the like. 3 , or SR 3 (In the formula, R 3 is hydrogen or C1-C6 alkyl). "Substituted" with reference to a group indicates that one or more hydrogen atoms bonded to member atoms within the group are replaced with a defined substituent or substituent selected from the group of suitable substituents. It should be understood that the term "substituted" includes an implicit provision that such substitution is in accordance with the allowed valences of the replaced atom and substituents, and that the substitution results in a stable compound. When it is stated that a group may contain one or more substituents, one or more member atoms within the group may be substituted. Furthermore, a single member atom within a group may be substituted with more than one substituent, provided that such substitution is in accordance with the allowed valences of the atom.

[0025] Nitroimidazole compounds for treating non-viral infections As noted above, the present invention provides compounds having general formula I or II or III for use in the treatment of non-viral infections or diseases caused by non-viral infections.

[0026] Compounds having general formula I, II or III

[0027] [ka]

[0028] is a compound (wherein R 1 is C1-C6 alkyl or C1-C6 haloalkyl, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl; R 2 wherein the C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl is optionally selected from halogen, OR 3 , or SR 3 and R 3 is hydrogen or C1-C6 alkyl) or a pharmaceutically acceptable salt thereof.

[0029] - Waiver of Rights According to the invention, the compounds for use according to the invention are compounds of general formula II or III, wherein R 1 is methyl, R 2 is ethyl, or C1-C4 alkyl substituted with halogen, OH, OMe, NH2, NH(CH3)2, or NH(CH2-CH3)2) isn't it.

[0030] According to the invention, the compounds for use according to the invention are compounds of general formula II or III, wherein R 1 is CH3, R 2 is C1-C4 alkyl substituted with halogen) isn't it.

[0031] According to the invention, the compounds for use according to the invention are compounds of general formula II or III, wherein R 1 is isopropyl, R 2 is C1-C4 alkyl substituted with halogen) isn't it.

[0032] According to the invention, the compounds for use according to the invention are compounds of general formula III, wherein R 1 and R 2 are both methyl) isn't it.

[0033] In one embodiment of the compound for use according to the present invention, R 1 is methyl, and the compound has formula Ia or IIa or IIIa

[0034] [ka]

[0035] It has.

[0036] In one embodiment of the compound for use according to the present invention, R 2 is C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, or n-hexyl.

[0037] In one embodiment of the compound for use according to the present invention, R 2 is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl.

[0038] In one embodiment of the compound for use according to the present invention, R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl, but-1-yn, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, or 2-propynyl.

[0039] In one embodiment of the compound for use according to the present invention, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl, which is substituted with halogen.

[0040] In one embodiment of the compound for use according to the present invention, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl, which is OR 3 is substituted with R 3 is hydrogen or methyl.

[0041] In one embodiment of the compound for use according to the present invention, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl, which is 3 is substituted with R 3 is hydrogen or methyl.

[0042] In one embodiment of the compound for use according to the invention, the compound has formula Ia

[0043] [ka]

[0044] and R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or but-1-yne, or R 2is C1-C6 alkyl, preferably methyl.

[0045] In one embodiment of the compound for use according to the invention, the compound is of formula IIa

[0046] [ka]

[0047] and R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or but-1-yne.

[0048] In one embodiment of the compound for use according to the invention, the compound is of formula IIa

[0049] [ka]

[0050] and R 2 is C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl or ethyl.

[0051] In one embodiment of the compound for use according to the invention, the compound is of formula IIa

[0052] [ka]

[0053] and R 2 is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, or dimethylallyl.

[0054] In one embodiment of the compound for use according to the invention, the compound is of formula IIIa

[0055] [ka]

[0056] and R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or but-1-yne.

[0057] Preferably, the compound is MF-01: 1-(2-methoxyethyl)-2-methyl-5-nitro-1H-imidazole:

[0058] [ka]

[0059] MF-02: 2-(methoxymethyl)-1-methyl-5-nitro-1H-imidazole:

[0060] [ka]

[0061] MF-03: 1-(2-ethoxyethyl)-2-methyl-5-nitro-1H-imidazole:

[0062] [ka]

[0063] MF-04: 2-(ethoxymethyl)-1-methyl-5-nitro-1H-imidazole:

[0064] [ka]

[0065] MF-05: 2-methyl-5-nitro-1-(2-propoxyethyl)-1H-imidazole:

[0066] [ka]

[0067] MF-06: 1-methyl-5-nitro-2-(propoxymethyl)-1H-imidazole:

[0068] [ka]

[0069] MF-07: 1-(2-(allyloxy)ethyl)-2-methyl-5-nitro-1H-imidazole:

[0070] [ka]

[0071] MF-08: 2-((allyloxy)methyl)-1-methyl-5-nitro-1H-imidazole:

[0072] [ka]

[0073] MF-09: 2-methyl-1-(2-((3-methylbut-2-en-1-yl)oxy)ethyl)-5-nitro-1H-imidazole:

[0074] [ka]

[0075] Metro-P2: 1-(2-methyl-5-nitro-1H-imidazol-1-yl)pent-4-yn-2-ol:

[0076] [ka]

[0077] Metro-P3: 2-methyl-5-nitro-1-((prop-2-yn-1-yloxy)methyl)-1H-imidazole:

[0078] [ka]

[0079] and Metro-P1: 2-methyl-5-nitro-1-(2-(prop-2-yn-1-yloxy)ethyl)-1H-imidazole:

[0080] [ka]

[0081] is selected from.

[0082] More preferably, the compound is

[0083] [ka]

[0084] is selected from.

[0085] Preferably, the non-viral infection is an infection caused by a protozoan, an anaerobic bacterium, or a microaerophilic bacterium.

[0086] Preferably, the protozoal infection is an infection caused by Trichomonas vaginalis, Giardia intestinalis (G. lambia), or Entamoeba histolytica.

[0087] More preferably, the non-viral infection is an infection caused by an anaerobic or microaerophilic bacterium.

[0088] Preferably, the non-viral infection is an infection caused by Helicobacter pylori, Clostridioides difficile, Fusobacterium nucleatum, or Gardnerella vaginalis.

[0089] In a preferred embodiment, the non-viral infection is an infection with a strain of H. pylori that is resistant to metronidazole.

[0090] The compounds of the present invention preferably bind to thiol peroxidases whose inhibition can induce toxic effects on bacteria. One such thiol peroxidase is Helicobacter thiol peroxidase HpTpx (O25151). The compounds of the present invention also preferably bind to the Helicobacter pylori chaperonin HpGroEL (P42383).

[0091] Treatment method As noted above, the present invention provides methods for treating non-viral infections or diseases caused by non-viral infections.

[0092] The method comprises the step of administering to a subject in need thereof a compound having general formula I, II or III according to the present invention or a pharmaceutical composition according to the present invention.

