WO2023118359A1 - Rhabdobranins and their medical use - Google Patents

Rhabdobranins and their medical use Download PDF

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WO2023118359A1
WO2023118359A1 PCT/EP2022/087332 EP2022087332W WO2023118359A1 WO 2023118359 A1 WO2023118359 A1 WO 2023118359A1 EP 2022087332 W EP2022087332 W EP 2022087332W WO 2023118359 A1 WO2023118359 A1 WO 2023118359A1
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alkyl
alkylene
compound
formula
pharmaceutically acceptable
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French (fr)
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Helge B. Bode
Yi-ming SHI
Jan J. CRAMES
Desalegne Abebew SYIT
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MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances

Definitions

  • the present invention relates to novel compounds termed rhabdobranins and pre-rhabdobranins and their medical use, in particular a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a pharmaceutical composition comprising the compound of formula (I) as defined herein and a pharmaceutically acceptable excipient.
  • the instant compounds and compositions are useful in the treatment or prevention of an infectious disease.
  • the present invention further relates to a disinfectant comprising the compound of formula (I) and to the non-therapeutic use of the instant compounds or disinfectants for disinfecting or sterilizing an inanimate object.
  • Antimicrobial (e.g., antibacterial, antifungal and/or antiprotozoan) agents have proved to be important weapons in the fight against pathogenic microorganisms.
  • a recognized and increasing problem with respect to the effectiveness of said antibacterial, antifungal and/or anti-protozoan agents relates to the emergence of strains that are highly resistant to such agents. It would therefore be highly desirable to find antibacterial agents that are active against a broad spectrum of bacteria, in particular resistant strains. It would also be advantageous to discover antibacterial agents that demonstrate high activity and selectivity toward their targets and are of low toxicity.
  • rhabdobranins are highly potent antibacterial agents, and are therefore particularly well suited for therapeutic use, e.g., for the treatment or prevention of an infectious disease.
  • BGCs biosynthetic gene clusters
  • Xenorhabdus and Photorhabdus living in mutualistic symbiosis with entomopathogenic nematodes produce a myriad of natural products to mediate bacteria-nematode-insect interactions.
  • BGCs Xenorhabdus and Photorhabdus
  • microorganisms e.g. bacteria
  • higher eukaryotes are ubiquitous and have essential medical, environmental, and evolutionary significance (Newman, D. K. & Banfield, J. F. Science 296, 1071-1077 (2002)).
  • Microorganisms supply nutrients (LeBlanc, J. G. et al. Curr. Opin. Biotechnol. 24, 160-168 (2013)), shape immune systems (Hooper, L. V. et al., Science 336, 1268-1273 (2012)), maintain diverse and productive communities (Eisenhauer, N. PLoS One 7, e34517 (2012)), and drive evolution (Rosenberg, E. & Zilber-Rosenberg, I.
  • microbe-host interactions can be relationships ranging from mutualistic/parasitic to pathogenic symbiosis (Newton, A. C. et al., Trends Microbiol. 18, 365-373 (2010)), in which microorganisms sense and respond to environmental changes with diffusible small molecules. These small molecules are also known as natural products or specialized metabolites, which affect not only the microbial host but also neighboring microbes and other organisms (Shi, Y.-M. & Bode, H. B., Nat. Prod. Rep. 35, 309-335 (2016)).
  • the rdb BGCs feature a peptidase encoded gene, suggesting a prodrug activation mechanism similar to the biosyntheses of xenocoumacin/amicoumacin that are potent antibiotics inhibiting mRNA translation (Shi, Y.-M. & Bode, H. B., Nat. Prod. Rep. 35, 309-335 (2016)) and colibactin that is a genotoxin alkylating DNA (Wilson, M. R. et al, Science 363, eaar7785 (2019)).
  • rdb GCF Although the nodes of the rdb GCF are adjacent to those of the rhabdopeptide/xenortide-like BGCs, the rdb BGCs connect neither to amicoumacin and xenocoumacin BGCs (Reimer, D., et al., Nat. Chem. Biol. 7, 888-890 (2011)).
  • rdb1-3 based on the presence/absence of the first A domain in RdbH and the TE domain in Rdbl (see Fig. 2), which might lead to products with distinct numbers of amino acid residues and non-linear biosynthetic assembly line logic, respectively.
  • the present inventors focused on rdb1 that contains five out of eight BGCs in this GCF, and attempted to activate the rdb1 in Xenorhabdus budapestensis DSM 16342 by inserting a PBAID promoter in front of rdb1A.
  • the X. budapestensis P BAD rdblA mutant yielded four N-myristoyl-D-asparagine congeners (see Example 1 , compounds 19-22), as well as a non-XAD-resin-bound hydrophilic compound with a low production level (see Example 1, compound 23; see also Fig. 6).
  • budapestensis P BAD rdb1A ⁇ rdblP mutant led to loss of compounds 19-22 and high production of four new peaks with larger masses, designated as pre-rhabdobranins A-D (see Example 1, compounds 24-27; and Fig. 3) with differences in the N- acylated moiety.
