New 12-epi-mollin compounds and uses thereof

Abstract

Compounds of formula (I), wherein R1 is (R1), wherein A is a hydrogen atom or a (C 1‑6 )alkyl group, and wherein any Q is independently of each other a nitrogen atom or CH, wherein R2 is (R2), for use as a medicament, and pharmaceutical compositions comprising said compounds as well as methods of treatment or prevention of diseases mediated by microorganisms utilizing the same.

Description

Technical Field

[0001] This invention relates to specific 12-epi-mutilin compounds and their use as pharmaceuticals. Background Technology

[0002] (Pleurotin) morin is a compound with the following formula:

[0003]

[0004] Pleuroromutilin is a naturally occurring antibiotic produced, for example, by basidiomycetes such as Pleurotus mutilus and P. passeckerianus; see, for example, The Merck Index, 12th edition, entry 7694.

[0005] Pharmaceutically active compounds derived from truncated pleurotin (a semi-synthetic compound) are inhibitors of ribosomal protein synthesis in bacteria. A representative human semi-synthetic truncated pleurotin is retapamulin (approved for short-term treatment of impetigo and infected minor lacerations, abrasions, or sutured wounds), a topical medication approved for this purpose. ), and lefamulin (approved as a treatment for adults with community-acquired bacterial pneumonia (CABP) Tiamulin Valnemulin These are two other semi-synthetic truncated pleurotin derivatives, which have been used systemically as antibiotics in veterinary medicine for many years.

[0006]

[0007]

[0008] Approved semi-synthetic compounds derived from truncated pleurotin have shown excellent activity against bacterial organisms, including, in particular, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus (including MRSA), Moraxella catarrhalis, Legionella pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae.

[0009] Lefamolin's activity covers common respiratory microorganisms, and the occurrence of resistant isolates is low (Mendes RE, Paukner S, Doyle TB, Gelone SP, Flamm RK, Sader HS. Antimicrob Agents Chemother. 2019 63(4),e02158-18; Wu, S.; Zheng, Y.; Guo Y.; Yin, D.; Zhu, D.; Hu, F. Frontiers in Microbiology, 2020, 11, 2314). However, individual bacterial phenotypes resistant to pleurotin (Long, KS; Poehlsgaard, J.; Kehrenberg, C.; Schwarz, S.; Vester, B. Antimicrob Agents Chemother. 2006, 50(7), 2500-2505) and lefamoline (Mendes RE, Paukner S, Doyle TB, Gelone SP, Flamm RK, Sader HS. Antimicrob Agents Chemother. 2019 63(4), e02158-18) have been described. The potential mechanisms of acquired famolin resistance identified to date include the following (in order of epidemiological relevance): i) target protection of ABC-F proteins, such as vga (AE) of Staphylococcus spp., lsa (E) of Streptococcus agalactiae, Enterococcus spp., and Staphylococcus aureus, and sal (A) of coagulase-negative Staphylococcus spp.; ii) target modifications, such as mutations in the rplC and rplD genes encoding ribosomal proteins located outside the PTC, mutations in the V domain of the 23S rRNA, or methylation of the 23S rRNA at position A2503 in the PTC mediated by Cfr methyltransferase (encoded by cfr) (Paukner S, Riedl R. Pleuromutilins: Potent Drugs for Resistant Bugs - Mode of Action and Resistance. Cold Spring Harb Perspect Med. 2017 Jan). 3;7(1):a027110.doi:10.1101 / cshperspect.a027110.PMID:27742734; PMCID:PMC5204327).Lefamolin was also the subject of the FDA's workshop on "Development Considerations of Antimicrobial Drugs for the Treatment of Gonorrhea" held on April 23, 2021. The slides for the presentation entitled “Development Considerations for a Syndromic Approach to Uncomplicated Urethritis / Cervicitis” and the transcript of the workshop are subsequently available for download from the FDA website (https: / / www.fda.gov / drugs / news-events-human-drugs / development-considerations-antimicrobial-drugs-treatment-gonorrhea-04232021-04232021, May 26, 2021), specifically from https: / / www.fda.gov / media / 149520 / download and https: / / www.fda.gov / media / 148225 / download (both links accessed on February 1, 2022).

[0010] A truncated pleurotin derivative, referred to as "12-diamero-morin," is disclosed in WO 2015 / 110481 A1. The term "12-diamero-morin" refers to a morin ring at position 12 where two substituents are substituted. The first substituent at position 12 is a methyl group having an inverse stereochemistry compared to the methyl group at position 12 in the naturally occurring truncated pleurotin ring. The second substituent at position 12 is a hydrocarbon group containing at least one nitrogen atom, and all other substituents in the morin ring have the same stereochemistry as the substituents at the corresponding positions in the naturally occurring truncated pleurotin ring; optionally in the form of a salt and / or solvate, particularly in the form of a salt.

[0011] These compounds have been found to exhibit interesting activity against both Gram-positive and Gram-negative bacteria.

[0012] Berner, H. et al. (Berner, H.; Schulz, G.; Schneider H. Tetrahedron 1980, 36, 1807-1811) described the first synthetic method concerning opposite stereochemistry. Summary of the Invention

[0013] Surprisingly, the novel 12-epio-moline (Examples 1-3) was found to combine interesting antibacterial activity (Example 4) with significant metabolic stability and low cytotoxicity (Examples 5 and 6).

[0014] Therefore, on the one hand, the present invention relates to compounds of formula (I),

[0015]

[0016] Where R1 is

[0017]

[0018] Where A is a hydrogen atom or (C) 1-6 )alkyl, and

[0019] Where each Q is independently a nitrogen atom or CH,

[0020] Where R2 is

[0021]

[0022] And their use as medicines, particularly in the treatment and prevention of bacterial-mediated diseases.

[0023] The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) as defined above.

[0024] On the other hand, the present invention relates to a method for treating or preventing bacterial-mediated diseases, including administering a compound of formula (I) to a subject in need of such treatment. Detailed Implementation

[0025] In the compound of formula (I), the methyl group at position 12 of the morin ring has an inverse stereochemistry compared to the stereochemistry of the methyl group at position 12 of the naturally occurring truncated pleurotin ring, and all other substituents of the morin ring have the same stereochemistry compared to the substituents at the corresponding positions of the naturally occurring truncated pleurotin ring. The naturally occurring truncated pleurotin ring is shown, for example, in the structure of the truncated pleurotin described above. Therefore, the compound of the present invention is a so-called 12-episomeric morin.

[0026] In the compound of formula (I), R1 is

[0027]

[0028] Where A is a hydrogen atom or (C) 1-6 )alkyl, and

[0029] Where each Q is independently a nitrogen atom or CH,

[0030] That is, heterocyclic vinyl, wherein the heterocyclic group is alkyl-substituted or unsubstituted pyridinyl, pyrimidinyl or pyrazinyl.

[0031] In a preferred embodiment, A is (C 1-3 )alkyl, that is, selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl and cyclopropyl (C 1-3 Alkyl, preferably methyl.

[0032] Even more preferably, R1 is selected from the group consisting of (E)-2-(pyrimidin-5-yl)-vinyl, (E)-2-(pyrimidin-5-yl)-vinyl and (E)-2-(3-methyl-pyrazin-2-yl).

[0033] In the compound of formula (I), R2 is

[0034]

[0035] Therefore, R2 is an amino-substituted bicyclic oxygen-containing heterocycle, or systematically, R2 is 3-amino-hexahydrofurano[3,2-b]furan-6-yl.

[0036] The compounds of the present invention can exist in the form of isomers and mixtures thereof, such as diastereomers and cis / trans conformational isomers. The compounds of the present invention may, for example, contain asymmetric carbon atoms, and therefore can exist in the form of diastereomers and mixtures thereof. Unless otherwise stated, any asymmetric carbon atom may exist in (R)-, (S)-, or (R,S)- configurations, preferably in (R)- or (S)- configurations.

[0037] In a preferred embodiment, R2 is derived from D-isomannitol. Therefore, R2 is preferably (3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl.

[0038] Therefore, the preferred compound of the present invention is the compound of formula (II).

[0039]

[0040] A and Q are defined as above.

[0041] The compounds particularly preferred by this invention are selected from the group consisting of compounds of formulas (III) to (V).

[0042]

[0043] System Name

[0044] The compound of formula (III) is

[0045] 12-Episode-12-Devinyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-pyridyl)-vinyl]-morin

[0046] The compound of formula (IV) is

[0047] 12-Episode-12-Devinyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(pyrimidin-5-yl)vinyl]-Morin

[0048] The compound of formula (V) is

[0049] 12-Diasterimeric-12-Devinyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-methyl-pyrazin-2-yl)-vinyl]-moline.

[0050] In one embodiment, the compound according to the invention is provided in the form of a salt and / or a solvate.

[0051] The compounds of the present invention can be protonated and form cations in acid addition salts, such as divalent cations, for example in dihydrochlorides.

[0052] The salts of the compounds of this invention include acid addition salts.

[0053] Pharmaceutically acceptable acid addition salts include salts of the compounds of the present invention with acids such as fumaric acid, tartaric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, citric acid, L-malic acid, hippuric acid, D-gluconic acid, L-lactic acid, benzoic acid, hydromaleic acid, hydrosulfuric acid, hydrophosphoric acid, hydrotartaric acid, hydrofumaric acid, hydromalic acid, hydrosuccinic acid, ethane-1,2-disulfonic acid, maleic acid, naphthalene-1,5-sulfonic acid, acetic acid, succinic acid, salicylic acid, azelaic acid, 2-[(2,6-dichlorophenyl)amino]phenylacetic acid, trifluoroacetic acid, hydrochloric acid, deuterium chloride, preferably hydrochloric acid, acetic acid, L-lactic acid, and maleic acid, more preferably hydrochloric acid. Pharmaceutically acceptable salts are described, for example, in Stahl, PH, Wermuth, CG, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Helvetica Chimica Acta / Wiley-VCH, 2001.

[0054] The free form of the compounds of the present invention can be converted into the corresponding salt form, and vice versa. The free or salt form and / or solvate form of the compounds of the present invention can be converted into the free or unsolvated salt form of the corresponding compounds, and vice versa.

[0055] The present invention also relates to compounds of the invention for use as medicines, optionally in the form of pharmaceutically acceptable salts and / or solvates.

[0056] The compounds of the present invention exhibit pharmacological activity and are therefore suitable for use as drugs.

[0057] For example, the compounds of the present invention exhibit antimicrobial properties, such as antibacterial activities against the following

[0058] Gram-positive bacteria, such as coagulase-positive staphylococci, including Staphylococcus aureus, including coagulase-negative staphylococci, such as Staphylococcus epidermidis and Staphylococcus haemolyticus, and streptococci, such as Streptococcus pyogenes and Streptococcus pneumoniae, and

[0059] • Targets Gram-negative bacteria, such as Moraxella catarrhalis, and Haemophilus influenzae, such as Haemophilus influenzae, as well as spirochetes, i.e. bacteria from the phylum Spirochete, such as the Borreliella species.

[0060] Therefore, in another aspect, the present invention provides compounds for treating and preventing bacterial-mediated diseases.