[0093] Preferably, a therapeutically effective amount of a compound having general formula I, II or III according to the present invention or a pharmaceutical composition according to the present invention is administered to a subject.

[0094] A "therapeutic amount" or "therapeutically effective amount" of a compound of the invention (i.e., a compound having general Formula I, II, or III) or a pharmaceutical composition of the invention, either term used interchangeably herein, is an amount that produces a desired therapeutic result.

[0095] The present invention also provides the use of a compound of the present invention (ie, a compound having general formula I or II or III) or a pharmaceutical composition of the present invention for the manufacture of a medicament.

[0096] Preferably, the non-viral infection is an infection caused by a protozoan, an anaerobic bacterium, or a microaerophilic bacterium.

[0097] Preferably, the protozoal infection is an infection with Trichomonas vaginalis, G. lamblia, or Entamoeba histolytica.

[0098] More preferably, the non-viral infection is an infection caused by an anaerobic or microaerophilic bacterium.

[0099] Preferably, the anaerobic or microaerophilic bacterial infection is an infection caused by Helicobacter pylori, Clostridioides difficile, Fusobacterium nucleatum, or Gardnerella.

[0100] In a preferred embodiment, the non-viral infection is an infection with a strain of H. pylori that is resistant to metronidazole.

[0101] Nitroimidazole compounds As noted above, the present invention provides compounds having the general formula III:

[0102] Compounds having general formula III

[0103] [ka]

[0104] is a compound (wherein R 1 is C1-C6 alkyl or C1-C6 haloalkyl, R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl; The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl may optionally be halogen, OR 3 , or SR 3 and R 3is hydrogen or C1-C6 alkyl) or a pharmaceutically acceptable salt thereof.

[0105] - Waiver of Rights According to the present invention, the compound of the present invention is R 1 and R 2 is not a compound in which both are methyl.

[0106] In accordance with the present invention, the compounds of the present invention have the following structure:

[0107] [ka]

[0108] It is not a compound having the formula:

[0109] According to the present invention, the compound of the present invention is R 1 is methyl, R 2 is ethyl or C1-C4 alkyl substituted with halogen, OH, OMe, NH2, or NH(CH3)2 Not a compound.

[0110] According to the present invention, the compound of the present invention is R 1 is CH3, R 2 is C1-C4 alkyl substituted with halogen Not a compound.

[0111] According to the present invention, the compound of the present invention is R 1 is isopropyl, R 2 is C1-C4 alkyl substituted with halogen Not a compound.

[0112] In accordance with the present invention, the compounds of the present invention have the following structure:

[0113] [ka]

[0114] It is not a compound having any of the following:

[0115] In one embodiment, the compound of formula III is R 1 is methyl, and the compound has the structure of formula IIIa

[0116] [ka]

[0117] It has.

[0118] In one embodiment, the compound of formula III is R 2 is C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, or n-hexyl.

[0119] In one embodiment, the compound of formula III is R 2 is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl.

[0120] In one embodiment, the compound of formula III is R 2 is a C3-C6 alkynyl, preferably a C3-C4 alkynyl, more preferably propargyl, but-1-yn, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, or 2-propynyl.

[0121] In one embodiment, the compound of formula III is R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl, which has a structure substituted with halogen.

[0122] In one embodiment, the compound of formula III is R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl, which is OR 3 is replaced by R 3 is hydrogen or methyl.

[0123] In one embodiment, the compound of formula III is R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 alkynyl, which is SR 3 is replaced by R 3 is hydrogen or methyl.

[0124] In a preferred embodiment, the compound has formula IIIa

[0125] [ka]

[0126] and R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or but-1-yne.

[0127] Preferred compounds having the general formula III are

[0128] [ka]

[0129] (Metro-P2: 1-(2-methyl-5-nitro-1H-imidazol-1-yl)pent-4-yn-2-ol.

[0130] As described above, the present invention provides: (i) at least one compound having the general formula III according to the present invention; (ii) optionally, pharmaceutical excipient(s) and / or carrier(s); The present invention provides a pharmaceutical composition comprising:

[0131] As mentioned above, the present invention provides compounds having the general formula III according to the invention for use in medicine.

[0132] The pharmaceutical composition or formulation may, according to the present invention, be selected from the group of formulations comprising tablets, layered tablets, coated tablets, pills, soft or hard capsules, microcapsules, oral delayed drug forms, transdermal systems, suppositories, micro- and nanocrystalline dosage forms, liposomal dosage forms, drops, nasal drops, sprays, emulsions, dispersions, solutions, sterile solutions, lyophilized formulations, powders, and inhalation sprays.

[0133] The application or use of the pharmaceutical composition or formulation according to the present invention is preferably selected from the group comprising internal, oral, sublingual, buccal, subcutaneous, intravenous, cutaneous, intrapulmonary or intranasal application or use.

[0134] The pharmaceutical compositions or formulations are preferably provided as sterile solutions or lyophilisates, parenteral, oral and internal delayed drug forms, transdermal systems, micro- and nanocrystalline dosage forms, liposomal dosage forms, microcapsules, emulsions, dispersions and are particularly suitable for subcutaneous, intravenous, cutaneous, transdermal, internal, oral or pulmonary use or application.

[0135] Lactose, starch, sorbitol, mannitol, sucrose, ethyl alcohol, and water, for example, can be used as pharmacologically and chemically compatible carriers, solvents, or adjuvants.

[0136] Furthermore, starch, modified starch, gelatin, natural sugar, natural or synthetic polymers such as gum acacia, guar, sodium alginate, carboxymethylcellulose, or polyethylene glycol may be contained as binders. Cyclodextrin, modified cyclodextrin, as well as benzoates, chlorides, acetates, and tartrates may be contained as stabilizers, and stearates, polyethylene glycol, and amino acids such as leucine may be used as adjuvants, usually at concentrations of 0.05% to 15%.

[0137] Liquid dosage forms include solutions, dispersions, and emulsions. Liquid dosage forms for parenteral use are sterile and contain water or water and a solubilizer, micelle-forming agent, or mixed micelle-forming agent, such as propylene glycol. Starch or modified starch, alginate, aluminate, bentonite, or microcrystalline cellulose can be used as a liquid formulation, usually at a concentration of 2% to 30% by weight.

[0138] Sugars, sugar alcohols, corn, rice, or potato starch, gelatin, gum arabic, tragacanth sugar, calcium ammonium alginate, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic substances can be used as adjuvants, usually at concentrations of 1% to 30% by weight. Pharmaceutical formulations for subcutaneous, intravenous, and transdermal use, as well as modified release dosage forms for parenteral and oral use, are claimed as preferred dosage forms. Such dosage forms usually consist of a matrix, particularly a matrix having polymers, often biodegradable polymers, as shaping and structural additives, into which at least one compound of the present invention is incorporated.