  • Pre-rhabdobranin D (compound 27) was purified from the X.
  • budapestensis P BAD rdb1A ⁇ rdblP ⁇ hfq was determined by HRMS and NMR spectroscopy (Tables 4 and 5, and Fig. 7).
  • pre-rhabdobranins are characterized by a proline-serine dipeptidyl side chain that branches off at the N atom of an aminomalonyl building block. This represents a highly uncommon T-shape peptide in contrast to the canonical linear- chain-elongation on thiotemplated assembly lines.
  • the present invention thus relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from -OH, -NH 2 , -O-(C 1-6 alkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl) or a moiety of the formula: wherein the alkyl in said -O-(C 1-6 alkyl), the alkyl in said -NH(C 1-6 alkyl), and any alkyl in said -N(C 1-6 alkyl)(C 1-6 alkyl) are each optionally substituted with one or more -OH and/or one or more -NH 2 ; wherein R 4 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(C 1-6 alkylene)-O-R 41 , -(C 1-6 alkylene)-S- R 41 , -(C 1-6 alkylene)-N(R 41 )-R 41 , -(C 1-6 alkyl
  • R 2 is selected from hydrogen, an amino acid or a peptide.
  • R 3 is hydrogen or a moiety of the formula: wherein R 5 is C 1-22 alkyl or C 2-22 alkenyl.
  • Each R 42 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OH, -O(C 1-6 alkyl), -O(C 1-6 alkylene)- OH, -O(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 alkyl), -(C 1-6 alkylene)-SH, -(C 1-6 alkylene)-S(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-OH, -N(C 1-6 alkyl)-OH,
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the invention likewise relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.
  • the present invention likewise relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or to a pharmaceutical composition of the invention for use as a medicament.
  • the present invention relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof, or to the pharmaceutical composition of the invention for use in the treatment of an infectious disease.
  • the present invention relates to use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment or prevention of an infectious disease.
  • the present invention relates to a method of treating or preventing an infectious disease, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, to a subject (preferably a human) in need thereof. It will be understood that a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof (or of the pharmaceutical composition) is to be administered in accordance with this method.
  • the present invention relates to a disinfectant comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the non-therapeutic use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or of the disinfectant of the present invention, for disinfecting or sterilizing an inanimate object.
  • Fig. 1 presents phylogeny and gene organization of the rdb BGCs.
  • the phylogenetic tree is based on protein sequences of BGCs.
  • BGC subclassification is indicated next to the branch.
  • Fig. 2 presents the domain organization of three types of rdb BGCs with predicted substrates of adenylation and acyltransferase domains.
  • T thiolation
  • A adenylation
  • C condensation
  • E epimerization
  • AT acyltransferase
  • KS ketosynthase
  • KR ketoreductase
  • DH dehydratase
  • ER enoyl reductase
  • cMT carbon methyltransferase
  • TE thioesterase
  • Ser serine
  • Asn asparagine
  • Mai malonyl
  • Pro proline
  • Leu leucine
  • Unk unknown. Presumably inactive domain is labeled with an asterisk.
  • Fig. 3 presents chemical structures of previously unidentified pre-rhabdobranins A-D (24-27) and rhabdobranin (23) from X. budapestensis DSM 16342, as well as the proposed late-stage biosynthesis involved in a prodrug activation mechanism, similar to xenocoumacin and colibactin.
  • the N-terminus capped acylated D- asparaginyl moiety (19-22) and the dipeptidyl branch are highlighted in grey.
  • the stereocenters were predicted by analyzing the conserved motif in C domain and KR domain that are responsible for stereocontrol.
  • Fig. 4 presents the proposed first steps in the biosynthesis of rhabdobranins. It starts with an N-capping PCP-bound asparagine in Rdb1 D with one of the four different acyl chains, followed by an arginine extension in Rdb1 F.
  • a fully reduced PKS (Rdb1 G) enrolls a malonyl for a two-carbon extension.
  • RdbU introduces an aminomalonyl unit for chain extension. Without being bound by theory, the aminomalonyl is considered to originate from such a pathway: a free-standing PCP (Rdb1A) is loaded with a serine by a free-standing A domain (Rdb1 C).
  • the hydroxymethyl group of serine is oxidized to carboxyl acid by two oxidases (Rdb1 B and Rdb1 L).
  • the AT domain in RdbU seems to be inactive and it is replaced by a free-standing AT domain (Rdb1E).
  • the Rdb1A bound aminomalonyl is transferred to the AGP of the RdbU by Rdb1E. After that, the chain is further extended with a leucine by Rdb 11. However, the second module of Rdb 11 seems to be inactive.
  • Fig. 5 presents the proposed biosynthesis of pre-rhabdobranin.
  • the first C domain of Rdb11 functions as a C terminal domain to enroll putrescine for off-loading.
  • a proline-serine dipeptidyl is synthesized by Rdb 1 H and then is off-loaded by nucleophilic attack of the amino group that is catalyzed by the C domain of Rdb1 H to afford a branched peptide.