[0061] In one implementation, the disease is mediated by bacteria selected from the group consisting of:

[0062] - Gram-positive bacteria, including

[0063] Staphylococci, such as Staphylococcus aureus,

[0064] • Streptococci, such as Streptococcus pneumoniae, β-hemolytic or viridans streptococcal species,

[0065] • Enterococci, such as Enterococcus faecium,

[0066] • Peptostreptococci, such as anaerobic Peptostreptococcus anaerobius,

[0067] Clostridium, such as Clostridium difficile and Clostridium perfringens,

[0068] • Propionibacteria (genus Cutibacterium, formerly known as Propionibacterium), such as Propionibacterium acnes, Propionibacterium avidum, and Propionibacterium granulosum.

[0069] • And Listeria monocytogenes, Eubacterium lentum, Finegoldia magna, Anaerococcus prevotii, and Peptoniphilus assaccharolyticus,

[0070] and

[0071] - Gram-negative bacteria, including

[0072] • Moraxella species, such as Moraxella catarrhalis,

[0073] Haemophilus species, such as Haemophilus influenzae and Haemophilus parainfluenzeae.

[0074] • Chlamydia, such as Chlamydophila pneumoniae and Chlamydia trachomatis.

[0075] • Neisseriaceae, such as Neisseria gonorrhoeae,

[0076] • Species of the genus Mycoplasma, such as Mycoplasma pneumoniae and Mycoplasma genitalium.

[0077] • Fusobacteria, such as *Fusobacterium fusiforme*, *Fusobacterium necrophorum*, *Fusobacterium mortiferum*, and *Fusobacterium varium*.

[0078] • Species of the genus *Prevotella*, such as *Prevotella buccae* and *Prevotella oris*.

[0079] • Species of the genus *Porphyromonas*, such as *Porphyromonas gingivalis* and *Porphyromonas asaccharolytica*.

[0080] • Legionella species, such as Legionella pneumophila,

[0081] • Spirochetes, more precisely, are bacteria selected from the phylum Spirochete, such as species of the genera *Borreliella*, *Leptospira*, and *Treponema*.

[0082] • As well as Bacteroides fragilis and Acinetobacter lwoffii.

[0083] The disease can be mediated by Gram-negative or Gram-positive bacteria, including aerobic, facultative anaerobic, or obligate anaerobic bacteria. In one embodiment, the disease is mediated by aerobic or facultative anaerobic bacteria, particularly aerobic or facultative anaerobic Gram-positive bacteria.

[0084] Preferably, the disease is mediated by bacteria selected from the group consisting of Staphylococcus and Streptococcus.

[0085] In particular, the disease is mediated by bacteria resistant to lefamolin. For example, bacteria with resistance mechanisms mediated by, for example, vga(A), lsa(E), or cfr.

[0086] In a preferred embodiment, the disease is selected from the group consisting of:

[0087] • Respiratory infections, including pneumonia, such as community-acquired bacterial pneumonia (CABP) and nosocomial pneumonia.

[0088] • Skin and / or soft tissue infections, including acute bacterial skin and skin structure infections (ABSSI),

[0089] Systemic infections, including sepsis,

[0090] • Prosthetic joint infection

[0091] Sexually transmitted infections (STIs), including syphilis,

[0092] Acne

[0093] Lyme disease and relapsing fever.

[0094] More preferably, the disease is a respiratory infection, including community-acquired pneumonia and nosocomial pneumonia, a skin and / or soft tissue infection, including acute bacterial skin and skin structure infections, sexually transmitted infections, or sepsis.

[0095] In one implementation, the disease is mediated by spirochetes, more specifically by bacteria selected from the phylum Spirochete.

[0096] The phylum Spirospira comprises different classes and orders. At the order level, it includes: Brachyspirales, Spirochaetale, or Leptospirales. Brachyspirales includes spirochetes known to cause veterinary diseases, including, for example, *Brachyspirahyodysenteriae*. Spirospirales or Leptospirales also include bacteria that mediate bacterial infections in humans. Within Spirospirales, there are taxa of the families Leptospiraceae and Leptospiraceae (as well as other families).

[0097] In a preferred embodiment of the invention, the invention relates to the use of the compounds according to the invention in the treatment or prevention of bacterial infections mediated by bacteria selected from the orders Spirochetes or Leptospira, more preferably Spirochetes. In one specific embodiment, the bacteria are selected from the families Leptospiraceae and Leptospiraceae (both belonging to the order Spirochetes).

[0098] More preferably, the bacteria are selected from the group consisting of the genera *Borreliella*, *Leptospira*, and *Treponema*, and more preferably from the group consisting of *Borreliella* and *Treponema*.

[0099] When referring to a specific genus, it should be understood that the term includes all species and subspecies within that genus. For example, the genus *Borrelia* encompasses all species of the genus *Borrelia* (*Borrelia* spp.).

[0100] Bacteria of the genus *Borrelia* within the family Borreliidae in the order Spirochetes cause relapsing fever. The disease is characterized by relapsing fever, the presence of prominent spirochetes on blood smears, and transmission via bites from insects such as lice or soft-bodied ticks (*T.*). Specific bacteria of interest include: *Borrelia crocidurae*, *Borrelia duttoni*, *Borrelia hermsii*, *Borrelia ispanica*, *Borreliamiyamotoi*, *Borrelia parkeri*, *Borrelia turicatae*, *Borrelia persica*, and *Borrelia recurrentis*.

[0101] The bacteria *Borreliella*, formerly known as *Borrethori*, now represent a separate genus within the order *Borrethoriales* and family *Borrethoriaceae*. *Borreliella* causes Lyme disease / Lyme borreropathiasis. Lyme borreropathiasis (LB) is a tick-borne bacterial infection caused by several members of the spirochete group *Borreliella burgdorferi*. It is the most prevalent tick-borne infection in temperate regions of Europe, North America, and Asia, and its geographic distribution is expanding. The *B. burgdorferi* complex comprises at least 15 genotypes worldwide; however, only six are significantly pathogenic to humans. All pathogenic genotypes cause erythema migrans, the early skin rash of LB. *B. afzelii* and *B. garinii* are the major pathogenic genotypes found in Europe, associated with cutaneous and neurological complications, respectively. *B. burgdorferi* (the major pathogenic genotype found in North America) is present in parts of Europe and can cause neurological and arthritis complications. In North America, *Borreliella mayonii* (also known as *Borrelia mayonii*) is a recently (2013) discovered bacterium that can cause Lyme disease. Based on limited information, the disease caused by *B. mayonii* appears similar to that caused by *B. burgdorferi*, but there are some differences. Like *B. burgdorferi*, *B. mayonii* causes fever, headache, rash, and neck pain within days of infection and may cause arthritis several weeks later. Unlike *B. burgdorferi*, *B. mayonii* also causes nausea and vomiting; large and widespread rashes; and high concentrations of the bacteria in the blood. Other pathogenic species have been identified in Europe: *B. bavariensis* and *B. spielmanii*, which are associated with neurological complications. In a preferred embodiment, the bacterium is *Borreliella* selected from the group of species mentioned in this paragraph, and more preferably *Borreliella burgdorferi* and *Borreliella garinii*.

[0102] In a preferred embodiment, the bacterial infection is mediated by bacteria of the family Borreliaceae, preferably Borreliella or the genus Borreliella, more preferably Borreliella. In particular, the bacterial infection is selected from the group consisting of Lyme disease and relapsing fever, preferably Lyme disease (including Lyme borreliosis).

[0103] Leptospirosis is caused by bacteria of the genus *Leptospira* within the order Leptospirales and family Leptospiraceae. Leptospirosis is a bacterial disease / infection affecting humans and animals. A rare but serious form of human leptospirosis includes Welch's disease, with symptoms including chest pain and swelling of the arms and legs. Hospitalization is usually required. Currently, the genus *Leptospira* includes 21 named species, such as *Leptospira interrogans* and *Leptospira inadai*.

[0104] Bacteria of the genus *Treponema* in the family Treponemaceae cause a variety of human diseases, also known as treponemal diseases.

[0105] Syphilis is a complex systemic disease caused by the highly aggressive *Treponema pallidum*. *Treponema pallidum* subspecies mediated sexually transmitted syphilis (the classic form of sexually transmitted syphilis); *Treponema pallidum* subcutaneous subspecies mediated endemic syphilis. *Treponema pallidum* slender subspecies mediated yaws. Yaws is a common chronic infectious disease, primarily occurring in warm, humid regions. This disease has many names (e.g., pian, parangi, paru, frambesia tropica). Yaws typically presents as lesions appearing as lumps on the skin of the face, hands, feet, and genital area.

[0106] Pintavirus infection, mediated by *Treponema carateum*, is a skin infection that occurs only in the Western Hemisphere and has been described in Central and South America, Cuba, and the Caribbean. Pintavirus is the most benign of the non-sexually transmitted treponemal diseases because it only affects the skin.

[0107] Treponema denticola is associated with the incidence and severity of periodontal disease (treponechoperodontitis) in humans. Elevated levels of Treponema denticola in the oral cavity are considered one of the main causes of periodontitis.

[0108] In a preferred embodiment, the bacteria is a spirochetes selected from the group of species mentioned in the preceding paragraph, and more preferably a pale spirochetes.

[0109] In a preferred embodiment, the bacterial infection is mediated by Treponema pallidum. In particular, the bacterial infection is selected from syphilis, including sexually transmitted syphilis and endemic syphilis, pinta disease, (Treponema pallidum) periodontitis and yaws, with syphilis being preferred.

[0110] Subjects requiring treatment for spirochetal-mediated diseases can be any live subject suffering from an infection mediated by spirochetes or bacteria selected from the phylum Spirochete. In particular, the subject can be a human or an animal, especially a human. Therefore, in one embodiment, the compound is administered (or configured for administration) to a human.

[0111] On the other hand, the present invention provides the use of the compound in the preparation of medicines, particularly in the preparation of medicines for treating and preventing the aforementioned diseases.

[0112] On the other hand, the present invention provides a method for treating bacterial-mediated diseases, the method comprising administering an effective amount of the compound of the present invention, for example in the form of a pharmaceutical composition, to a subject who requires such treatment.

[0113] In another aspect, the present invention provides a method for treating acne, comprising administering an effective amount of the compound of the present invention, for example in the form of a pharmaceutical composition, to a subject who requires such treatment.

[0114] Treatment includes both therapy and prevention.

[0115] For antimicrobial and acne treatment, the appropriate dosage will naturally vary depending on factors such as the chemical properties and pharmacokinetic data of the compounds of the invention used, the individual host, the mode of administration, and the nature and severity of the condition being treated. However, generally, to obtain satisfactory results in larger mammals (e.g., humans), the indicated daily dose of the compounds of the invention is in the range of about 0.5 mg to 3 g, conveniently administered, for example, in divided doses up to four times daily. If the compounds are administered intravenously, administration may also include continuous infusion.

[0116] Preferably, the compound used according to the invention is administered by inhalation, intravenous or subcutaneous injection, or oral administration.

[0117] The compounds of the present invention can be administered via any conventional route, such as enteric, including nasal, buccal, rectal, and oral administration; parenteral, including intravenous, intramuscular, and subcutaneous administration; or topical, including transdermal, intranasal, and intratracheal administration, such as in the form of coated or uncoated tablets, capsules, injectable solutions, or suspensions, such as in ampoules, vials, creams, gels, pastes, inhaled powders, foams, tinctures, lip balms, drops, sprays, or suppositories, such as in a manner similar to macrolides such as erythromycin, clarithromycin, or azithromycin.