[0139] As used herein, the term "pharmaceutically acceptable salts" includes salts of compounds of general formula III prepared using relatively non-toxic (i.e., pharmaceutically acceptable) acids or bases, depending on the specific substituents found on the compounds of the present invention. For example, if a compound of the present invention contains an acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. If a compound of the present invention contains a basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, partially neutralized phosphoric acid, sulfuric acid, partially neutralized sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid and galacturonic acid. Certain specific compounds of the present invention may contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts. The neutral or acid forms of the compounds of the present invention can be regenerated by contacting the salt with a base, and the parent compound can be isolated using conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention. The compounds of the present invention may have chiral or asymmetric carbon atoms (optical centers) and / or double bonds. Racemates, diastereomers, geometric isomers, and individual optical isomers are encompassed by the present invention. The compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms.In general, the solvated forms are equivalent to the unsolvated forms and are also encompassed by the present invention.The compounds of the present invention may further exist in multiple crystalline or amorphous forms.

[0140] The compounds of the present invention may also be in the form of so-called prodrugs. Prodrugs of the compounds of the present invention are compounds that easily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0141] Further Description of the Preferred Embodiments Novel antibiotic compounds based on the nitroimidazole skeleton are disclosed that exhibit over 60-fold enhanced activity against Helicobacter pylori compared to the parent compound metronidazole. Furthermore, they also exhibit moderate activity against resistant isolates. Modifications to enhance activity were primarily made at the free alcohol of the N-1 hydroxyethyl or C2-hydroxymethyl chain to form an ether bond.

[0142] Mechanism of action studies point to enhanced binding (compared to metronidazole) to the chaperonin HpgGroEL and to thiol peroxidase, the inhibition of which induces toxic effects on bacteria due to inhibition of the overall oxidative stress response. This compound is non-toxic to human cells, exhibits favorable plasma stability, and possesses favorable ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic properties, making it a promising candidate for use as an antibiotic.

[0143] Disclosed herein are nitroimidazole compounds with enhanced antibacterial activity for treating infections caused by Helicobacter pylori and other anaerobic or microaerophilic bacteria or protozoa. Cytotoxicity was evaluated in human cells, and these compounds showed no cytotoxicity. Thus, nitroimidazole compounds are promising drug candidates with favorable safety profiles.

[0144] The following examples and figures are illustrative of the present invention but are not intended to be limiting thereof. [Example]

[0145] Example 1 Materials and Methods 1.1 Reagents and solvents Unless otherwise noted, commercially available reagents and starting materials were obtained from Sigma Aldrich, TCI Europe, VWR, Roth, BLDpharm, and Alfa Aesar, and starting compounds were used without further purification and stored as directed. Industrial solvents for purification were used after simple distillation.

[0146] All air- and moisture-sensitive reactions were carried out in flame-dried glassware under an argon atmosphere using standard Schlenk techniques. Anhydrous solvents and water-sensitive liquid chemicals were transferred using argon-flushed syringes.

[0147] 1.2 Thin-layer chromatography (TLC) Thin-layer chromatography (TLC) was performed using silica-coated plates (aluminum, Merck, silica 60 F254). For visualization, spots were detected using UV light (254 nm and 366 nm) or by staining with potassium permanganate solution (3.00 g KMNO4, 20.0 g K2CO3, and 5.00 mL 5% NaOH (aq.) in 300 mL water) followed by heat treatment. Column chromatography was performed using silica gel (40–63 μm (Si 60)) from Merck.

[0148] 1.3 High-Pressure Liquid Chromatography (HPLC) The indicated compounds were purified using preparative reversed-phase HPLC using a Waters 2545 quaternary gradient module equipped with a fraction collector on a YMC Triart C18 column (250 × 10 mm, 5 μm). The gradient is shown in Table 1, using ddHO and HPLC-grade acetonitrile (without TFA) as the mobile phase.

[0149] [Table 1]

[0150] 1.4 Nuclear magnetic resonance spectroscopy (NMR) Nuclear magnetic resonance (NMR) spectra were measured at room temperature on a Bruker AVHD-400 or AVHD-300. Chemical shifts are given as δ values ​​in ppm (parts per million) and are calibrated against the residual proton signal of the solvent relative to the internal standard tetramethylsilane: Chloroform-d1( 1 H-NMR: δ=7.26 ppm 13 C-NMR: δ=77.2 ppm

[0151] NMR multiplicities are designated as singlet (s), doublet (d), triplet (t), quartet (q), pseudosextet (ps), or multiplet (m). Coupling constants, J, are reported in Hertz (Hz). 1 H-NMR and 13 The assignment of C-NMR signals is determined by two-dimensional NMR spectroscopy (COSY, HSQC, HMBC).

[0152] 1.5 Mass spectrometry (MS) High-resolution mass spectrometry (HR-MS) was performed on an LTQ-FT Ultra mass spectrometer (Thermo Fisher Scientific) using electrospray ionization (ESI). Low-resolution LC-MS measurements were performed on an MSQ Plus mass spectrometer (Thermo Fisher Scientific). Mass spectrometry data were processed using Xcalibur 2.2 (Thermo Fisher Scientific).

[0153] Example 2 Synthesis 2.1 Metro-P1 (2-methyl-5-nitro-1-(2-(prop-2-yn-1-yloxy)ethyl)-1H-imidazole)

[0154] [ka]

[0155] To a suspension of metronidazole (200 mg, 1.17 mmol, 1.00 eq.) and CsCO (838 mg, 2.57 mmol, 2.20 eq.) in DMF (4 mL) was added a propargyl bromide solution (80% in toluene, 0.30 mL, 2.78 mmol, 2.40 eq.) and heated to 50 °C for 96 h. The reaction mixture was quenched by the addition of HO (5 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were then washed with 5% aqueous LiCl (aq., 15 mL) and brine (20 mL), dried over NaSO, and the solvent was removed in vacuo. The crude product was further purified by column chromatography (100% EtOAc) and high-performance liquid chromatography (HPLC) to give 74.4 mg of the desired probe (30%, 1.17 mmol) as a white solid.

[0156] TLC:R f =0.45(EtOAc)[UV]. 1 H NMR(400MHz,CDCl3)δ(ppm)=2.39(t, 4 J=2.3Hz,1H,H-12),2.52(s,3H,H-6),3.86(t, 3 J=4.9Hz,2H,H-8),4.08(d, 4 J=2.3Hz,2H,H-10),4.51(t, 3 J=4.9Hz,2H,H-7),7.96(s,1H,H-4). 13C NMR(101MHz,CDCl3)δ(ppm)=14.8(C-6),46.6(C-7),58.7(C-10),68.6(C-8),75.3(C-12),78.8(C-11),133.4(2×C,C-4 / C-5)152.0(C-2). HR-MS(ESI): m / z=calc. [M+H] + :210.0878,found:210.0874.