  • Fig. 6 presents HPLC-MS analysis of (pre-)rhabdobranins in the promoter exchange mutants of X. budapestensis DSM 16342 in LB medium, a, EICs of the X. budapestensis P BAD rdb1A and X. budaptersis P BAD rdb1A ⁇ rdb1P mutants.
  • Fig. 7 presents the NMR and MS spectral data of pre-rhabdobranin D (27). a, 2D NMR correlations of pre-rhabdobranin D. b, 1 H NMR spectrum of pre-rhabdobranin D (27) in DMSO-d 6 .
  • Fig. 8 presents the activity of rhabdobranins and pre-rhabdobranins against B. subtilis B168, E. coli MG1655, M. luteus and S. cerevisiae CEN.PK2.
  • the strain used for inoculation is indicated on the left side for each row of inoculants. In each plate, the colonies on the left side were induced with 0.4% arabinose (column labelled with “+”) as opposed to the colonies on the right side (labelled with “-”), which have not been induced.
  • Fig. 9 presents the NMR spectra of rhabdobranin.
  • a 1 H NMR spectrum of rhabdobranin in D 2 O.
  • b 13 C NMR spectrum of rhabdobranin in D 2 O.
  • c HSQC spectrum of rhabdobranin in D 2 O.
  • d HMBC spectrum of rhabdobranin in D 2 O.
  • e 1 H- 1 H COSY spectrum of rhabdobranin in D 2 O.
  • Fig. 11 presents antimicrobial activity of rhabdobranin and pre-rhabdobranins against Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2.
  • a disc diffusion assay was performed by applying either 5 ⁇ L (1), 10 ⁇ L (2) or 20 ⁇ L (3) of an aqueous 10 mM rhabdobranin solution (a) or an aqueous 10 mM pre-rhabdobranin solution (b). Water was applied as a control (C).
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) may also be referred to as rhabdobranins (if R 3 is hydrogen) or pre-rhabdobranins (if R 3 is different from hydrogen).
  • R 1 is selected from -OH, -NH Z , -O-(C 1-6 alkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl) or a moiety of the formula: wherein the alkyl in said -O-(C 1-6 alkyl), the alkyl in said -NH(C 1-6 alkyl), and any alkyl in said -N(C 1-6 alkyl)(C 1-6 alkyl) are each optionally substituted with one or more (e.g., one, two or three) -OH and/or one or more (e.g. , one, two or three) -NH Z .
  • one or more e.g., one, two or three
  • -NH Z e.g., one, two or three
  • R 1 is a moiety of the formula:
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(C 1-6 alkylene)-O-R 41 , -(C 1-6 alkylene)-S-R 41 , -(C 1-6 alkylene)-N(R 41 )-R 41 , -(C 1-6 alkylene)-CO-R 41 , -(C 1-6 alkylene)-COO-R 41 , -(C 1-6 alkylene)-O-CO-(C 1-6 alkyl), -(C 1-6 alkylene)-CO-N(R 41 )-R 41 , -(C 1-6 alkylene)-N(R 41 )-CO-(C 1-6 alkyl), -(C 1-6 alkylene)-CO-N(R 41 )-O-R 41 , -(C 1-6 alkylene)-CO-N(R 41 )-O-R 41 , -(C
  • R 4 is selected from hydrogen, C 1-6 alkyl, -(C 1-6 alkylene)-NH 2 , -(C 1-6 alkylene)-NH-(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 alkyl)(C 1-6 alkyl), -(C 1-6 alkylene)-COOH, -(C 1-6 alkylene)-COO-(C 1-6 alkyl), -(C 1-6 alkylene)-CO- NH 2 , -(C 1-6 alkylene)-CO-NH-(C 1-6 alkyl), -(C 1-6 alkylene)-CO-N(C 1-6 alkyl)(C 1-6 alkyl), -(C 1-6 alkyleneJ-SOaH , and -(C 1-6 alkylene)-SO3-(C 1-6 alkyl), wherein said alkyl and any alkylene group comprised in any of the aforementioned R 4 groups are each optional
  • R 4 is selected from -CH 2 CH 2 -COOH, -CH 2 -COOH, -CH 2 -SO3H, -CH 2 CH 2 -CO-NH 2 , -CH 2 -CO- NH 2 , -CH 2 -NH 2 , -(CH 2 ) 2 -NH 2 , -(CH 2 ) 3 -NH 2 , -(CH 2 ) 4 -NH 2 , -CH(-CH 3 )-(CH 2 ) 2 -NH 2 , -C(-OH)-(CH 2 ) 3 -NH 2 , -CH 2 -C(-OH)- (CH 2 ) 2 -NH 2 , and -(CH 2 ) 2 -C(-OH)-C(-CH 2 -OH)-NH 2 .
  • R 4 is selected from -CH 2 CH 2 -COOH and -(CH 2 ) 4 -NH 2 .
  • R 2 is selected from hydrogen, an amino acid or a peptide.
  • R 2 is an amino acid or a peptide.
  • R 2 may be selected from serine, glycyl-serine and prolylserine. More preferably, R 2 is a peptide.