[0118] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts, such as acid addition salts or in free form, optionally in solvate form. The salt forms of the compounds of the present invention exhibit the same level of activity as the free and optionally solvate forms.

[0119] The compounds of the present invention can be used alone or in combination with one or more other pharmaceutically active agents for pharmaceutical treatment according to the present invention. Such other pharmaceutically active agents include, for example, other antibiotics and anti-inflammatory agents, and, if the compounds of the present invention are used to treat acne, the other agents also include agents having anti-acne activity.

[0120] Combinations include fixed combinations, in which two or more active pharmaceutical agents are in the same formulation; kits, in which two or more active pharmaceutical agents are sold in the same package as separate formulations, for example with instructions for co-administration; and free combinations, in which the active pharmaceutical agents are packaged separately but instructions for simultaneous or sequential administration are given.

[0121] On the other hand, the present invention provides pharmaceutical compositions comprising the compounds of the present invention in free form or pharmaceutically acceptable salt form and / or solvate form, in combination with at least one pharmaceutical excipient, such as a carrier or diluent, including fillers, binders, disintegrants, flow conditioners, flow enhancers, flow aids, lubricants, sugars and sweeteners, flavorings, flavor masking agents, preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts and / or buffers for regulating osmotic pressure.

[0122] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound according to the invention, and further comprising another pharmaceutically active agent.

[0123] Such pharmaceutical compositions can be manufactured using methods similar to conventional methods, such as mixing, spray drying, granulation, coating, dissolving, or lyophilizing processes. Unit dosage forms may contain, for example, from about 0.5 mg to about 2000 mg, or, for example, from 10 mg to about 1500 mg.

[0124] Subjects requiring the treatment considered in this invention can be any live subject suffering from a bacterial-mediated disease. In particular, the subject can be a human or an animal.

[0125] The compounds of the present invention are also suitable as veterinary agents, such as veterinary active compounds, for the prevention and treatment of microbial diseases, such as bacterial diseases, in animals such as poultry, pigs and calves, and for diluting fluids used in artificial insemination and egg immersion techniques.

[0126] On the other hand, the present invention provides compounds of the present invention for use as veterinary agents.

[0127] In another aspect, the present invention provides compounds of the present invention for preparing veterinary compositions that can be used as veterinary agents.

[0128] On the other hand, the present invention provides a veterinary method for the prevention and treatment of microbial diseases, such as bacterial diseases, comprising administering an effective amount of the compound of the present invention, for example in the form of a veterinary composition, to a subject requiring such treatment.

[0129] On the other hand, the present invention provides compounds according to general formula (VI).

[0130]

[0131] in

[0132] The methyl group at position 12 of the morin ring exhibits reverse stereochemistry compared to the stereochemistry of the methyl group at position 12 of the naturally occurring truncated pleurotin ring.

[0133] - All other substituents in the morin ring have the same stereochemistry as the substituents at the corresponding positions in the naturally occurring truncated pleurotin ring.

[0134] R'1 is substituted with a heterocyclic group (C 1-16 )alkyl or (C 2-16 Alkenyl groups, including aliphatic heterocyclic groups and aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from N, O, and S, provided that at least one heteroatom is a nitrogen atom, or

[0135] R'1 is a group of the following formula

[0136]

[0137] Where YN(R3R4) is

[0138] -(C 1-16 )alkyl-N(R3R4),

[0139] -(C 1-16 )alkyl-(C 6-14 )aryl-N(R3R4),

[0140] -(C 1-16 )alkyl-(C 6-14 )Aryl-(C 1-16 )alkyl-N(R3R4),

[0141] -(C 1-16 )alkyl-(C 1-13 Heterocyclic group -N(R3R4),

[0142] -(C 1-16 )alkyl-(C 1-13 Heterocyclic group-(C 1-16 )alkyl-N(R3R4),

[0143] -carbonyl-N(R3R4),

[0144] -(C 1-4 )alkyl-carbonyl-N(R3R4),

[0145] -(C 2-16 alkenyl-N(R3R4),

[0146] -(C 2-16 )alkenyl-(C 6-14 )aryl-N(R3R4),

[0147] -(C 2-16 )alkenyl-(C 6-14 )aryl-(C 1-16 )alkyl-N(R3R4),

[0148] -(C 2-16 )alkenyl-(C 1-13 Heterocyclic group -N(R3R4),

[0149] -(C 2-16 )alkenyl-(C 1-13 Heterocyclic group-(C 1-16 )alkyl-N(R3R4),

[0150] The heterocyclic group includes aliphatic and aromatic heterocyclic groups containing at least one heteroatom selected from N, O, and S, and wherein alkyl, aryl, heterocyclic or alkenyl groups are optionally substituted, and includes substituents optionally having heteroatoms selected from O, N, S, and halogens.

[0151] R3 and R4 are independent of each other.

[0152] -hydrogen,

[0153] -(C 1-16 )alkyl,

[0154] -(C 2-16 alkenyl,

[0155] -hydroxyl group (C 1-16 )alkyl,

[0156] -amino-(C 1-16 )alkyl,

[0157] -Single or double-(C) 1-6 )alkylamino-(C 1-16 )alkyl,

[0158] -Guidino(C 1-16 )alkyl, urea (C 1-16 )alkyl or thiourea group (C 1-16 )alkyl,

[0159] -Amino(C1-6 )alkyl-(C 6-14 )aryl-(C 1-6 )alkyl,

[0160] -Amino(C 1-6 )alkyl-(C 6-14 aryl,

[0161] -Guidino(C 1-6 )alkyl-(C 6-14 )aryl-(C 1-6 )alkyl,

[0162] -amino-(C 1-6 )alkoxy-(C 1-6 )alkyl,

[0163] -Amino(C 3-8 )cycloalkyl,

[0164] -Amino(C 1-6 )alkyl-(C 3-8 )cycloalkyl,

[0165] -Amino(C 3-8 )cycloalkyl-(C 1-6 )alkyl,

[0166] -Amino(C 1-6 )alkyl-(C 3-8 )cycloalkyl-(C 1-6 )alkyl,

[0167] -(C 1-13 Heterocyclic group-(C 1-16 )alkyl,

[0168] -(C 6-14 )aryl-(C 1-16 )alkyl,

[0169] -(C 1-13 Heterocyclic groups,

[0170] -amino-(C 6-14 )aryl-(C 1-16 )alkyl,

[0171] -amino-(C 1-6 )alkoxy-(C 6-14 )aryl-(C 1-6 )alkyl,

[0172] -Amino(C 1-6 )alkyl-(C 6-12 aryl-carbonyl,

[0173] -Amino(C 1-6)alkyl-amide-(C 6-12 )Aryl(C 1-6 )alkyl,

[0174] -(C 1-4 )alkyl carbonyl,

[0175] -carbamimidoyl, carbamoyl, thiocarbamoyl

[0176] The heterocyclic groups include aliphatic and aromatic heterocyclic groups containing at least one heteroatom selected from N, O, and S.

[0177] and

[0178] The alkyl, cycloalkyl, heterocyclic, alkenyl, or aryl groups may optionally be further substituted with the following groups.

[0179] -Amino(C 1-4 )alkyl, amide, mono- or di-(C 1-4 )alkyl-amide, (C 1-6 Alkoxy-carbonyl, halogen, oxo, hydroxyl

[0180] X is sulfur or oxygen, especially sulfur, and

[0181] R'2 is a hydrocarbon group containing 1 to 22 carbon atoms, optionally containing a heteroatom selected from N, O, S, or halogens, especially N or O.

[0182] Or its pharmaceutically acceptable salt, solvate, prodrug, or metabolite.

[0183] Naturally occurring truncated pleurotin has the formula (PLEU).

[0184]

[0185] For the treatment or prevention of bacterial infections mediated by spirochetes, particularly bacterial infections mediated by bacteria selected from the phylum Spirochete, preferably, said bacteria are selected from the order Spirocheteles or Leptospirales, more preferably from the group consisting of the genera *Borreliella*, *Leptospira*, and *Treponema*.

[0186] The present invention also provides a method for treating or preventing bacterial infection, comprising administering to a subject requiring such treatment a compound of general formula (VI) as defined above, or an ester of a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein the bacterial infection is mediated by spirochetes or bacteria selected from the phylum Spirochete, and the use of the compound in the preparation of a medicament for the specific treatment or prevention described above.

[0187] The above-described embodiments and preferred embodiments for diseases mediated by spirochetes are similarly applicable to compounds of general formula (VI) used for that particular purpose or method.

[0188] Regarding compounds of general formula (VI), in the preferred embodiment,

[0189] a) R'2 is

[0190] -(C 1-16 )alkyl,

[0191] -(C 3-12 )cycloalkyl,

[0192] -(C 1-13 Heterocyclic groups,

[0193] -(C 6-14 aryl

[0194] The heterocyclic group includes aliphatic and aromatic heterocyclic groups containing at least one heteroatom selected from N, O, and S, and wherein the alkyl, cycloalkyl, aryl, or heterocyclic group is unsubstituted or optionally substituted with a substituent having a heteroatom selected from O, N, S, and halogens.

[0195] b) R'2 is

[0196] alkyl,

[0197] Optionally substituted with the following groups

[0198] -hydroxyl or amino,

[0199] -(C 3-12 ) cycloalkyl, wherein the cycloalkyl group is optionally further surrounded by an amino group or an amino (C 1-4 )alkyl substitution, wherein the amino or aminoalkyl group is optionally further replaced by an amino (C 1-6 )alkyl carbonyl and optionally (C 1-4 )alkyl substitution,

[0200] -(C 2-11 ) heterocyclic group, wherein the nitrogen in the ring as a heteroatom is optionally further replaced by an amino group (C 1-6 )alkyl carbonyl substitution,

[0201] cycloalkyl,

[0202] Optionally substituted with the following groups

[0203] -Amino(C 1-4 )alkyl, wherein the amino group is optionally further substituted with an amino (C 1-6 )alkyl carbonyl,

[0204] hydroxyl group

[0205] Amino group, wherein the amino group is optionally further surrounded by an amino group (C). 1-6 )alkyl carbonyl and optionally (C 1-4 )alkyl substitution,

[0206] -Amino and hydroxyl groups, wherein the amino group is optionally further modified by an amino group (C). 1-6 )alkyl carbonyl and optionally (C 1-4 )alkyl substitution,

[0207] -(C 1-4 )alkylamino, wherein the alkyl group is optionally further substituted with one or more halogen atoms;

[0208] aliphatic (C) 2-11 Heterocyclic groups,

[0209] It contains 1 to 4 heteroatoms selected from N, O, and S, wherein the nitrogen in the ring, which is a heteroatom, may optionally be further substituted by the following groups.

[0210] -(C 1-4 )alkyl,

[0211] -Amino(C 1-6 )alkyl carbonyl,

[0212] Aryl,

[0213] Optionally substituted with the following groups

[0214] -Hydroxy, halogen, amino, hydroxyl (C 1-4 )alkyl, bis-(hydroxy(C 1-4 alkyl), amino (C) 1-4 )alkyl, bis-(amino(C 1-4 )alkyl), wherein amino (C 1-4 The amino groups in the alkyl group may optionally be further substituted.