[0157] 2.2 2-(2-methyl-5-nitro-1H-imidazol-1-yl)acetaldehyde (part of the Metro-P2 synthesis)

[0158] [ka]

[0159] To 160 mL of CHCl is added dropwise 2.00 mL (20.0 mmol, 1.10 eq) of oxalyl chloride under an argon atmosphere. The solution is cooled to −78° C., and 10 mL of DMSO is added dropwise to the stirred solution. After 20 min, 3.42 g (20 mmol, 1.00 eq.) of metronidazole dissolved in 15 mL of DMSO is added. After stirring for an additional 20 min, 33 mL (240 mmol, 12.0 eq) of NEt is added. The reaction mixture is stirred for an additional 10 min at −78° C. and then warmed to room temperature. The mixture is diluted with EtOAc (400 mL) and washed with water (4 × 75 mL). The aqueous phase is extracted with EtOAc (3 × 50 mL). The combined organic layers are washed with brine (150 mL), dried over NaSO, and the solvent is removed in vacuo. The crude residue obtained is purified by flash silica gel chromatography (CH2Cl2 / MeOH 40:1 v / v) to give the target compound (1.20 g, 7.09 mmol, 32%) as an orange viscous oil.

[0160] TLC:R f = 0.78(CH2Cl2 / MeOH10:1)[UV]. 1H NMR(400MHz,CDCl3)δ(ppm)=2.41(s,3H,H-6),5.21(s,2H,H-7),7.99(s,1H,H-4),9.75(s,1H,H-8). 13 C NMR(101MHz, CDCl3)δ(ppm)=14.0(C-6),54.8(C-7),132.8(C-4),132.9(C-5),150.4(C-2),191.6(C-9). LR-MS: m / z = calc. [M+H] + :170.06,found:170.11.

[0161] Metro-P2 (1-(2-methyl-5-nitro-1H-imidazol-1-yl)pent-4-yn-2-ol)

[0162] [ka]

[0163] A mixture of 620 mg (25.5 mmol, 1.78 eq.) magnesium turnings, 3.56 g (15.8 mmol, 1.10 eq.) ZnBr, and iodine (5 mol%) in dry THF (5 mL) is stirred at room temperature for 15 min. Then, a solution of propargyl bromide (1.55 mL, 80% in toluene, 14.4 mmol, 1.00 eq.) in dry THF (15 mL) is added dropwise. Once the reaction mixture begins to reflux, it is cooled to 0 °C. After complete addition of the bromide, the reaction mixture is stirred at room temperature for 1 h. Assuming complete conversion, the crude material is used directly in the subsequent step.

[0164] Metronidazole-aldehyde (500 mg, 2.96 mmol, 1.00 eq) was dissolved in dry THF (8 mL) and 5.30 mL (3.84 mmol, 1.30 eq) of the previously prepared Grignard reagent was added. The mixture was stirred at room temperature for 2 min and then poured into water. Saturated aqueous NH4Cl (20 mL) was added to dissolve the precipitate, and the organic layer was separated. The aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with brine (2 × 20 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography (100% EtOAc) and HPLC to give 34 mg (5%, 0.16 mmol) of the desired probe Metro-P2.

[0165] TLC:R f =0.41(EtOAc)[UV]. 1 H NMR(300MHz,CDCl3)δ(ppm)=2.18(t, 4 J=2.7Hz,1H,H-12),2.56-2.60(m,2H,H-10),2.72(s,3H,H-6),4.14-4.36(m,2H,H-8,H-9)4.77(d, 3 J=11.8Hz,1H,H-8),8.06(s,1H,H-4). 13 C NMR(75MHz,CDCl3)δ(ppm)=14.6(C-6),25.4(C-10),50.7(C-8),69.0(C-9),72.3(C-12),78.5(C-11),132.7(C-4),140.2(C-5),152.1(C-2). HR-MS(ESI): m / z=calc. [M+H] + :210.0878,found:210.0874.

[0166] 2.3 Metro-P3 (2-methyl-5-nitro-1-((prop-2-yn-1-yloxy)methyl)-1H-imidazole)

[0167] [ka]

[0168] To a suspension of (2-methyl-5-nitro-1H-imidazol-1-yl)methanol (250 mg, 1.59 mmol, 1.00 eq) and CsCO (1.20 g, 3.91 mmol, 2.30 eq) in THF (10 mL) is added a propargyl bromide solution (80% in toluene, 0.40 mL, 3.66 mmol, 1.20 eq) and heated to 70 °C for 96 h. The reaction mixture is quenched by the addition of dH0 (5 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers are then washed with brine (20 mL) and water (20 mL), dried over NaSO, and the solvent is removed in vacuo. The crude product was further purified by column chromatography (hexane / EtOAc 1:1) and high performance liquid chromatography (HPLC) to give 136.5 mg of the desired probe Metro-P3 (44%, 0.70 mmol) as a white solid.

[0169] TLC:R f =0.36(EtOAc)[UV]. 1 H NMR(300MHz,CDCl3)δ(ppm)=2.51(t, 4 J=2.4Hz,1H,H-11),4.05(s,3H,H-6),4.25(d, 4 J=2.4Hz,2H,H-9),4.79(s,2H,H-7),7.97(s,1H,H-4). 13 C NMR(75MHz,CDCl3)δ(ppm)=34.2(C-6),58.5(C-9),63.2(C-7),76.2(C-11),78.2(C-10),129.6(2×C,C-4,C-5),147.8(C-2). HR-MS(ESI): m / z=calc. [M+H] + :196.0717,found:196.0715.

[0170] 2.4 MF-01 (1-(2-methoxyethyl)-2-methyl-5-nitro-1H-imidazole)

[0171] [ka]

[0172] CsCO (1.71 g, 5.28 mmol, 4.50 eq.) was added to metronidazole (200 mg, 1.17 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 min. Methyl iodide (582 μL, 1.33 g, 9.36 mmol, 8.00 eq.) was added and the solution was stirred at room temperature for 21 h. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc and then filtered. The crude product was purified by flash silica chromatography (SiO, hexane / EtOAc = 1 / 1, 2.5 × 20 cm) and HPLC to give MF-01 (28.4 mg, 153 μmol, 13%) as a white solid.

[0173] TLC:R f =0.35(EtOAc)[UV]. HPLC:t R =5.0 min 1 H-NMR (400MHz, CDCl3): δ[ppm]=2.75(s,3H,H-6),3.30(s,3H,H-9),3.73(t, 3 J=4.8Hz,2H,H-8),4.59(t, 3 J=4.8Hz,2H,H-7),8.07(s,1H,H-4). 13 C-NMR (101MHz, CDCl3): δ[ppm]=13.6(q,C-6),47.6(t,C-7),59.4(q,C-9),70.7(t,C-8),126.9(d,C-4),136.6(s,C-5),150.8(s,C-2). HR-MS(ESI): m / z=calc. [M+H] + :186.0873,found:186.0871.