  • Said amino acid (in R 2 ) is preferably an amino acid selected from serine and threonine, more preferably said amino acid is serine. As shown in formula (I), said amino acid is bound to an amino group forming part of the compound of formula (I). It will be understood that the amino acid is attached via an amide bond formed from its carboxylic acid group (-COOH) and the amino group (which carries R 2 ) in formula (I).
  • the carboxylic acid group of the amino acid, which forms an amide bond with the amino group in formula (I) may be, e.g., the a-amino group (particularly in the case of any of the 20 standard proteinogenic a-amino acids).
  • the amino acid may be present in L-configu ration or D- configuration, preferably in L-configuration.
  • Said peptide (in R 2 ) preferably consists of 2, 3, 4 or 5 amino acids, more preferably of 2 or 3 amino acids, and even more preferably said peptide is a dipeptide (i.e. , a peptide consisting of 2 amino acids).
  • R 2 may be a dipeptide consisting of a first amino acid which is serine or threonine (preferably serine) and a second amino acid which is selected from any one of the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai), wherein said dipeptide is attached to the remainder of the compound of formula (I) via the first amino acid.
  • Particularly preferred dipeptides include glycylserine or prolyl-serine (each of which is attached via the serine residue in the respective dipeptide).
  • said peptide is attached to the amino group carrying R 2 in the compound of formula (I) via an amide bond formed from a carboxylic acid group (-COOH) of the peptide, preferably the main chain carboxylic acid group (or a-amino group) of its C-terminal amino acid.
  • a carboxylic acid group (-COOH) of the peptide preferably the main chain carboxylic acid group (or a-amino group) of its C-terminal amino acid.
  • prolyl-serine is attached to the amino group carrying R 2 in the compound of formula (I) by an amide bond formed from the -COOH group of serine.
  • Each of the amino acids comprised in said peptide may be present in L-configuration or D-configuration.
  • R 2 is selected from glycyl-serine and prolyl-serine.
  • R 2 may be, for example, glycyl- L-serine, L-prolyl-L-serine, or D-prolyl-L-serine. It is particularly preferred that R 2 is D-prolyl-L-serine.
  • R 3 is hydrogen or a moiety of the formula:
  • R 3 is a moiety of the formula:
  • R 5 is C 1-22 alkyl or C 2-22 alkenyl.
  • R 5 is selected from:
  • Each R 42 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OH, -0(C 1-6 alkyl), -0(C 1-6 alkylene)- OH, -O(C 1-6 alkylene)-0(C 1-6 alkyl), -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(C 1-6 alkylene)-SH, -S(C 1-6 alkylene)-S(C 1-6 alkyl), -(C 1-6 alkylene)-SH, -(C 1-6 alkylene)-S(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-OH, -N(C 1-6 alkyl)-OH,
  • each R 42 is independently selected from C 1-6 alkyl, -OH, -0(C 1-6 alkyl), -0(C 1-6 alkylene)-OH, -0(C 1-6 alkylene)-O(C 1-6 alkyl), -(C 1-6 alkylene)-OH, -(C 1-6 alkylene)-O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl), halogen, C 1-6 haloalkyl, -0-(C 1-6 haloalkyl), -CN, -CHO, -CO(C 1-6 alkyl), -COOH, -COO(C 1-6 alkyl), -O-CO(C 1-6 alkyl), -CO-NH 2 , -CO-NH(C 1-6 alkyl), -CO-N
  • the compounds of formula (I) wherein R 3 is not hydrogen may also be referred to as pre-rhabdobranins.
  • R 1 is -OH or -NH(C 1-6 alkyl), wherein the alkyl in said -NH(C 1-6 alkyl) is optionally substituted with one or more -OH and/or one or more -NH 2 .
  • Particularly preferred C 1-6 alkyl groups are ethyl, n-propyl, and n-butyl.
  • the alkyl group in said -NH(C 1-6 alkyl) is substituted with one group -NH 2 .
  • R 1 is -OH, -NH-CH 2 CH 2 -NH 2 , -NH-CH 2 CH 2 CH 2 -NH 2 , or -NH-CH 2 CH 2 CH 2 CH 2 - NH 2 . Even more preferably, R 1 is -OH or -NH-CH 2 CH 2 CH 2 CH 2 -NH 2 .
  • R 1 is -OH.
  • R 1 is -NH-CH 2 CH 2 CH 2 CH 2 -NH 2 .
  • R 1 is a moiety of the formula: wherein R 4 is -CH 2 CH 2 -COOH.
  • R 1 is a moiety of the formula: wherein R 4 is -(CH 2 ) 4 -NH 2 .
  • R 2 is hydrogen
  • R 2 is an amino acid selected from serine and threonine.
  • R 2 is serine.
  • R 2 is a peptide.
  • R 2 is selected from glycyl-serine and prolyl-serine.
  • R 2 is selected from hydrogen, serine, glycyl-serine and prolyl-serine.
  • R 3 is hydrogen.
  • R 3 is a moiety of the formula: wherein R 5 is C 1-22 alkyl or C 2-22 alkenyl. Preferably, R 5 is C 13-14 alkyl or C 13-14 alkenyl.