[0215] -aminocarbonyl, wherein nitrogen is optionally substituted by the following groups

[0216] -Amino(C 1-12 )alkyl, bis-(amino(C 1-12 )alkyl), hydroxyl (C) 1-6 )alkyl, bis(hydroxy(C) 1-6 )alkyl) or diamino (C 1-6 )alkyl,

[0217] -(C 1-12 )alkyl group, which may optionally be substituted with the following groups

[0218] -Amino group, which may optionally be acylated, particularly by replacing the formyl group with the following group, (C 1-4)alkyl carbonyl group, comprising 1 to 3 heteroatoms, particularly N, and 4 to 8, particularly 5 to 6 ring members, saturated or unsaturated heterocyclic groups, (C 6-14 ) aryl, especially phenyl, the aryl group optionally surrounded by an amino group (C 1-4 )alkyl substitution,

[0219] or

[0220] The nitrogen in the amino carbonyl group is (C 3-8 A portion of heterocyclic groups, including aliphatic and aromatic heterocyclic groups comprising one or more heteroatoms selected from N, O, S, preferably N, wherein the heterocycle is optionally further modified by an amino group (C 1-4 Alkyl substitution;

[0221] -(C 1-6 )alkyl, wherein (C 1-6 The alkyl group may optionally be substituted with an amino carbonyl group, wherein the nitrogen of the amino carbonyl group may optionally be further replaced by an amino group (C). 1-12 )alkyl, diamino-(C 1-12 )alkyl, bis-(amino(C 1-12 )alkyl), hydroxyl (C) 1-6 )alkyl, bis-(hydroxy(C 1-6 alkyl) substitution,

[0222] -Acylamino(C 1-4 )alkyl,

[0223] Aromatic groups (C) containing 1 to 4 heteroatoms 1-13 Heterocyclic groups,

[0224] Among them, aromatic heterocyclic groups are selectively bound by (C) 1-6 Alkyl, amino, or hydroxyl groups are substituted, wherein the alkyl group is optionally further substituted with a halogen or amino group, or the aromatic heterocyclic group is optionally substituted with an amino carbonyl group, wherein the amino group is optionally further substituted with an amino (C) group. 1-12 )alkyl, bis-(amino(C 1-12 )alkyl), hydroxyl (C) 1-6 )alkyl, bis-(hydroxy(C 1-6 )alkyl) or diamino (C 1-6 Alkyl substitution.

[0225] c) R'2 is an amide-phenyl, amide (C 1-4 )alkyl-phenyl, wherein the nitrogen of the amide group is not substituted or is replaced by an amino group (C 1-8 Alkyl substitution, wherein the alkyl group may optionally be further substituted.

[0226] d)R'2 is

[0227] -Amino(C 3-12)cycloalkyl,

[0228] -Amino(C 1-4 )alkyl(C 3-12 )cycloalkyl,

[0229] -Amino(C 3-12 )cycloalkyl (C 1-4 )alkyl, or

[0230] -Amino(C 1-4 )alkyl(C 3-12 )cycloalkyl (C 1-4 )alkyl,

[0231] Where the amino group is not substituted or is replaced by an amino group (C 1-6 )alkyl carbonyl, or amino (C 1-6 )alkyl carbonyl and (C 1-4 Alkyl substitution.

[0232] e)R'2 is a (C) group containing 1 to 4 heteroatoms selected from N, O, and S. 2-11 Heterocyclic groups, wherein if nitrogen is present in the ring as a heteroatom, the nitrogen is unsubstituted or optionally further substituted by the following groups.

[0233] -(C 1-4 )alkyl,

[0234] -Amino(C 1-6 )alkyl carbonyl.

[0235] f)X is S,

[0236] R'1 is as defined above, and R'2 is

[0237] Aminoethyl-acylaminomethyl-phenyl, aminopropyl-acylaminomethyl-phenyl, hydroxyphenyl-(amino)ethyl-acylaminomethyl-phenyl, aminomethyl-phenyl-(amino)ethyl-acylaminomethyl-phenyl, aminopropyl-acylaminophenyl, aminomethyl-phenylmethyl-acylamino-phenyl, aminomethyl-phenyl, aminoacetyl-aminomethyl-phenyl, bis(aminomethyl)phenyl, bisaminopropyl-acylaminomethyl-phenyl, (2-amino)-aminopropyl-acylaminomethyl-phenyl, aminoethyl-aminomethyl-phenyl, aminopropyl-aminomethyl-phenyl, allyl-aminomethyl-phenyl, aminomethyl-phenylmethyl-aminomethyl-phenyl, hydroxymethyl-phenyl, bis(hydroxymethyl)-phenyl, (tetrafluoro-hydroxymethyl)-phenyl, amino-hydroxy-cyclohexyl, hydroxyethyl, aminoethyl, piperazine carbonyl-phenyl, aminomethyl-piperidine-carbonyl-phenyl, piperidinylmethyl-acylamino-phenyl, pyridinylmethyl- Acylaminophenyl, acetylaminopropyl-acylaminophenyl, formylaminopropyl-acylaminophenyl, acylaminophenyl, aminohexyl-acylaminophenyl, aminoethyl-acylaminophenyl, (5-amino)-4H-[1,2,4]triazol-3-yl, pyridyl, hydroxyphenyl, fluorophenyl, purine, aminophenyl, acetylaminomethyl-phenyl, cyclopropyl-aminomethyl-phenyl, aminopropyl-acylaminopyridyl, hydroxypropyl-acylaminophenyl Amino-purine, difluoroethylamino-cyclohexyl, amino-hydroxy-cyclohexyl, azepanyl, aminomethylcyclohexylmethyl, N-methyl-piperidinyl, piperidinyl, aminomethylcyclohexyl, aminopropylphenyl, phenyl, N-aminomethylcarbonyl-piperidinyl, N-aminoethylcarbonyl-piperidinyl, N-aminomethylcarbonyl-piperidinylmethyl, aminomethylamidoaminomethylcyclohexyl, aminomethyl-pyridinyl, aminomethylamidoaminocyclohexyl.

[0238] g) The compound has formula (VII)

[0239]

[0240] R'2 is defined above.

[0241] n is 1 to 12

[0242] R3 is H, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, aminooctyl, aminodecyl, dimethylaminopropyl, dimethylamidepentyl, guanidinobutyl, guanidinohexyl, formamidinyl, aminomethylcyclohexylmethyl, aminopropoxypropyl, aminocyclohexyl, hydroxyhexyl, dihydroxypropyl, aminomethylphenylmethyl, guanidinomethylphenylmethyl, phenylmethyl, morpholinopropyl, piperidinyl, hexyl, pyridylethyl, allyl, amide-benzyl, aminopropyl-amide-benzyl, (2-amino)-amide-ethyl-benzyl, (2-amino)-dimethylamide-ethyl-benzyl, 2-amino-1-aminomethyl-ethyl, 5-amino-5-ethoxycarbonyl-pentyl, aminomethylphenylpropyl, aminomethylphenyl, aminophenylmethyl, aminoethoxyphenylmethyl, aminomethyl-fluorophenyl-methyl, aminomethyl-difluorophenyl-methyl, and

[0243] R4 is H, (C 1-4 )alkyl carbonyl or aminomethylphenyl carbonyl.

[0244] h)R'2 is as defined above and

[0245] R'1 is aminomethylphenylpropyl, aminoethylaminomethylphenylvinyl, aminoethylaminomethylphenylethyl, aminomethylphenylethyl, aminomethylphenylethyl, pyridylvinyl, aminoethylamino-fluorophenyl-vinyl.

[0246] i) The compounds are selected from the following groups:

[0247] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0248] 12-Epidermo-12-Devinyl-14-O-{{4-[(2-amino-ethylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0249] 12-Epidermo-12-Devinyl-14-O-{{4-([bis-(3-amino-propyl)-carbamoyl]-methyl}-phenylthioalkyl)-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0250] 12-Epidermo-12-Devinyl-14-O-{{4-[(2,3-diamino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0251] 12-Epidermo-12-Devinyl-14-O-{{4-[(2-amino-ethylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(2-amino-ethylamino)-methyl]moline,

[0252] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(2-amino-ethylamino)-methyl]moline,

[0253] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(4-amino-butylamino)-methyl]moline,

[0254] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(5-amino-phenylamino)-methyl]moline,

[0255] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]phenylthioalkyl}-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0256] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0257] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]phenylthioalkyl}-acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0258] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(4-guanidino-butylamino)-methyl]moline,

[0259] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(allylamino)-methyl]moline,

[0260] 12-Epidermoline-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-aminomethylmoline,

[0261] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(benzylamino)-methyl]moline,

[0262] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(4-guanidinylmethyl-benzylamino)-methyl]moline,

[0263] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(6-hydroxy-hexylamino)-methyl]moline,

[0264] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(2,3-dihydroxypropylamino)-methyl]moline,

[0265] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(4-piperidinylamino)-methyl]moline,

[0266] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-morpholin-4-yl-propylamino)-methyl]moline,

[0267] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]phenylthioalkyl}-acetyl}-12-[(3-dimethylamino-propylamino)-methyl]moline,

[0268] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[(S)-5-amino-5-ethoxycarbonyl-pentylamino-methyl]moline,

[0269] 12-Epidermo-12-Devinyl-14-O-{[4-(4-aminomethyl-benzylcarbamoyl)-phenylthioyl]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0270] 12-Epidermo-12-Devinyl-14-O-{[4-(4-aminomethylbenzylcarbamoyl)-phenylthioyl]acetyl}-12-[(6-guanidinyl-hexylamino)methyl]moline,

[0271] 12-Epidermo-12-Devinyl-14-O-{[(4-piperazinylcarbamoyl)-phenylthioalkyl]acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0272] 12-Epidermo-12-Devinyl-14-O-{[4-(4-aminomethyl-piperidin-1-carbonyl)-phenylthioalkyl]acetyl}-12-[(6-guanidinyl-hexylamino)methyl]moline,

[0273] 12-Epidermo-12-Devinyl-14-O-{(4-[(piperidin-4-ylmethyl)-carbamoyl]-phenylthioyl)-acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0274] 12-Epidermo-12-Devinyl-14-O-{(4-[(pyridin-4-ylmethyl)-carbamoyl]-phenylthioalkyl)-acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0275] 12-Epidermo-12-Devinyl-14-O-{[3-(3-aminopropylcarbamoyl)-phenylthioalkyl]acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0276] 12-Epidermo-12-Devinyl-14-O-{[4-(3-acetylamino-propylcarbamoyl)-phenylthio]-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0277] 12-Epidermo-12-Devinyl-14-O-{[4-(3-formylamino-propylcarbamoyl)-phenylthioalkyl]-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0278] 12-Epidermo-12-Devinyl-14-O-{[4-(3-amino-propylcarbamoyl)-phenylthio]acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0279] 12-Epidermo-12-Devinyl-14-O-{(4-[(3-aminopropylcarbamoyl)-phenylthio)-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0280] 12-Epidermo-12-Devinyl-14-O-{(4-[(3-aminopropylcarbamoyl)-phenylthio)-acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0281] 12-Epidermo-12-Devinyl-14-O-{[4-(3-aminopropylcarbamoyl)-phenylthio]acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0282] 12-Epidermo-12-Devinyl-14-O-{[4-(3-aminopropylcarbamoyl)-phenylthio]acetyl}-12-[(8-amino-octylamino)-methyl]moline,