[0174] 2.5 MF-02 (2-(methoxymethyl)-1-methyl-5-nitro-1H-imidazole)

[0175] [ka]

[0176] Cs2CO3 (1.04 g, 3.18 mmol, 2.50 eq.) was added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (200 mg, 1.27 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 min. Methyl iodide (560 μL, 1.26 g, 8.89 mmol, 7.00 eq.) was added and the solution was stirred at room temperature for 21 h. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc and then filtered. The crude product was purified by flash silica chromatography (SiO2, hexane / EtOAc = 1 / 1) and HPLC to give MF-02 (84.8 mg, 495 μmol, 39%) as a white solid.

[0177] TLC:R f =0.48(EtOAc)[UV]. HPLC:t R =6.6 min. 1 H-NMR (400MHz, CDCl3): δ[ppm]=3.41(s,3H,H-8),4.04(s,3H,H-6),4.65(s,2H,H-7),7.98(s,1H,H-4). 13 C-NMR (101MHz, CDCl3): δ[ppm]=34.4(q,C-6),58.9(q,C-8),66.3(t,C-7),130.2(d,C-4),148.5(s,C-5),157.3(s,C-2).

[0178] 2.6 MF-03 (1-(2-ethoxyethyl)-2-methyl-5-nitro-1H-imidazole)

[0179] [ka]

[0180] 200 mg of metronidazole (1.00 eq., 1.17 mmol) and 457 mg of cesium carbonate (1.20 eq., 1.40 mmol) are suspended in 5 mL of dry THF. 0.20 mL of ethyl bromide (2.40 eq., 306 mg, 2.80 mmol) is slowly added to this suspension, which is then heated to reflux. Over a period of 60 hours, 4.80 equivalents of ethyl bromide (612 mg, 5.60 mmol) and 1 equivalent of cesium carbonate (380 mg, 1.16 mmol) are added. The suspension is quenched with 20 mL of demineralized water. The reaction mixture is extracted with ethyl acetate (3 × 20 mL). The combined organic layers are washed with 20 mL of saturated NaCl solution and dried over sodium sulfate. Excess solvent is removed in vacuo. The crude product is separated by chromatography (SiO2, hex / EtOAc = 1:5) to give an orange-brown solid (37.8 mg, 0.19 mmol, 16%).

[0181] TLC:R f =0.30(hexane / EtOAc 1:5)[UV]. 1 H-NMR(400MHz, CDCl3):δ[ppm]=1.10(t, 3 J=7.0Hz,3H,H-10),2.58(s,3H,H-6),3.41(q, 3 J=7.0Hz,2H,H-9),3.73(t, 3 J=5.0Hz,2H,H-8),4.51(t, 3 J=5.0Hz,2H,H-7),7.98(s,1H,H-4). 13 C-NMR (100MHz, CDCl3): δ[ppm]=14.4(C-6),15.1(C-10),47.1(C-7),67.1(C-9),69.1(C-8),131.6(C-4),138.4(C-5),151.7(C-2). HR-MS(ESI): m / z=calc. [M+H] + :200.1030,found:200.1029.

[0182] 2.7 MF-04 2-(ethoxymethyl)-1-methyl-5-nitro-1H-imidazole (MF-RP-09)

[0183] [ka]

[0184] Cs2CO3 (2.49 g, 7.64 mmol, 4.00 eq) and tetrabutylammonium iodide (TBAI, 317 mg, 0.45 mol%) were added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (300 mg, 1.91 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 min. Ethyl bromide (0.56 mL, 7.64 mmol, 4.00 eq.) was added, and the solution was stirred at reflux for 21 h. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The crude product was dissolved in EtOAc, filtered, and purified by flash silica chromatography (SiO2, hexane / EtOAc = 1 / 2) followed by HPLC. Pure MF-04 was obtained as a yellow oil (80.0 mg, 1.11 mmol, 58%).

[0185] TLC:R f =0.44(hexane / EtOAc2:1)[UV]. HPLC:t R =7.7min 1 H NMR(400MHz,CDCl3)δ[ppm]=1.22(t, 3 J=7.1Hz,3H,H-9),3.57(q, 3 J=7.1Hz,2H,H-8),4.04(s,3H),4.66(s,2H),7.95(s,1H). 13 C NMR(100MHz, CDCl3)δ=15.1(C-9),33.9(C-6),64.7(C-8),66.8(C-7),130.8(C-4),139.7(C-5),149.0(C-2). HR-MS(ESI): m / z=calc. [M+H] + :186.0873,found:186.0872.

[0186] 2.8 MF-05 (2-methyl-5-nitro-1-(2-propoxyethyl)-1H-imidazole)

[0187] [ka]

[0188] Cs2CO3 (1.14 g, 3.51 mmol, 4.99 eq.) is added to metronidazole (150 mg, 876 μmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 min. Propyl iodide (0.85 mL, 8.76 mmol, 10.0 eq.) is added and the solution is stirred at reflux overnight. The reaction mixture is filtered and the solvent is removed under reduced pressure. The crude product is purified by flash silica chromatography (SiO2, hexane / EtOAc = 1 / 2) to give MF-05 (38.5 mg, 184 μmol, 21%) as a yellow oil.

[0189] TLC:R f =0.23(hexane / EtOAc 1:2)[UV]. 1 H NMR(400MHz,CDCl3)δ[ppm]=0.83(t, 3 J=7.1Hz,3H,H-11),1.49(ps, 3 J=7.1Hz,2H,H-10),2.58(s,3H,H-6),3.31(t, 3 J=7.1Hz,2H,H-9),3.73(t, 3 J=4.5Hz,2H,H-8),4.52(t, 3 J=4.5Hz,2H,H-7),7.99(s,1H,H-4). 13 C NMR(100MHz,CDCl3)δ[ppm]=10.6(C-11),14.4(C-6),22.9(C-10), 47.1(C-7),69.3(C-9),73.4(C-8),131.9(C-4),138.3(C-5),151.6(C-2). HR-MS(ESI): m / z=calc. [M+H] +:214.1186,found:214.1184.

[0190] 2.9 MF-06 (1-methyl-5-nitro-2-(propoxymethyl)-1H-imidazole)

[0191] [ka]

[0192] Cs2CO3 (3.32 g, 7.64 mmol, 4.00 eq.) was added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (400 mg, 2.55 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 min. Propyl iodide (1.59 mL, 15.3 mmol, 6.00 eq.) was added and the solution was stirred at reflux overnight. The reaction mixture was filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography (SiO2, hexane / EtOAc = 1 / 2) to give pure MF-06 as a yellow oil (57.6 mg, 281 μmol, 11%).