  • R 3 is a moiety of the formula: wherein R 5 is selected from:
  • R 5 is selected from:
  • R 5 is selected from:
  • R 1 is -OH
  • R 2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
  • R 1 is -NH-CH 2 CH 2 CH 2 CH 2 -NH 2 .
  • R 2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
  • R 1 is a moiety of the formula: wherein R 4 is -CH 2 CH 2 -COOH.
  • R 2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
  • R 1 is a moiety of the formula: wherein R 4 is -(CH 2 ) 4 -NH 2 .
  • R 2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
  • Said serine is preferably L-serine.
  • Said glycyl-serine is preferably glycyl-L-serine.
  • Said prolyl-serine is preferably D-prolyl-L-serine. More preferably, R 2 is glycyl-L-serine or D-prolyl-L-serine, even more preferably D-prolyl- L-serine.
  • R 1 is selected from -OH and -NH-CH 2 CH 2 CH 2 CH 2 -NH 2 .
  • R 3 is hydrogen
  • R 2 is hydrogen
  • R 3 is hydrogen
  • the absolute configuration of the carbon atom that carries the group -C(O)R 1 is preferably as follows:
  • the absolute configuration of the carbon atom that carries the group -NH-R 3 is as follows:
  • the absolute configuration of the two carbon atoms that carry the groups -NH-R 2 and -OH, respectively is as follows:
  • the absolute configuration of the carbon atom that carries the group -NHR 3 and of the two carbon atoms that carry the groups -NHR 2 and -OH is as follows:
  • the compound of formula (I), including also any one of the above-described specific embodiments, has the following absolute configuration:
  • the moiety of formula has the following absolute configuration:
  • the moiety of the formula has the following absolute configuration:
  • a particularly preferred compound of formula (I) in accordance with the present invention is any one of the following compounds or a pharmaceutically acceptable salt thereof:
  • each R is independently selected from:
  • the compounds of formula (I) can be prepared e.g., in accordance with, or in analogy to, the procedure described in Example 2.
  • hydrocarbon group refers to a group consisting of carbon atoms and hydrogen atoms.
  • alkyl refers to a monovalent saturated acyclic (i.e. , non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond.
  • a “C 1-6 alkyl” denotes an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tertbutyl).
  • alkyl preferably refers to C 1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
  • alkenyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond.
  • C 2-6 alkenyl denotes an alkenyl group having 2 to 6 carbon atoms.
  • Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl).
  • alkenyl preferably refers to C 2-4 alkenyl.
  • alkynyl refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g. , one or two) carbon-to-carbon double bonds.
  • C 2-6 alkynyl denotes an alkynyl group having 2 to 6 carbon atoms.
  • Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl.
  • the term ''alkynyl preferably refers to C 2-4 alkynyl.
  • alkylene refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched.
  • a “C 1-6 alkylene” denotes an alkylene group having 1 to 6 carbon atoms, and the term “C 0-6 alkylene” indicates that a covalent bond (corresponding to the option "Co alkylene”) or a C 1-6 alkylene is present.
  • Preferred exemplary alkylene groups are methylene (-CH 2 -), ethylene (e.g., -CH 2 -CH 2 - or -CH(-CH 3 )-), propylene (e.g., -CH 2 -CH 2 -CH 2 -, -CH(-CH 2 -CH 3 )-, -CH 2 -CH(-CH 3 )-, or -CH(-CH 3 )-CH 2 -), or butylene (e.g., -CH 2 -CH 2 - CH 2 -CH 2 -).
  • alkylene preferably refers to C 1-4 alkylene (including, in particular, linear C 1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
  • carbocyclyl refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • “carbocyclyl” preferably refers to aryl or cycloalkyl.
  • heterocyclyl refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic.
  • each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • heterocyclyl preferably refers to heteroaryl or heterocycloalkyl.
  • aryl refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic).
  • Aryl may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl.
  • an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.
  • heteroaryl refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • aromatic ring group comprises one or more (such as, e.g., one, two, three
  • each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heteroaryl may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1 -benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyr
  • heteroaryl preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
  • cycloalkyl refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings).
  • Cycloalkyl may, e.g., referto cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl.
  • cycloalkyl preferably refers to a C 3-11 cycloalkyl, and more preferably refers to a C 3-7 cycloalkyl.
  • a particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).
  • heterocycloalkyl refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group).
  • each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatomcontaining ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.
  • Heterocycloalkyl may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4- yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepan
  • heterocycloal kyl preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atom
  • halogen refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).
  • haloalkyl refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group.
  • Haloalkyl may, e.g., refer to -CF 3 , -CHF 2 , -CH 2 F, -CF 2 -CH 3 , -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 2 -CH 3 , -CH 2 -CF 2 -CF 3 , or -CH(CF 3 ) 2 .
  • a particularly preferred “haloalkyl” group is -CF 3 .
  • the terms "bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.
  • the terms ''optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent.
  • the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent.
  • the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted.
  • a component of a composition is indicated to be “optional”
  • the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
  • substituents such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety.