[0283] 12-Epidermo-12-Devinyl-14-O-{[4-(3-aminopropylcarbamoyl)-phenylthioalkyl]acetyl}-12-[(10-amino-decylamino)-methyl]moline,

[0284] 12-Epidermoline-12-Devinyl-14-O-{(4-carbamoyl-phenylthio)acetyl}-12-[(6-guanidinyl-hexylamino)methyl]moline

[0285] 12-Epidermo-12-Devinyl-14-O-{[4-(3-amino-propylcarbamoyl)-phenylthio]-acetyl}-12-{[3-(3-amino-propoxy)-propylamino)]-methyl}moline,

[0286] 12-Epidermo-12-Devinyl-14-O-{[4-(3-amino-propylcarbamoyl)-phenylthio]-acetyl}-12[(2-pyridin-4-yl-ethylamino)-methyl]moline,

[0287] 12-Epidermo-12-Devinyl-14-O-{[4-(6-amino-hexylcarbamoyl)-phenylthio]acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0288] 12-Epidermo-12-Devinyl-14-O-{[4-(2-amino-ethylcarbamoyl)-phenylthioalkyl]acetyl}-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0289] 12-Epidermo-12-Devinyl-14-O-{[4-(3-aminopropylcarbamoyl)-phenylthio]-acetyl}-12-{[3-(4-aminomethyl-phenyl)-propylamino]-methyl}moline,

[0290] 12-Epidermo-12-Devinyl-14-O-{[(4-aminomethyl-cyclohexyl)-methylthio]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0291] 12-Episode-14-O-[(1-methyl-piperidin-4-ylthioalkyl)-acetyl}-12-[(6-guanidino-hexylamino)-methyl]moline,

[0292] 12-Episode-14-O-[(piperidin-4-ylthioalkyl)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0293] 12-Epidermo-12-Devinyl-14-O-{[(4-aminomethyl-cyclohexyl)-thioalkyl]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0294] 12-Epidermo-12-Devinyl-14-O-{[4-(3-amino-propyl)-phenylthio]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0295] 12-Epidermo-12-Devinyl-14-O-{(4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl)-acetyl}-12-{[(3-amino-propyl)-acetylamino]-methyl}moline,

[0296] 12-Epidermo-12-Devinyl-14-O-{(4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioyl)-acetyl}-12-(3-amino-propylcarbamoyl)moline,

[0297] 12-Epidermo-12-Devinyl-14-O-{[4-(3-amino-propylcarbamoyl)-phenylthioyl]-acetyl}-12-(4-aminomethyl-benzylcarbamoyl)moline,

[0298] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylcarbamoyl)-methyl]-phenylthioalkyl}-acetyl}-12-[2-(3-amino-propylamino)-ethyl]moline,

[0299] 12-Epidermo-12-Devinyl-14-O-[(3-hydroxymethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0300] 12-Epidermo-12-Devinyl-14-O-[(3-hydroxymethyl-phenylthio)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0301] 12-Epidermo-12-Devinyl-14-O-[(3-hydroxymethyl-phenylthio)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0302] 12-Epidermo-12-Devinyl-14-O-[(3-hydroxymethyl-phenylthio)-acetyl]-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0303] 12-Epidermoline-12-Devinyl-14-O-[(4-hydroxymethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0304] 12-Epidermo-12-Devinyl-14-O-[(4-hydroxymethyl-phenylthio)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0305] 12-Epidermoline-12-Devinyl-14-O-[(4-hydroxymethyl-phenylthio)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline

[0306] 12-Epidermoline-12-Devinyl-14-O-[(3,5-bis-hydroxymethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline

[0307] 12-Epidermo-12-Devinyl-14-O-{[(2,3,5,6-tetrafluoro-4-hydroxymethyl)-phenylthioalkyl]-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]-moline,

[0308] 12-Epidermo-12-Devinyl-14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylthioalkyl]acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0309] 12-Epidermo-12-Devinyl-14-O-{[(1R,2R,4R)-4-amino-2-hydroxy-cyclohexylthioalkyl]-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0310] 12-Epidermo-12-Devinyl-14-O-[(2-hydroxy-ethylthioalkyl)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0311] 12-Episode-12-Devinyl-14-O-[(2-amino-ethylthioalkyl)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0312] 12-Episode-12-Devinyl-14-O-{[(5-amino-4H-1,2,4-triazol-3-yl)thioalkyl]acetyl}-12-[(6-amino-hexylamino)methyl]moline,

[0313] 12-Episode-12-Devinyl-14-O-[(2-amino-ethylthioalkyl)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0314] 12-Episode-12-Devinyl-14-O-[(pyridin-4-ylthioalkyl)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0315] 12-Episode-12-Devinyl-14-O-[(pyridin-4-ylthioalkyl)acetyl]-12-[(6-guanidinyl-hexylamino)methyl]moline,

[0316] 12-Epidermoline-12-Devinyl-14-O-[(3-hydroxy-phenylthio)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline

[0317] 12-Episode-12-Devinyl-14-O-[(4-fluoro-phenylthio)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0318] 12-Epidermo-12-Devinyl-14-O-{[(7H-purin-6-yl)-thioalkyl]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0319] 12-Episode-12-Devinyl-14-O-[(3-amino-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0320] 12-Epidermoline-12-Devinyl-14-O-(phenylthioalkyl-acetyl)-12-[(4-aminomethyl-benzylamino)-methyl]moline

[0321] 12-Episode-12-Devinyl-14-O-[(4-fluoro-phenylthio)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0322] 12-Episode-12-Devinyl-14-O-[(pyridin-2-ylthioalkyl)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0323] 12-Episode-12-Devinyl-14-O-[(pyridin-4-ylthioalkyl)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0324] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl)]-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0325] 12-Epidermo-12-Devinyl-14-O-{[1-(3-amino-propionyl)-piperidin-4-yl-thioalkyl)]-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0326] 12-Epidermo-12-Devinyl-14-O-{[1-(3-amino-propionyl)-piperidin-4-yl-thioalkyl]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0327] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-methylthio]-acetyl}-12-[(4-aminomethyl-phenylamino)-methyl]moline,

[0328] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-methylthioalkyl]-acetyl}-12-[(4-amino-benzylamino)-methyl]moline,

[0329] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12{2-[4-(2-amino-ethoxy)-benzylamino]-methyl}moline,

[0330] 12-Epidermo-12-Devinyl-14-O-{{4-[(2-amino-acetylamino)-methyl]-cyclohexylthioalkyl}-acetyl}-12-[{4-[(2-amino-ethoxy)-benzylamino]-methyl}moline,

[0331] 12-Epidermo-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0332] 12-Epidermo-12-Devinyl-14-O-[(3-aminomethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0333] 12-Epidermo-12-Devinyl-14-O-[(3-aminomethyl-phenylthio)-acetyl]-12-[(6-guanidinyl-hexylamino)-methyl]moline,

[0334] 12-Epidermo-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0335] 12-Episode-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0336] 12-Epidermo-12-Devinyl-14-O-[(3-aminomethyl-phenylthio)-acetyl]-12-[((4-aminomethyl-cyclohexyl)-methylamino)-methyl]moline,

[0337] 12-Epidermoline-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-{[(4-aminocyclohexyl)-amino]-methyl}moline,

[0338] 12-Episode-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(hexylamino)-methyl]moline,

[0339] 12-Epidermo-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(4-carbamoylphenyl)-methylamino)-methyl]moline,

[0340] 12-Epidermoline-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-{[4-(3-amino-propylcarbamoyl)-benzylamino]-methyl}moline,

[0341] 12-Epidermo-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(5-dimethylcarbamoyl-phenylamino)-methyl]moline,

[0342] 12-Epidermoline-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-{[4-(2-amino-2-carbamoyl-ethyl)-benzylamino]-methyl}moline,

[0343] 12-Epidermoline-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-{[4-(2-amino-2-dimethylcarbamoyl-ethyl)-benzylamino]-methyl}moline,

[0344] 12-Epidermo-12-Devinyl-14-O-{[5-aminomethyl-pyridin-2-yl-thioalkyl)]-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0345] 12-Epidermo-12-Devinyl-14-O-{[5-aminomethyl-pyridin-2-yl-thioalkyl)]-acetyl}-12-[(4-aminomethyl-3-fluoro-benzylamino)-methyl]moline,

[0346] 12-Epidermo-12-Devinyl-14-O-{[(4-aminomethyl-cyclohexyl)-methylthioalkyl)-acetyl]{[(4-aminomethyl-cyclohexyl)-methylthioalkyl]-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]moline,

[0347] 12-Epidermo-12-Devinyl-14-O-{1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-[(4-aminomethyl-3-fluoro-benzylamino)-methyl]moline,

[0348] 12-Epidermo-12-Devinyl-14-O-{{4-[(2-amino-acetylamino)-methyl]-cyclohexylthioalkyl}-acetyl}-12-[(4-aminomethyl-3-fluoro-benzylamino)-methyl]moline,

[0349] 12-Epidermo-12-Devinyl-14-O-{[5-aminomethyl-pyridin-2-yl-thioalkyl]acetyl}-12-[(4-aminomethyl-2,5-difluoro-benzylamino)-methyl]moline,

[0350] 12-Epidermo-12-Devinyl-14-O-[(4-aminomethyl-phenylthio)-acetyl]-12-[(2-amino-1-aminomethyl-ethylamino)-methyl]moline,

[0351] 12-Epidermo-12-Devinyl-14-O-[(5-aminomethyl-pyridin-2-yl-thioalkyl)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0352] 12-Epidermo-12-Devinyl-14-O-{(4-[(2-amino-acetylamino)-methyl]-phenylthioalkyl)-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0353] 12-Epidermo-12-Devinyl-14-O-{(4-[(2-amino-3-(4-hydroxy-phenyl)-propionylamino)-methyl]-phenylthioalkyl)-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0354] 12-Epidermo-12-Devinyl-14-O-{(4-[(3-amino-propionylamino)-methyl]-phenylthioalkyl)-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0355] 12-Epidermo-12-Devinyl-14-O-{(4-[(2-amino-acetylamino)-methyl]-phenylthioalkyl)-acetyl}-12-[4-aminomethyl-benzylamino-methyl]moline,

[0356] 12-Epidermo-12-Devinyl-14-O-{(4-[(2-amino-acetylamino)-methyl]-phenylthioalkyl)-acetyl}-12-(6-amino-hexylamino-methyl)moline,

[0357] 12-Epidermo-12-Devinyl-14-O-{[(3-acetylamino-methyl)-phenylthio]-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0358] 12-Epidermo-12-Devinyl-14-O-{(4-{[2-amino-3-(4-aminomethyl-phenyl)-propionylamino]-methyl}-phenylthioalkyl)-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0359] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylamino)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0360] 12-Epidermo-12-Devinyl-14-O-{{3-[(3-amino-propylamino)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0361] 12-Epidermo-12-Devinyl-14-O-{{4-[(4-aminomethyl-benzylamino)-methyl]-phenylthioalkyl}-acetyl}-12-[(3-amino-propylamino)-methyl]moline,