[0193] TLC:R f =0.57(hexane / EtOAc 1:3)[UV]. 1 H NMR(400MHz,CDCl3)δ[ppm]=0.91(t, 3 J=7.2Hz,3H,H-10),1.61(ps, 3 J=7.2Hz,2H,H-9),3.44(t, 3 J=7.2Hz,2H,H-8),4.02(s,3H,H-6),4.62(s,2H,H-7),7.93(s,1H,H-4). 13 C NMR(100MHz,CDCl3)δ[ppm]=10.6(C-10),22.9(C-9),33.8(C-6),65.3(C-8),73.0(C-7),131.6(C-4,C-5),149.2(C-2). HR-MS(ESI): m / z=calc. [M+H] +:200.1030,found:200.1028.

[0194] 2.10 MF-07 (1-(2-(allyloxy)ethyl)-2-methyl-5-nitro-1H-imidazole)

[0195] [ka]

[0196] 200 mg of metronidazole (1.17 mmol, 1.00 eq) and 762 mg of cesium carbonate (2.34 mmol, 2.00 eq) are suspended in 10 mL of dry THF. 0.30 mL of allyl bromide (2.80 mmol, 3.00 eq) is slowly added to this suspension, which is then heated to 70 °C. After 23 h, the suspension is quenched with 20 mL of demineralized water. The reaction mixture is extracted with ethyl acetate (3 × 20 mL). The combined organic layers are washed with 20 mL of saturated NaCl solution and dried over sodium sulfate. Excess solvent is removed in vacuo. The crude product is separated by chromatography (1:5 hexane / ethyl acetate) to give pure MF-07 (74.5 mg, 0.35 mmol, 30%) as a golden brown solid.

[0197] TLC:R f =0.40(hexane / EtOAc 1:5)[UV]. 1 H NMR(400MHz,CDCl3)δ[ppm]=2.57(d, 3 J=2.6Hz,3H,H-6),3.75(t, 3 J=5.1Hz,2H,H-8),3.84-3.93(m,2H,H-9),4.52(t, 3 J=5.1Hz,2H,H-7),5.09-5.20(m,2H,H-11),5.66-5.81(m,1H,H-10),7.98(d, 3 J=2.6Hz,1H,H-4). 13C-NMR (100MHz, CDCl3): δ[ppm]=14.5(C-6),46.9(C-7),68.7(C-8),72.3(C-9),117.7(C-11),132.0(C-4),133.8(C-10),138.4(C-5),151.7(C-2). HR-MS(ESI): m / z=calc. [M+H] + :212.1030,found:212.1030.

[0198] 2.11 MF-08 (2-((allyloxy)methyl)-1-methyl-5-nitro-1H-imidazole)

[0199] [ka]

[0200] Cs2CO3 (1.56 g, 4.77 mmol, 3.00 eq.) was added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (250 mg, 1.59 mmol, 1.00 eq.) dissolved in THF (12 mL) and stirred at room temperature for 30 min. Allyl iodide (0.44 mL, 4.77 mmol, 3.00 eq.) was added and the solution was stirred at reflux for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography (SiO2, hexane / EtOAc = 1 / 1) and HPLC to give pure MF-08 as a colorless oil (138 mg, 700 μmol, 44%).

[0201] TLC:R f =0.40(hexane / EtOAc 1:1)[UV]. 1 H NMR(400MHz,CDCl3)δ[ppm]=4.02-4.06(m,5H,H-6,H-8),4.66(s,2H,H-7),5.20-5.37(m,2H,H-10),5.77-5.96(m,1H,H-9)),7.95(s,1H,H-4). 13C NMR(100MHz,CDCl3)δ[ppm]=33.9(C-6),64.1(C-8),72.0(C-7),118.8(C-10),131.0(C4,C5),133.3(C-9),148.8(C-2). HR-MS(ESI): m / z=calc. [M+H] + :198.0873,found:198.0872.

[0202] 2.12 MF-09 (2-methyl-1-(2-((3-methylbut-2-en-1-yl)oxy)ethyl)-5-nitro-1H-imidazole)

[0203] [ka]

[0204] 200 mg of metronidazole (1.17 mmol, 1.00 eq) and 762 mg of cesium carbonate (2.34 mmol, 2.00 eq) are suspended in 9 mL of dry THF. 0.40 mL of 3,3-dimethylallylbromide (3.51 mmol, 3.00 eq) is slowly added to the reaction mixture, which is then heated to reflux. After 18 h, the suspension is quenched with 20 mL of demineralized water. The reaction mixture is extracted with ethyl acetate (3 × 20 mL). The combined organic layers are washed with 20 mL of saturated NaCl solution and dried over sodium sulfate. Excess solvent is removed in vacuo. The crude product is separated by chromatography (hexane / EtOAc) and then purified by HPLC. The desired product MF-08 is obtained pure as a white solid (29.0 mg, 0.12 mmol, 10%).

[0205] TLC:R f =0.42(hexane / EtOAc 1:5)[UV]. 1 H-NMR (400MHz, CDCl3): δ[ppm]=1.17(s,3H,H-13),1.76(s,3H,H-12),2.52(s,3H,H-6),4.47(t, 3 J=5.0Hz,2H,H-8),4.59(m, 3J=7.3Hz,1.5Hz,4H,H-9,H-7),5.32(tt,1H,H-10),7.98(s,1H,H-4). 13 C-NMR (100MHz, CDCl3): δ[ppm]=14.2(C-6),18.1(C-12),25.8(C-13),45.4(C-7),65.3 (C-9),65.6(C-8),117.5(C-10),130.1(C-4),132.6(C-11),140.9(C-5),151.1(C-2). HR-MS(ESI): m / z=calc. [M+H] + :240.1343,found:240.1343.

[0206] Example 3 Biological Testing 3.1 Inhibition assay The compounds of the present invention were tested against a number of bacterial strains. Tables 2 and 3 below summarize the results and show the minimum inhibitory concentration (MIC) values ​​of the compounds against the indicated bacterial strains.

[0207] [Table 2]

[0208] For H. pylori, the determined MICs of metronidazole (12.5–50 μM) are within the literature-reported MIC range of 10–50 μM for susceptible strains (Megraud 2007; Wu et al., 2000), which is important for the accuracy and comparability of MIC values ​​obtained with this assay. The MIC values ​​of Metro-P2 (12.5–50 μM) were identical to those of metronidazole. Surprisingly, the MIC values ​​of Metro-P1 (250–380 nM) and Metro-P3 (190–250 nM) were up to 100-fold more potent than those determined for metronidazole (12.5–50 μM). A significant increase in antibiotic activity was observed, which may be due to the modification of the free hydroxyl group with an ether moiety in both probes. Therefore, several derivatives were synthesized and further evaluated for antibacterial activity in susceptible and resistant H. pylori strains.

[0209] Additionally, MIC assays were performed on susceptible and metronidazole-resistant H. pylori strains over a concentration range of 100 nM to 1 mM. MIC determinations for susceptible H. pylori strains were performed in duplicate, and the assay readout was visual after 3 days of incubation with metronidazole or each probe. The resulting values ​​are summarized in Table 3.