  • the "optionally substituted" groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent.
  • the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.
  • substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.
  • amino acid refers, in particular, to any one of the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) but also to non- proteinogenic and/or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclohexylalanine, phenyla
  • an "amino acid” preferably refers to an a-amino acid, more preferably to any one of the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably present as the L-isomer).
  • the term “amino acid” may also refer to a monovalent or divalent radical derived from an “amino acid” as described herein above, wherein preferably an amino group and/or a carboxylic acid group may serve as point(s) of attachment, preferably through an amide bond.
  • amino acid may refer to an amino acyl moiety attached to the rest of the molecule, e.g., through a -CO- group formed from its carboxylic acid group.
  • peptide refers to a polymer of two or more amino acids linked via amide bonds that are formed between an amino group of one amino acid and a carboxylic acid group of another amino acid.
  • amino acids comprised in the peptide or protein may be selected from the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) but also from non-proteinogenic and/or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclo
  • the amino acid residues comprised in the peptide or protein are selected from a-amino acids, more preferably from the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably all present as the L-isomer).
  • the peptide may be unmodified or may be modified, e.g., at its N-terminus, at its C-terminus and/or at a functional group in the side chain of any of its amino acid residues (particularly at the side chain functional group of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu, and/or Arg residues).
  • Such modifications may include, e.g., the attachment of any of the protecting groups described for the corresponding functional groups in: Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006. Such modifications may also include the covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide), the glycosylation and/or the acylation with one or more fatty acids (e.g., one or more C 8-30 alkanoic or alkenoic acids; forming a fatty acid acylated peptide or protein).
  • PEG polyethylene glycol
  • modified peptides or proteins may also include peptidomimetics, provided that they contain at least two amino acids that are linked via an amide bond (formed between an amino group of one amino acid and a carboxyl group of another amino acid).
  • the amino acid residues comprised in the peptide or protein may, e.g., be present as a linear molecular chain (forming a linear peptide) or may form one or more rings (corresponding to a cyclic peptide).
  • the peptide may also form oligomers consisting of two or more identical or different molecules.
  • peptide may also refer to a monovalent radical derived from a “peptide” as described herein above, wherein preferably an amino group or a carboxylic acid group, in particular the N-terminal amino group or the C-terminal carboxylic acid group, serves as point of attachment, preferably through an amide bond.
  • peptide may refer to a peptidyl moiety attached to the rest of the molecule through a -CO- group (formed from a carboxylic acid group, e.g., from its C-terminal carboxylic acid group).
  • compositions comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).
  • the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.
  • the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia”, i.e. , “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of' and “consisting of'.
  • a comprising B and C has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).
  • the scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g. , by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation.
  • Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylam
  • Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nic
  • Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt.
  • a particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt.
  • the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.
  • the present invention also specifically relates to the compound of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.
  • the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.
  • the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (orcis/trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto/enol tautomers or thione/thiol tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form.
  • the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates and non-racemic mixtures).
  • the racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization.
  • the present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms.
  • the formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.
  • the scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom.
  • the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2 H; also referred to as "D").
  • the invention also embraces compounds of formula (I) which are enriched in deuterium.
  • Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D).
  • the content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art.
  • a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D 2 O).
  • deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014.
  • the content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy.
  • it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1 H hydrogen atoms in the compounds of formula (I) is preferred.
  • the present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18 F, 11 C, 13 N, 15 0, 76 Br, 77 Br, 120 l and/or 124 l.
  • a positron-emitting isotope of the corresponding atom such as, e.g., 18 F, 11 C, 13 N, 15 0, 76 Br, 77 Br, 120 l and/or 124 l.
  • Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET).
  • the invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18 F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11 C atoms, (ill) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13 N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15 O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76 Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention as defined herein, and a pharmaceutically acceptable excipient.
  • the present invention further relates to the said pharmaceutical composition comprising a compound of formula (I) ora pharmaceutically acceptable saltthereof of the present invention, and a pharmaceutically acceptable excipient for use in therapy.
  • the compounds and/or chemical entities provided herein may be administered as compounds per se or may be formulated as medicaments.
  • the medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
  • the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin,
  • the pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.
  • preservatives particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic
  • compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in “Remington: The Science and Practice of Pharmacy' 1 , Pharmaceutical Press, 22 nd edition.
  • the pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • the compounds of formula (I) or the pharmaceutically acceptable salts thereof or the above described pharmaceutical compositions comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof may be administered to a subject by any convenient route of administration, whether systemically/peri pherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Said compounds or pharmaceutically acceptable salts or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the compounds, the pharmaceutically acceptable salts or the pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing.
  • the compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as “oral-gastrointestinal” administration.
  • said compounds, pharmaceutically acceptable salts or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid.
  • Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention or a pharmaceutically acceptable salt thereof.
  • Said compounds, pharmaceutically acceptable salts or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route.
  • they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • dry powder formulations of the compounds of formula (I) or the pharmaceutically acceptable salt thereof for pulmonary administration, particularly inhalation may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification/spray drying process.