[0362] 12-Epidermo-12-Devinyl-14-O-[(3-allylaminomethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0363] 12-Epidermo-12-Devinyl-14-O-{{4-[(3-amino-propylamino)-methyl]-phenylthioalkyl}-acetyl}-12-{[3-(3-amino-propoxy)-propylamino]-methyl}moline,

[0364] 12-Epidermo-12-Devinyl-14-O-[(4-cyclopropylaminomethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0365] 12-Epidermo-12-Devinyl-14-O-[(4-cyclopropylaminomethyl-phenylthio)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0366] 12-Epidermo-12-Devinyl-14-O-{{4-[(4-aminomethyl-benzylamino)-methyl]-phenylthioalkyl}-acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0367] 12-Epidermo-12-Devinyl-14-O-{{4-[(4-aminomethyl-benzylamino)-methyl]-phenylthioalkyl}-acetyl}-12-[(4-aminomethyl-benzylamino)-methyl]-morin,

[0368] 12-Episode-12-Devinyl-14-O-[5-(3-amino-propylcarbamoyl)-pyridin-2-ylthioalkyl]acetyl-12-[(6-amino-hexylamino)-methyl]moline,

[0369] 12-Epidermo-12-Devinyl-14-O-[(2,5-bis-aminomethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0370] 12-Epidermo-12-Devinyl-14-O-[(3,5-bis-aminomethyl-phenylthio)-acetyl]-12-[(3-amino-propylamino)-methyl]moline,

[0371] 12-Epidermo-12-Devinyl-14-O-{[(3-amino-propylcarbamoyl)-phenylthioalkyl]-acetyl}-12-[(2-guanidino-ethyl]moline,

[0372] 12-Epidermo-12-Devinyl-14-O-{[4-(3-hydroxy-propylcarbamoyl)-phenylthio]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0373] 12-Episode-12-Devinyl-14-O-[(2-hydroxy-ethylthioalkyl)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0374] 12-Epidermo-12-Devinyl-14-O-{[3-(2,2-difluoro-ethylamino)-cyclohexylthio]acetyl}-12-[(6-amino-hexylamino)-methyl]moline,

[0375] 12-Episode-12-Devinyl-14-O-[(2-amino-7H-purine-6-ylthioalkyl)-acetyl]-12-[(6-amino-hexylamino)-methyl]moline,

[0376] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[(6-amino-hexylamino)methyl]moline,

[0377] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[(6-guanidinyl-hexylamino)methyl]moline,

[0378] 12-Epidermo-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[(4-aminomethyl-benzylamino)methyl]moline,

[0379] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[(6-amino-octylamino)methyl]moline,

[0380] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl)]-acetyl}-12-[(6-amino-hexylamino)-ethyl]moline,

[0381] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl)]-acetyl}-12-[(4-aminomethyl-benzylamino)-ethyl]moline,

[0382] 12-Epidermo-12-Devinyl-14-O-[5-hydroxymethyl-pyridin-2-yl-thioalkylacetyl]-12-[(4-aminomethyl-3-fluoro-benzylamino)-ethyl]moline,

[0383] 12-Epidermo-12-Devinyl-14-O-{4-[(2-amino-acetylamino)-cyclohexylthio]-acetyl}-12-[(4-aminomethyl-3-fluoro-benzylamino)-ethyl]moline,

[0384] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-[(4-aminomethyl-3-fluoro-benzylamino)-ethyl]moline,

[0385] 12-Episode-12-Devinyl-14-O-[(5-aminomethyl-pyridin-2-yl-thioalkyl)-acetyl]-12-[(4-aminomethyl-2,5-difluoro-benzylamino)-ethyl]moline,

[0386] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-[(4-aminomethyl-2,5-difluoro-benzylamino)-ethyl]moline,

[0387] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12{2-[4-(2-amino-ethoxy)-benzylamino]-ethyl}moline,

[0388] 12-Epidermo-12-Devinyl-14-O-{{4-[(2-amino-acetylamino)-methyl]-cyclohexylthioalkyl}-acetyl}-12-[(4-aminomethyl-3-fluoro-benzylamino)-ethyl]moline,

[0389] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[(4-aminomethyl-phenylamino)ethyl]moline,

[0390] 12-Epidermo-12-Devinyl-14-O-{{4-[(2-amino-acetylamino)]-cyclohexylthioalkyl}-acetyl}-12-[(4-aminomethyl-phenylamino)-ethyl]moline,

[0391] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-methylthio]-acetyl}-12-[(4-aminomethyl-phenylamino)-ethyl]moline,

[0392] 12-Epidermoline-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-(8-amino-octyl)moline,

[0393] 12-Epidermo-12-Devinyl-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-[3-(4-aminomethyl-phenyl)-propyl]moline,

[0394] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-yl-thioalkyl)acetyl]-12-[3-(4-aminomethyl-phenyl)-propyl]moline,

[0395] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-yl-thioalkyl)acetyl]-12-(6-amino-hexyl)moline,

[0396] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-yl-thioalkyl)acetyl]-12-(8-amino-octyl)moline,

[0397] 12-Epidermoline-12-Devinyl-14-O-{{4-[(2-amino-acetylamino)-methyl]-cyclohexylthioalkyl}-acetyl}-12-[2-{4-[(2-amino-ethylamino)-methyl]-phenyl}-vinyl)moline,

[0398] 12-Epidermolyte-12-Devinyl-14-O-{{4-[(2-amino-acetylamino)-methyl]-cyclohexylthioalkyl}-acetyl}-12-[2-{4-[(2-amino-ethylamino)-methyl]-phenyl}-ethyl)moline,

[0399] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[2-(4-aminomethyl-phenyl)-ethyl]-moline,

[0400] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-((E)-2-pyridin-3-ylvinyl)moline,

[0401] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)-acetyl]-12-((E)-2-{4-[(2-amino-ethylamino)-methyl]-phenyl}-vinyl)moline,

[0402] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-[2-{4-[(2-amino-ethylamino)-methyl]-phenyl}-ethyl)moline,

[0403] 12-Episode-12-Devinyl-14-O-[(azacyclohepta-4-ylthioalkyl)acetyl]-12-((E)-2-{4-[(2-amino-ethylamino)-methyl]-3-fluoro-phenyl}-vinyl)moline,

[0404] 12-Episode-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-((E)-2-{4-[(2-amino-ethylamino)-methyl]-phenyl}-vinyl)moline,

[0405] 12-Epimerosal-14-O-{[1-(2-amino-acetyl)-piperidin-4-yl-thioalkyl]-acetyl}-12-[2-{4-[(2-amino-ethylamino)-methyl]-phenyl}-ethyl)moline,

[0406] 12-Epidermo-12-Devinyl-14-O-[(5-aminomethyl-pyridin-2-ylthioalkyl)-acetyl]-12-[2-(4-aminomethyl-benzoylamino)-ethyl]moline,

[0407] 12-Episode-12-Devinyl-14-O-[(piperidin-4-ylthioalkyl]acetyl]-12-[2-(3-methyl-pyrazin-2-yl)vinyl]-moline

[0408] j) The compound is 12-episode-12-devinyl-14-O-[(piperidin-4-ylthioalkyl]-acetyl]-12-[2-(3-methyl-pyrazin-2-yl)-vinyl]-moline.

[0409] Compounds defined according to a) through i) are generally known from WO 2015 / 110481 A1, the disclosure of which is incorporated herein by reference. The specific compound defined according to j) is a compound according to formula (VIII).

[0410]

[0411] The publication is in WO 2021 / 209596, the contents of which are also incorporated herein by reference. In the following text, 12-differentiated morin as defined by j) or equation (VIII) is also referred to as “BC-9842”.

[0412] Example

[0413] The common name "mutilin" refers to the IUPAC systematic name (1S,2R,3S,4S,6R,7R,8R,14R)-3,6-dihydroxy-2,4,7,14-tetramethyl-4-vinyl-tricyclo[5.4.3.0]. 1,8 Tetradecano-9-one.

[0414]

[0415] In the following embodiments, the truncated pleurotin derivatives were numbered using a Morin numbering system similar to that described by H. Berner (Berner, H.; Schulz, G.; Schneider H. Tetrahedron 1980, 36, 1807-1811):

[0416]

[0417] In the compounds of the present invention, such as in the compounds of Examples 1 to 3, the stereochemistry of the methyl group at position 12 (and consequently the stereochemistry of the second group attached to position 12 of the morin ring) is reversed (episomeric morin derivative), and furthermore, the vinyl group is modified and various substituents are introduced to replace the vinyl group:

[0418]

[0419] The 12-episode-truncated pleurotin and 14-O-chloroacetyl-12-episode-morin described below are compounds of the following formulas:

[0420]

[0421] Methods for preparing 12-episode-truncated pleurotin derivatives are disclosed, for example, in WO 2015 / 110481 A1. Alternatively, the synthetic method via 14-O-chloroacetyl-12-episode-moline as disclosed in Example 1 can be used. 14-O-chloroacetyl-12-episode-moline is prepared as described in WO 2021 / 219399 A1.

[0422] In this document, including in the examples and reaction schemes, the following abbreviations are used.

[0423] 1 H-NMR proton nuclear magnetic resonance spectroscopy

[0424] ℃ Celsius

[0425] BOC tert-butyloxycarbonyl

[0426] DMF (dimethylformamide)

[0427] EtOAc (ethyl acetate)

[0428] MIC (Minimum Inhibitory Concentration)

[0429] m / z mass-to-charge ratio

[0430] MS mass spectrometry

[0431] nm nanometer

[0432] Example 1

[0433] 12-Episode-12-Devinyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-pyridyl)-vinyl]-morin dihydrochloride

[0434] Step 1: S-[(3S,3aR,6S,6aS)-3-(tert-butoxycarbonylamino)-2,3,3a,5,6,6a-hexahydrofurano [3,2-b]furan-6-yl]thioacetate

[0435] (S-[(3S,3aR,6S,6aS)-3-(tert-butoxycarbonylamino)-2,3,3a,5,6,6a- hexahydrofuro[3,2-b]furan-6-yl] ethanethioate)

[0436] To dichloromethane (50 mL), 7.46 g of N-[(3S,3aR,6R,6aR)-6-hydroxy-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-3-yl]carbamate (WO2003082260 Example I-OC) (7.00 g) was added, and the mixture was stirred overnight at room temperature. The resulting reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated to dryness under reduced pressure. The evaporation residue was dissolved in DMF (300 mL), potassium thioacetate (42.4 g) was added, and the mixture was heated to an oil bath temperature of 110 °C with stirring until the reaction was complete. The resulting reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated to dryness under reduced pressure. The evaporation residue was purified by silica gel chromatography using cyclohexane / EtOAc 5:1 to give the title compound (10 g) as a light brown solid.

[0437] 1H-NMR (400MHz, CDCl3, δ, ppm): 4.57-4.52, 4.50-4.43 (2m, 2x1H), 4.20-4. 10,4.00-3.92,3.78-3.70(3m,3x2H),2.28(s,3H,COCH3),1.37(s,9H,Boc).

[0438] MS m / z:348[M+HCOO - ].