[0210] [Table 3]

[0211] MIC shifts were observed for metronidazole and all test compounds against drug-resistant H. pylori, suggesting similar resistance mechanisms. However, Metro-P3, MF03, MF05, MF06, and MF08 had better MIC values ​​(62.5 μM) in resistant H. pylori than metronidazole and Metro-P2 (250-500 μM), which were closer to the lower end of the MIC range of metronidazole (10-50 μM) in susceptible H. pylori strains (Megraud 2007; Wu et al., 2000).

[0212] 3.2 Target Identification Target identification experiments identified two to-date unknown protein targets of metronidazole in H. pylori, namely: - Helicobacter pylori chaperonin HpGroEL (P42383), and - Thiol peroxidase HpTpx (O25151) was also shown to be involved in the mechanism of action of these compounds.

[0213] MS-based binding site studies identified the hydroxylamine intermediate of the metronidazole-probe bound to the active site cysteine ​​of these proteins as a suicide inhibitor. Furthermore, HpTpx and HpGroEL could be successfully modified with metronidazole or Metro-P3 during recombinant protein expression (exemplary example shown for HpTpx in Figure 4). Furthermore, functional activity assays for both enzymes demonstrated reduced or complete loss of activity: ATPase activity assays showed up to a 60% reduction in HpGroEL upon modification with metronidazole or Metro-P3. Antioxidant activity assays demonstrated that covalent binding of metronidazole or Metro-P3 to HpTpx in the active site resulted in a modification-dependent decrease in activity, resulting in a reduced effectiveness in eliminating oxidative stress that leads to cell death in whole H. pylori bacteria. However, most intriguingly, novel compounds, such as Metro-P3, modified HpTpx more readily than metronidazole (as shown in vitro during recombinant protein expression in E. coli, Figure 6, and in situ in H. pylori).

[0214] 3.3 Crystal structure analysis Furthermore, crystal structure analysis revealed that the binding motifs of metronidazole and Metro-P3 for HpTpx are completely different. This further indicates that even small structural changes can significantly alter the binding affinity and mechanism of action of nitroimidazoles in H. pylori (Fig. 7). Metro-P3 binds to the reduced state of HpTpx (the more stable and cytoplasmic form in H. pylori, Fig. 7B) and stabilizes the ligand by forming a helical dipole, whereas metronidazole binds to HpTpx immediately after the disulfide bridge opens in the catalytic cycle (Fig. 7A). The formation of the active site disulfide bridge in HpTpx constrains the protein structure (the cysteines are far apart), making the oxidized state of HpTpx thermodynamically less stable. Moreover, due to the difference in binding motif, we further demonstrate that Metro-P3 is more advantageous in inhibiting the activity of HpTpx, supporting our invention that our slight structural changes result in significant changes in the mechanism of action compared to the current gold standard, metronidazole.

[0215] In summary, HpTpx is a major contributor to the enhanced activity of our novel nitroimidazole compounds, which exhibit over 60-fold enhanced activity against H. pylori compared to the parent compound metronidazole.

[0216] 3.4 Cytotoxicity Mohindra and Rauth (1976) reported the IC value of metronidazole in HeLa cells after 14 days of incubation without medium changes. 50We reported that metronidazole had a potency of ≥10 mM, making it a nontoxic drug for human cells. However, the incubation time was very long, and because Metro-P1 and Metro-P3 are up to 100-fold more potent than metronidazole in H. pylori, it was important to determine whether this enhanced antibacterial activity was also directly related to increased toxicity to human cells. Therefore, we performed MTT assays in HeLa and HepG2 cells at various compound concentrations (ranging from 1 μM to 1 mM) for 24 hours.

[0217] [Table 4]

[0218] All test compounds had IC values ​​below 1 mM final concentration in HeLa and HepG2 cell lines, as no reduction in metabolic activity could be observed after assay readout. 50 Only for Metro-P1, a slight decrease in metabolic activity could be observed at a final concentration of 10 mM, and Metro-P1 began to show cytotoxicity to HeLa cells at concentrations above 10 mM. However, because Metro-P1 is not soluble in DMSO at higher concentrations, an accurate IC 50 It was not possible to determine the IC value of the compound. 50 The values ​​are summarized in Table 4. Some selected examples are shown in FIG.

[0219] 3.5 Plasma stability Additionally, compounds Metro-P1, Metro-P2, Metro-P3, and MF01–MF09 were subjected to in vitro plasma stability assays in mouse serum for 28 hours. All test compounds showed excellent stability, and half-lives could not be determined. For example, after 28 hours, 75% of Metro-P1, 99% of Metro-P2, 82% of Metro-P3, 66% of MF01, 81% of MF03, and 87% of MF07 were still present in the samples and had not degraded (see Figure 3).

[0220] [Table 5]

[0221] 3.6 ADME (Absorption, Distribution, Metabolism, and Excretion Studies) To further explore the safety of the nitroimidazole compounds of the present invention, six promising candidates (Metro-P1, Metro-P3, MF-01, MF-02, MF-03, and MF-07) were characterized for their absorption, distribution, metabolism, and excretion (ADME) properties. Four of the six compounds achieved the required ADME thresholds, indicating that the compounds of the present invention have immense potential for further drug development (Table 6).

[0222] [Table 6]

[0223] 3.7 Pharmacological Data Further pharmacokinetic data were obtained. The results of pharmacokinetic experiments in mice for the four compounds are shown in Figure 8. It is desirable for concentrations in plasma, urine, and feces to vary depending on the type of infection. Here, Metro-P3 already exhibited PK data ideal for treating infections in the gastrointestinal tract: Metro-P3 concentrations in plasma and urine were low, while concentrations in feces were higher and more sustained, prolonging the compound's residence time in the gastrointestinal tract and thus favoring the treatment of Helicobacter pylori in the human stomach. However, MF-01 and MF-03 exhibited high plasma and urine concentrations and were not rapidly cleared. Therefore, the compounds of the present invention can be fine-tuned for various treatments and infection patterns.

[0224] The features disclosed in the above description, in the claims and / or in the accompanying drawings may, both individually and in any combination thereof, be material for realizing the invention in diverse forms thereof.