  • said compounds, pharmaceutically acceptable salts or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2 -octyldodecanol, benzyl alcohol and water.
  • the present invention thus relates to the compounds, pharmaceutically acceptable salts or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route.
  • Preferred routes of administration are oral administration or parenter
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
  • a proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose.
  • the unit dose may be administered, e.g., 1 to 3 times per day.
  • the unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the compound of formula (I) or the pharmaceutically acceptable salt thereof is useful in the treatment or prevention of an infectious disease.
  • the present invention relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infectious disease.
  • the compound of formula (I) or the pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the compound of formula (I)).
  • the compound of formula (I), the pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof can also be administered in combination with one or more further therapeutic agents.
  • the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used.
  • the combination of the compound of formula (I) with one or more further therapeutic agents may comprise the simultaneous/concomitant administration of the compound of formula (I) and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential/separate administration of the compound of formula (I) and the further therapeutic agent(s).
  • either the compound of formula (I) according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I), or they may be administered in two or more different (separate) pharmaceutical formulations.
  • the present invention relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infectious disease.
  • the present invention further relates to the pharmaceutical composition of the present invention comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infectious disease.
  • the said infectious disease is selected from a bacterial infectious disease, a protozoan infectious disease, and a fungal infectious disease.
  • the present invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a bacterial infectious disease caused by Gram-positive bacteria.
  • the said Gram-positive bacteria are selected from: Listeria spp., including e.g. Listeria monocytogenes or Listeria welshimeri; Staphylococcus spp., including e.g.
  • Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus lugdunensis, Staphylococcus schleiferi, or Staphylococcus caprae
  • Streptococcus spp. including e.g. Streptococcus pneumoniae, Streptococcus viridans, Streptococcus pyogenes, or Streptococcus agalactiae
  • Enterococcus spp. including e.g. Enterococcus faecalis or Enterococcus faecium
  • Bacillus spp. including e.g.
  • Mycobacterium spp. including e.g. Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium kanasasii, Mycobacterium avium, Mycobacterium paratuberculosis, Mycobacterium scrofulaceam, Mycobacterium microti, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium intracellulare, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium fortuitum, Mycobacterium chelonei, or Mycobacterium marinum; Nocardia spp., including e.g. Nocardia asteroids; Micrococcus luteus
  • the present invention further relates to the compound of formula (I) or pharmaceutically acceptable salt thereof the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a bacterial infectious disease caused by Gram-negative bacteria.
  • the said Gram-negative bacteria are preferably selected from: Neisseria spp., including e.g. Neisseria gonorrhoeae or Neisseria meningitides; Moraxella spp., including e.g. Moraxella catarrhalis; Hemophilus spp., including e.g. Hemophilus influenzae; Klebsiella spp., including e.g.
  • Pseudomonas spp. including e.g. Pseudomonas aeruginosa
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the invention can be combined with one or more anti-bacterial agents.
  • the said anti-bacterial agent is preferably effective against an infectious disease caused by Gram-positive bacteria.
  • the said Grampositive bacteria are selected from: Listeria spp., including e.g. Listeria monocytogenes or Listeria welshimeri; Staphylococcus spp., including e.g.
  • Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus lugdunensis, Staphylococcus schleiferi, or Staphylococcus caprae
  • Streptococcus spp. including e.g. Streptococcus pneumoniae, Streptococcus viridans, Streptococcus pyogenes, or Streptococcus agalactiae
  • Enterococcus spp. including e.g. Enterococcus faecalis or Enterococcus faecium
  • Bacillus spp. including e.g.
  • Mycobacterium spp. including e.g. Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium kanasasii, Mycobacterium avium, Mycobacterium paratuberculosis, Mycobacterium scrofulaceam, Mycobacterium microti, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium intracellulare, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium fortuitum, Mycobacterium chelonei, or Mycobacterium marinum; Nocardia spp., including e.g.
  • the said anti-bacterial agent is preferably effective against an infectious disease caused by Gramnegative bacteria.
  • the said Gram-negative bacteria are preferably selected from: Neisseria spp., including e.g. Neisseria gonorrhoeae or Neisseria meningitides; Moraxella spp., including e.g. Moraxella catarrhalis; Hemophilus spp., including e.g. Hemophilus influenzae; Klebsiella spp., including e.g.
  • Pseudomonas spp. including e.g. Pseudomonas aeruginosa or P
  • the present invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a protozoan infectious disease.
  • the said protozoan infectious disease is caused by a protozoan of the phylum Apicomplexa. More preferably, the said protozoan infectious disease is caused by a protozoan selected from: Plasmodium spp., including e.g. Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi; Leishmania spp., including e.g.
  • Trypanosoma spp. including e.g. Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma simiae, Trypanosoma avium, Trypanosoma congolense, Trypanosoma equinum, Trypanosoma equiperdum, Trypanosoma evansi, or Trypanosoma suis; Babesia spp., including e.g. Babesia microti or Babesia bigemina; and Toxoplasma spp., including e.g. Toxoplasma gondii.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same of the present invention can be used in combination with an antiprotozoan agent.