[0439] Step 2: 12-Differential epimer-14-O-{[(3S,3aR,6S,6aS)-3-(tert-butoxycarbonylamino)-2,3,3a,5, 6,6a-Hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-Morin

[0440] Methanol (15 mL), tetrahydrofuran (3 mL), S-[(3S,3aR,6S,6aS)-3-(tert-butoxycarbonylamino)-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioacetate (2.00 g), and potassium carbonate solution (5 M aqueous solution, 2.64 mL) were added to 14-O-chloroacetyl-12-episode-moline (2.62 g) and stirred overnight at room temperature. The resulting reaction mixture was concentrated to dryness, dissolved in ethyl acetate, and washed twice with a semi-saturated NaCl solution. The combined aqueous phases were extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na₂SO₄ and evaporated to dryness under reduced pressure. The evaporation residue was purified by silica gel chromatography using cyclohexane / EtOAc 3:2 to give the title compound (3.68 g) as a colorless solid.

[0441] 1H-NMR (400MHz, CDCl3, δ, ppm, characteristic signals, Morin numbering system): 5.74 (dd, 1H, H-19, J=17.2, 10.8Hz), 5.63 (d, 1H, H-14, J=8.0Hz), 5.26-5.16 (m, 2H, H-20), 4.75-4.55, 4.54-4.45, 4.20-4.05, 3.97-3.86, 3.77-3.62, 3.46-3.35 and 3.32-3.18 (7m, 12H, NH, isomannitol, H-11, H-22), 1.58-1.39 (m, 12H, BOC, CH3-15), 1.22 (s, 3H, CH3-18), 0.95 (d, 3H, CH3-17, J = 6.8 Hz), 0.72 (d, 3H, CH3-16, J = 6.8 Hz).

[0442] MS m / z:666[M+HCOO - ].

[0443] Step 3: 2-Diastereo-12-desenyl-14-O-{[(3S,3aR,6S,6aS)-3-(tert-butyloxycarbonylamine)} (E)-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-pyridine) [Base)-vinyl]-Morin

[0444] 3-Bromo-pyridine (0.49 mL, 3 equivalents) and bis-(benzonitrile)-palladium(II) chloride (247 mg, 0.4 equivalents) were suspended in ethylene glycol (40 mL). Then, the product from step 2 of Example 1 (1 g, 1 equivalent), N-methylmorpholine (1.41 mL, 8 equivalents), and ethylene glycol (40 mL) were added sequentially, and the resulting mixture was stirred at 100 °C for 10 hours. The reaction mixture was diluted with ethyl acetate (500 mL), extracted with HCl / NaCl solution (500 mL, 0.1 M HCl aqueous solution + 500 mL 5% NaCl aqueous solution, 1:1), and extracted twice with 5% NaCl aqueous solution (500 mL). The combined aqueous phases were washed with ethyl acetate (250 mL). All organic phases were combined, washed with saturated NaCl aqueous solution (250 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The evaporation residue was purified by silica gel chromatography using EtOAc as the eluent to obtain the title compound (719 mg) as a colorless solid.

[0445] 1¹H-NMR (400MHz, CDCl₃, δ, ppm, characteristic signals, Morin numbering system): 8.76, 8.46, 7.86 and 7.40 (4m, 4H, aromat.), 6.48 and 6.43 (2d, 2H, H-19, H-20, J = 16.4Hz), 5.66 (d, 1H, H-14, J = 8.4Hz), 4.80–4.64, 4.64–4.57, 4.53–4.47. 4.18-4.08, 3.94-3.86, 3.76-3.64, 3.44-3.38 and 3.32-3.20 (8m, 12H, NH, isomannitol, H-22, H-11), 1.50-1.35 (m, 15H, BOC, CH3-15, CH3-18), 0.99 (d, 3H, CH3-17, J=6.8Hz), 0.74 (d, 3H, CH3-16, J=6.8Hz).

[0446] MS m / z:699[M+H + ],743[M+HCOO - ].

[0447] Step 4: 12-episomeric-12-desynthetic-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5, 6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-pyridyl)-vinyl]-molybdenum Lindi hydrochloride

[0448] The product (719 mg) from step 3 of Example 1 was dissolved in dichloromethane (24 mL) and trifluoroacetic acid (7 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The resulting residue was dissolved in a small amount of dichloromethane and hydrogen chloride (2 M ether solution, 7 mL) was added. The mixture was stirred at room temperature for 1 hour and filtered. The precipitate was washed with ether, dissolved in water, and freeze-dried to give the title compound (651 mg) as a colorless solid.

[0449] 1 ¹H-NMR (400MHz, DMSO-d⁶, δ, ppm, characteristic signals, Morin numbering system): 8.95-8.85, 8.76-8.43, 8.00-7.88 (3m, 7H, aromatic, NH), 6.84 and 6.51 (2d, 2H, H⁻¹⁹, H⁻²⁰, J = 16.4Hz), 5.56 (d, 1H, H⁻¹⁴, J = 8.4Hz), 4.80-4 0.60, 4.12-4.02, 3.98-3.80, 3.74-3.60 and 3.54-3.36 (5m, 11H, isomannitol, H-22, H-11), 1.40 (s, 3H, CH3-15), 1.21 (s, 3H, CH3-18), 0.86 (d, 3H, CH3-17, J = 6.8 Hz), 0.67 (d, 3H, CH3-16, J = 6.8 Hz).

[0450] MS m / z:599[M+H + ],633[M+Cl - ],643[M+HCOO - ].

[0451] Example 2

[0452] 12-Episode-12-Devinyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(pyrimidin-5-yl)-vinyl]-morin dihydrochloride

[0453] Step 1: 2-Diastereo-12-desynthetidyl-14-O-{[(3S,3aR,6S,6aS)-3-(tert-butyloxycarbonylamino)} (E)-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(pyrimidin-5- [Base)-vinyl]-Morin

[0454] Using 5-bromopyrimidine (767 mg, 3 equivalents) instead of 3-bromopyrimidine as the starting material, the reaction was carried out in a similar manner to step 3 of Example 1 (same scale and reaction time) to give the title compound (813 mg) as a colorless solid.

[0455] 1 ¹H-NMR (400MHz, CDCl₃, δ, ppm, characteristic signals, Morin numbering system): 9.10, 8.89 (2s, 3H, aromat.), 6.54 and 6.42 (2d, 2H, H-19, H-20, J = 16.4Hz), 5.65 (d, 1H, H-14, J = 8.0Hz), 4.74–4.62, 4.62–4.57, 4.53–4.47, 4.18– 4.08, 3.97-3.87, 3.75-3.65, 3.44-3.39 and 3.32-3.20 (8m, 12H, NH, isomannitol, H-22, H-11), 1.50-1.35 (m, 15H, BOC, CH3-15, CH3-18), 0.98 (d, 3H, CH3-17, J = 7.2 Hz), 0.74 (d, 3H, CH3-16, J = 6.8 Hz).

[0456] MS m / z:700[M+H + ],744[M+HCOO - ].

[0457] Step 2: 12-episomeric-12-desynthetidyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5, 6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(pyrimidin-5-yl)-vinyl]- Morin dihydrochloride

[0458] The product (813 mg) from step 1 of Example 2 was dissolved in dichloromethane (27.5 mL) and trifluoroacetic acid (8 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours and evaporated to dryness. The resulting residue was dissolved in a small amount of dichloromethane and hydrogen chloride (2 M ether solution, 8 mL) was added. The mixture was stirred at room temperature for 1 hour and filtered. The precipitate was washed with ether, dissolved in water, and lyophilized to give the title compound (668 mg) as a pale yellow to yellow solid.

[0459] 1 ¹H-NMR (400MHz, DMSO-d⁶, δ, ppm, characteristic signals, Morin numbering system): 9.02, 8.87 (2s, 3H, aromat.), 8.62 (s, 3H, NH), 6.72 and 6.33 (2d, 2H, H⁻¹⁹, H⁻²⁰, J = 16.4Hz), 5.56 (d, 1H, H⁻¹⁴, J = 8.0Hz), 4.74–4.57, 4 .13-4.03, 3.98-3.90, 3.72-3.60 and 3.57-3.35 (5m, 11H, isomannitol, H-22, H-11), 1.40 (s, 3H, CH3-15), 1.19 (s, 3H, CH3-18), 0.85 (d, 3H, CH3-17, J = 6.8 Hz), 0.67 (d, 3H, CH3-16, J = 6.4 Hz).

[0460] MS m / z:600[M+H + ],634[M+Cl - ],644[M+HCOO - ].

[0461] Example 3

[0462] 12-Episode-12-Devinyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-methyl-pyrazin-2-yl)-vinyl]-morin dihydrochloride

[0463] Step 1: 2-Diastereo-12-desynthetidyl-14-O-{[(3S,3aR,6S,6aS)-3-(tert-butyloxycarbonylamino)} (E)-2,3,3a,5,6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-methyl- [Pyrazine-2-yl)-vinyl]-moline

[0464] Using 2-bromo-3-methylpyrazine (1.11 g, 4 equivalents) instead of 3-bromo-pyridine as the starting material, the reaction was carried out in a similar manner to step 3 of Example 1 (on the same scale, at 110 °C for 24 hours) to give the title compound (154 mg) as a pale yellow solid.

[0465] 1 H-NMR (400MHz, CDCl3, δ, ppm, characteristic signal, Morin numbering system):

[0466] 8.40–8.28 (m, 2H, aromatic), 6.93 and 6.69 (2d, 2H, H-19, H-20, J = 15.6 Hz), 5.66 (d, 1H, H-14, J = 8.4 Hz), 4.75–4.45, 4.17–4.03, 3.95–3.87, 3.76–3.62, 3.46–3.36 and 3.33–3 .20(6m,12H,NH,isomannitol,H-22,H-11),2.62(s,3H,CH3-aromat.),1.48-1.33(m,15H,BOC,CH3-15,CH3-18),0.97(d,3H,CH3-17,J=7.2Hz),0.73(d,3H,CH3-16,J=6.8Hz).

[0467] MS m / z:714[M+H + ],758[M+HCOO - ].

[0468] Step 2: 12-episomeric-12-desynthetidyl-14-O-{[(3S,3aR,6S,6aS)-3-amino-2,3,3a,5, 6,6a-hexahydrofurano[3,2-b]furan-6-yl]thioalkylacetyl}-12-[(E)-2-(3-methyl-pyrazin-2-yl)-ethyl [Alkenyl]-Morin dihydrochloride

[0469] The product (284 mg) from step 1 of Example 3 was dissolved in dichloromethane (9 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The resulting residue was dissolved in a small amount of dichloromethane and diethyl ether, and hydrogen chloride (2 M diethyl ether solution, 3 mL) was added. The mixture was stirred at room temperature for 30 minutes and filtered. The precipitate was dissolved in water and lyophilized to give the title compound (204 mg) as a pale yellow to yellow solid.

[0470] 1¹H-NMR (400MHz, DMSO-d⁶, δ, ppm, characteristic signals, Morin numbering system): 8.48 (bs, 3H, NH), 8.34 and 8.27 (2s, 2H, aromatic), 7.08 and 6.46 (2d, 2H, H⁻¹⁹, H⁻²⁰, J = 15.6Hz), 5.53 (d, 1H, H⁻¹⁴, J = 7.6Hz), 4.70–4.53, 4.09–3.97, 3. 95-3.83, 3.73-3.52 and 3.52-3.30 (5m, 11H, isomannitol, H-22, H-11), 2.50 (s, 3H, CH3-aromat.), 1.35 (s, 3H, CH3-15), 1.18 (s, 3H, CH3-18), 0.80 (d, 3H, CH3-17, J = 6.4 Hz), 0.62 (d, 3H, CH3-16, J = 6.4 Hz).