[0225] References Ang CW, Jarrad AM, Cooper MA, Blaskovich MA, Journal of Medicinal Chemistry 2017, 60, 7636-7657. Bandow JE, Broetz H, Leichert LIO, Labischinski H, Hecker M, Antimicrobial Agents and Chemotherapy 2003, 47, 948-955. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J, Clin. Infect. Dis. 2009, 48, 1-12. Davies J, Davies D, Microbiology and Molecular Biology Reviews 2010, 74, 417-433. Foroumadi A et al. Arch. Pharm. Res. 2004, 27(5), 502-506. Jamshidi H et al. Chem. Biol. Drug Des. 2022, 100, 935-946. Lehours P, Yilmaz, O., Helicobacter 2007, 12, 1-3. Li Z-Z et al. Eur J Med Chem. 2019, 179, 723-735. Loefmark S, Edlund C, Nord CE, Clinical infectious diseases 2010, 50, S16-S23. Megraud F, Gut 2004, 53,1374-1384. Megraud F, Gut 2007, 56, 1502-1502. Mohindra JK, Rauth AM, Cancer Res., 1976, 36, 930-936. Perez‐Perez GI, Rothenbacher D, Brenner H, Helicobacter 2004, 9, 1-6. Vakil N, Megraud F, Gastroenterology 2007, 133, 985-1001. Wu H, Shi XD, Wang HT, Liu JX, J. Antimicrob. Chemother., 2000, 46, 121-123. Zagari RM, Rabitti S, Eusebi LH, Bazzoli F, Eur J Clin Invest. 2018, 48, e12857.

Claims

1. A compound of general formula I or II or III for use in the treatment of a non-viral infection or a disease caused by a non-viral infection. 【Chemistry 1】 (In the formula, R １ is C １ -C ６ Alkyl or C １ -C ６ is haloalkyl, R ２ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ３ -C ６ is alkynyl, R ２ Regarding the above C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ３ -C ６ The alkynyl may optionally be halogen, OR ３ , or SR ３ and R ３ is hydrogen or C １ -C ６ alkyl) or a pharmaceutically acceptable salt thereof, However, for compounds of general formula II or III, R １ is methyl, R ２ is not ethyl, nor halogen, OH, OMe, NH ２ , NH(CH ３ ) ２ , or NH(CH ２ -CH ３ ) ２ C substituted with １ -C ４ Not alkyl, R １ is CF ３ When R ２ is a halogen-substituted C １ -C ４ Not alkyl, R １ is isopropyl, R ２ is a halogen-substituted C １ -C ４ Not alkyl, However, for general formula III, R １ and R ２ Both the compound and salt cannot be methyl.

2. R １ is methyl and the compound has formula Ia or IIa or IIIa 【Chemistry 2】 2. A compound for use as claimed in claim 1, having the formula:

3. R ２ But C １ -C ６ Alkyl, preferably C １ -C ４ alkyl, more preferably methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, or n-hexyl. or R ２ But C ２ -C ６ Alkenyl, preferably C ２ -C ５ alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl. or R ２ But C ３ -C ６ Alkynyl, preferably C ３ -C ４ A compound for use as claimed in claim 1 or 2, which is alkynyl, more preferably propargyl, but-1-yn, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl or 2-propynyl.

4. R ２ is substituted with halogen １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ３ -C ６ Alkynyl, OR ３ (In the formula, R ３ is hydrogen or methyl), or SR ３ (In the formula, R ３ is hydrogen or methyl) A compound for use as claimed in any one of claims 1 to 3, which is

5. Formula Ia 【Transformation 3】 and R ２ But C ３ -C ６ Alkynyl, preferably C ３ -C ４ alkynyl, more preferably propargyl or but-1-yne, or R ２ But C １ -C ６ alkyl, preferably methyl; Alternatively, Formula IIa 【Chemistry 4】 and R ２ But C ３ -C ６ Alkynyl, preferably C ３ -C ４ alkynyl, more preferably propargyl or but-1-yne, or R ２ But C １ -C ６ Alkyl, preferably C １ -C ４ alkyl, more preferably methyl or ethyl; ２ But C ２ -C ６ Alkenyl, preferably C ２ -C ５ alkenyl, more preferably allyl, vinyl, or dimethylallyl; Alternatively, Formula IIIa 【Transformation 5】 and R ２ But C ３ -C ６ Alkynyl, preferably C ３ -C ４ A compound for use as claimed in any one of claims 1 to 4, which is alkynyl, more preferably propargyl or but-1-yne. 【Request Item 6】 【Transformation 6】 Preferably, 【Transformation 7】 A compound for use as claimed in any one of claims 1 to 5, selected from:

7. the non-viral infection is an infection caused by a protozoan, an anaerobic bacterium, or a microaerophilic bacterium; Preferably, the infection is caused by Helicobacter pylori, Clostridioides difficile, Trichomonas vaginalis, Giardia intestinalis (G. lambia), Entamoeba histolytica, Fusobacterium nucleatum, or Gardnerella vaginalis, and / or a compound for use as claimed in any one of claims 1 to 6, wherein said infection is an infection caused by a strain of Helicobacter pylori that is resistant to metronidazole.

8. General formula III 【Transformation 8】 (In the formula, R １ is C １ -C ６ Alkyl or C １ -C ６ is haloalkyl, R ２ is C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ３ -C ６ is alkynyl, Said C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ３ -C ６ The alkynyl may optionally be halogen, OR ３ , or SR ３ and R ３ is hydrogen or C １ -C ６ alkyl) or a pharmaceutically acceptable salt thereof, however R １ and R ２ Both of the groups cannot be methyl. R １ is methyl, R ２ is not ethyl, nor halogen, OH, OMe, NH ２ , or NH(CH ３ ) ２ C substituted with １ -C ４ Not alkyl, R １ is CF ３ When R ２ is a halogen-substituted C １ -C ４ Not alkyl, R １ is isopropyl, R ２ is a halogen-substituted C １ -C ４ Not an alkyl, compound or salt.

9. R １ is methyl and the compound is 【Chemistry 9】 9. The compound of claim 8 having the formula:

10. R ２ But C １ -C ６ Alkyl, preferably C １ -C ４ alkyl, more preferably methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, or n-hexyl. or R ２ But C ２ -C ６ Alkenyl, preferably C ２ -C ５ alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, or 4-pentenyl. or R ２ But C ３ -C ６ Alkynyl, preferably C ３ -C ４ The compound according to claim 8 or 9, which is alkynyl, more preferably propargyl, but-1-yne, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, or 2-propynyl.

11. R ２ is substituted with halogen １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ３ -C ６ Alkynyl, OR ３ (In the formula, R ３ is hydrogen or methyl), or SR ３ (In the formula, R ３ is hydrogen or methyl) The compound according to any one of claims 8 to 10, wherein

12. Formula IIIa 【Chemistry 10】 and R ２ But C ３ -C ６ Alkynyl, preferably C ３ -C ４ A compound according to any one of claims 8 to 11, which is alkynyl, more preferably propargyl or but-1-yne. 【Request Item 13】 【Chemistry 11】 The compound according to any one of claims 8 to 12, wherein

14. (i) at least one compound according to any one of claims 8 to 13, (ii) optionally, pharmaceutical excipient(s) and / or carrier(s); 10. A pharmaceutical composition comprising:

15. A compound according to any one of claims 8 to 13 for use in medicine.

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