[0471] MS m / z:614[M+H + ],648[M+Cl - ],658[M+HCOO - ].

[0472] Example 4

[0473] In vitro activity against bacteria, including lefamoline-resistant isolates, was determined using the standard broth microdilution method, according to the Clinical and Laboratory Standards Institute (CLSI) document (Performance Standards for Antimicrobial Susceptibility Testing) M100Ed29E (2019) and (Dilution Methods for Antimicrobial Susceptibility Testing of Aerobic Bacteria) or other versions from previous years. Data were obtained using cationic-regulated Mueller Hinton broth (CAMHB).

[0474] The results of Examples 1 to 3 are compared with those of Compound Example 154 (12-epistois-12-desethinyl-14-O-[(azacyclohept-4-ylthioalkyl)acetyl]-12-((E)-2-pyridin-3-yl-vinyl)moline hydrochloride) and Lefamorin, as specified in WO 2015 / 110481 A1, and are summarized in Table 1.

[0475] Table 1:

[0476]

[0477] The compounds of Examples 1 to 3 showed MICs ≤ 0.1 μg / ml against Staphylococcus aureus ATCC49951 and Streptococcus pneumoniae ATCC49619. Furthermore, the compounds of Examples 1 to 3 showed MICs ≤ 2 μg / ml against lefamoline-resistant Staphylococcus aureus strains mediated by, for example, cfr or vga(A) and lefamoline-resistant Streptococcus agalactiae strains mediated by, for example, LSA(E) resistance mechanisms.

[0478] Example 5

[0479] The metabolic stability of the compounds of the present invention was determined using cryopreserved primary mouse or human hepatocytes. The compounds were added to Krebs-Henseleit buffer (KHB) at concentrations ranging from 1.00 to 2.63 x 10⁻⁶. 5 Incubate at 37°C and 5% CO2 for 4 hours (in triplicate) with and without 1 μg / mL of the test compound. Dissolve the test compound in dimethyl sulfoxide (DMSO) and further dilute with KHB to ensure the DMSO concentration in the assay is ≤0.2%. To assess non-enzymatic degradation under assay conditions, samples of each test compound were also incubated in the absence of hepatocytes. Samples were taken immediately and after 4 hours of incubation. Incubation was stopped by adding an equal volume of acetonitrile, vortexing, and freezing the reaction mixture. After thawing, vortexing, and centrifugation, the centrifuged mixture was diluted with acidified (1% formic acid) water, and the disappearance of the parent compound or the appearance of metabolites was analyzed using LC / MS. Metabolic stability values ​​correspond to the percentage of the parent compound remaining after 4 hours of incubation.

[0480] The results of Examples 1 to 3 are compared with Example 154 of WO 2015 / 110481 A1 in Table 2.

[0481] Table 2:

[0482]

[0483] Examples 1 to 3 demonstrate metabolic stability ≥50% after incubation with primary mice and ≥20% after incubation with primary human hepatocytes. This represents a significant improvement in their usability as pharmaceutical substances, especially compared to the low metabolic stability of Example 154 of WO 2015 / 110481.

[0484] Example 6

[0485] The cytotoxicity of the compounds of this invention was determined using a human hepatocyte assay. Primary human hepatocytes were incubated for 2 hours at various concentrations (in triplicate) of the test compounds. Cell viability was then measured using the manufacturer's (Perkin Elmer) ATPlite luminescent assay system. ATP is a marker of cell viability because it is present in all metabolically active cells and its concentration decreases rapidly when cells die or undergo apoptosis. The ATPlite assay system is based on the light produced by the reaction of ATP with added luciferase and D-luciferin, where the emitted light is proportional to the ATP concentration (within certain limits).

[0486] The results of Examples 1 to 3 are compared with those of Example 154 from WO 2015 / 110481 A1 in Table 3.

[0487] Table 3

[0488]

[0489] The compounds according to the present invention, especially the compounds of Examples 2 and 3, exhibit high IC50 cytotoxicity. 50 The values ​​confirm their excellent tolerability and promising safety profile as drugs.

[0490] Example 7

[0491] The in vitro activity of several 12-epimerico-morin against several bacteria of the genus Propionibacterium was investigated. Bacteria formerly known as Propionibacterium include *Propionibacterium acnes*, which is associated with or known to mediate acne. MIC values ​​were determined by standard agar dilution according to the Clinical and Laboratory Standards Institute (CLSI) document (Methods for the Testing of Antimicrobial Susceptibility of Anaerobic Bacteria, M11Ed09 (2018)) or other versions from previous years. Data were determined using inoculum grown at 35°C for 48 hours on Brucella agar plates suspended in thioglycolate medium at McFarland densities of 1–1.5 and spotted onto Wilkins-Chalgren agar containing different 2-fold dilutions of the test compound (equivalent to 10⁻⁶ spots per spot). 4 (each colony-forming unit). After incubation at 37°C under anaerobic conditions for 48 hours, the MIC was read.

[0492] The results of Examples 1 to 3, as well as the results of 12-diamero-morin BC-9842 and Lefamorin, are summarized in Table 4.

[0493] Table 4:

[0494]

[0495] The compounds in Examples 1 to 3, as well as BC-9842, exhibited MIC values ​​that were as good as or slightly better than those of lefamoline.

[0496] Example 8

[0497] Objective: To evaluate the in vitro antibacterial activity of 12-epimeromorin, lefamorin, and other class of antibiotic control drugs against several Borreliella strains.

[0498] method:

[0499] The minimum inhibitory concentrations (MICs) of five (n=5) Boreliella burgdorferi isolates (ATCC51990, 55131, 35211, 35210, 53899) and one (n=1) Boreliella garinii isolate (ATCC51991) were determined using the broth microdilution technique (Dever, LL, Jorgensen, JH, Barbour, AG. In vitro antimicrobial susceptibility testing of Boreliella burgdorferi: a microdilution MIC method and time-kill studies. J Clin Microbiol. 30(10), 2692-2697. (1992) doi:10.1128 / jcm.30.10.2692-2697.1992; Feng, J., Wang, T., Shi, W., et al. Identification of novel activity against Boreliella burgdorferi Persisters using an FDA-approved drug library. Emerg Microb Infect 3, e49 (2014) doi:10.1038 / emi.2014.53). The general procedure for broth microdilution is performed according to CLSI guidelines M7 and M100-S31 (CLSI. (2018) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; 11th edition. M07.; CLSI. (2021) Performance Standards for Antimicrobial Susceptibility Testing; 31st edition. M100-S31).

[0500] In short, *Borreliella* species were grown in BSK II medium at 36°C under microaerophilic conditions until they reached the logarithmic or stationary growth phase. Growth phase was determined semi-quantitatively by fluorescence microscopy of cells stained with the fluorescent dyes SYBR Green I and propidium iodide. 10 5 -10 6 Inoculate broth microdilution plates containing sequentially 2-fold dilutions of the test compound with an inoculum of 1 spirochetes / mL. Cover the inoculated microdilution plates with an adhesive film to ensure microaerophilic culture conditions and incubate at 36°C for 5 days or until bacterial growth is observed in the positive control wells. Read the MIC of the logarithmic growth phase culture after 5 or 6 days of incubation (when the growth control shows good growth), and read the MIC of the stationary growth phase culture after 8 days of incubation.

[0501] result:

[0502] The MIC values ​​obtained from logarithmic and stationary growth phase cultures are summarized in Table 1 below. MIC results for individual isolates varied slightly across different experiments, but were within one (or at most two) 2-fold dilution factors. Therefore, MIC values ​​are expressed as a range covering different experiments for the Borreliella species (n=6), including B. burgdorferi (n=5) and B. garinii (n=1) in either logarithmic or stationary growth phases (Table 1).

[0503] Table 5: In vitro antibacterial activity of lefamoline and control antibiotics against Borreliella species.

[0504]

[0505] The compounds in Examples 1-3, as well as BC-9842, showed activity comparable to or even better than lefamoline. For the logarithmic growth phase, the MICs for all Examples 1-3 ranged from ≤0.001 to 0.004 μg / mL; the stable growth phase cultures were similar (≤0.001–0.008 μg / mL). Lefamoline and 12-epimer-moline are among the most active compounds compared to other classes of antibiotics used to treat Lyme disease, including doxycycline, ceftriaxone, cefuroxime, or azithromycin. The MIC value of truncated pleurotin was approximately two orders of magnitude higher.

Claims

1. Compounds of formula (I), (I) Where R1 is ， Where A is a hydrogen atom or (C) 1-6 )alkyl, and Where each Q is independently a nitrogen atom or CH, Where R2 is 。 2. The compound according to claim 1, wherein A is (C 1-3 )alkyl, the (C 1-3 The alkyl group is selected from the group consisting of methyl, ethyl, 1-propyl, 2-propyl and cyclopropyl.

3. The compound according to claim 1, wherein A is a methyl group.

4. The compound according to claim 1, wherein the compound is a compound of formula (II). (II), Wherein A and Q are as defined in claim 1.

5. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of formulas (III), (IV), and (V). (III), (IV), (V)。 6. The compound according to claim 1, wherein the compound is in the form of a salt.

7. The compound according to claim 1, wherein the compound is in the form of a dihydrochloride salt.

8. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 7, in combination with at least one pharmaceutical excipient.

9. Use of the compound of any one of claims 1 to 7 in the preparation of a medicament for treating or preventing bacterial infections.

10. The use according to claim 9, wherein the bacterial infection is mediated by bacteria selected from the group consisting of Gram-positive and Gram-negative bacteria.

11. The use according to claim 10, wherein the bacterial infection is mediated by Gram-positive bacteria selected from the group consisting of Staphylococcus, Streptococcus, Enterococcus, Clostridium, Peptostreptococcus, Propionibacterium, Listeria monocytogenes, Eubacterium lentum, Finegoldia magna, Anaerococcus prevotii, and Peptoniphilus assaccharolyticus.

12. The use according to claim 10, wherein the bacterial infection is mediated by Gram-negative bacteria selected from the group consisting of *Moraxella*, *Haemophilus*, *Chlamydia*, *Neisseria*, *Mycoplasma*, *Fusobacterium*, *Prevotella*, *Porphyromonas*, *Legionella*, *Spirometra*, *Bacteroides fragilis*, and *Acinetobacter lwoffii*.

13. The use according to claim 10, wherein the bacterial infection is mediated by bacteria selected from the group consisting of Staphylococcus and Streptococcus.

14. The use according to claim 10, wherein the bacterial infection is mediated by bacteria resistant to lefamolin.

15. The use according to claim 14, wherein the bacterial infection is mediated by bacteria having lefamoline resistance mediated by VGA (A), LSA (E), or CFR.

16. The use according to claim 10, wherein the bacterial infection is selected from the group consisting of: • Respiratory tract infection • Skin and / or soft tissue infections, • Sepsis, • Prosthetic joint infection, • Sexually transmitted infections (STIs), • Acne, and • Lyme disease and relapsing fever.

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