  • the antiprotozoan agent to be used in combination with the compound of the invention or the pharmaceutical composition of the invention is useful in the treatment and/or prevention of protozoan infectious disease is caused by a protozoan selected from: Plasmodium spp., including e.g. Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi; Leishmania spp., including e.g.
  • Trypanosoma spp. including e.g. Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma simiae, Trypanosoma avium, Trypanosoma congolense, Trypanosoma equinum, Trypanosoma equiperdum, Trypanosoma evansi, or Trypanosoma suis; Babesia spp., including e.g. Babesia microti or Babesia bigemina; and Toxoplasma spp., including e.g. Toxoplasma gondii.
  • the present invention further relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same for use in combination with an antiprotozoan agent, wherein the antiprotozoan agent is preferably selected from acranil, tinidazole, ipronidazole, ethylstibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, and suramin.
  • the antiprotozoan agent is preferably selected from acranil, tinidazole, ipronidazole, ethylstibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, and suramin.
  • the present invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a fungal infectious disease.
  • the fungal infectious disease may also be, e.g., a yeast infectious disease.
  • the said fungal infectious disease is caused by a fungus selected from: Aspergillus spp., including e.g. Aspergillus fumigatus, Aspergillus flavus, or Aspergillus clavatus; Candida spp., including e.g.
  • Candida albicans Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guilliermondii
  • Cryptococcus spp. including e.g. Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, or Cryptococcus gattii
  • Histoplasma spp. including e.g. Histoplasma capsulatum
  • Pneumocystis spp. including e.g.
  • Stachybotrys spp. including e.g. Stachybotrys chartarum; Basidiobolus spp., including e.g. Basidiobolus ranarum; Blastomyces spp., including e.g. Blastomyces dermatitidis; Coccidioides spp., including e.g. Coccidioides immitis or Coccidioides posadasii; Conidiobolus spp., including e.g. Conidiobolus coronatus or Conidiobolus incongruous; and Madurella spp., including e.g.
  • the present invention thus also relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a yeast infectious disease, wherein the yeast infectious disease is preferably caused by a yeast selected from: Candida spp., including e.g. Candida albicans, Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guilliermondii; or Cryptococcus spp., including e.g. Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, or Cryptococcus gattii.
  • Candida spp. including e.g. Candida albicans, Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guillier
  • the compounds of the formula (I) can be used in combination with one or more other medicaments.
  • the other medicament will be a further medicament which is useful in treating, ameloriating or preventing a fungal infection, more preferably a further medicament which is useful in treating, ameloriating or preventing a fungal infection that is caused by a fungus selected from Aspergillus spp., including e.g. Aspergillus fumigatus, Aspergillus flavus, or Aspergillus clavatus; Candida spp., including e.g.
  • Candida albicans Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guilliermondii
  • Cryptococcus spp. including e.g. Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, or Cryptococcus gattii
  • Histoplasma spp. including e.g. Histoplasma capsulatum
  • Pneumocystis spp. including e.g.
  • Stachybotrys spp. including e.g. Stachybotrys chartarum; Basidiobolus spp., including e.g. Basidiobolus ranarum; Blastomyces spp., including e g. Blastomyces dermatitidis; Coccidioides spp., including e.g. Coccidioides immitis or Coccidioides posadasii; Conidiobolus spp., including e.g. Conidiobolus coronatus or Conidiobolus incongruous; and Madurella spp., including e.g. Madurella mycetomatis or Madurella grisea.
  • the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention comprising the compound of formula (I) ora pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in combination with an antifungal agent.
  • the compound of the formula (I), the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the same can be used in combination with one or more antifungal agents capable of at least one of: a) inhibiting ergosterol biosynthesis; b) binding to ergosterol; c) inhibiting 1 ,3-P-glucan synthase; d) inhibiting epoxidase; e) inhibiting leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2.
  • one or more antifungal agents capable of at least one of: a) inhibiting ergosterol biosynthesis; b) binding to ergosterol; c) inhibiting 1 ,3-P-glucan synthase; d) inhibiting epoxidase; e) inhibiting leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2.
  • the additional antifungal agent may be for example be selected from the group consisting of polyene antifungal agents (such as Natamycin, Rimocidin, Filipin, Nystatin, Amphotericin B orCandicin), azole antifungal agents (such as miconazole, ketoconazole, clotromazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, seraconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole terconazole, or abafungin), allylamine antifungal agents (such as Terbinafme, Amorolfine, Naftifme or Butenafme) and echinocandins (such as Anidulafungin, Caspofungin or Micafung
  • the compound of formula (I), the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the same may also be useful in treating and/or preventing a fungal infection disease, wherein the said fungal infectious disease cannot be treated in a curable manner by any of the antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis; b) binding to ergosterol; c) inhibiting 1 ,3-P-glucan synthase; d) inhibiting epoxidase; e) inhibiting leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2.
  • the compound of formula (I) of the present invention or the pharmaceutical composition comprising the same may also be useful in treating and/or preventing fungal infectious disease that is resistant to any of the agents selected from the group consisting of polyene antifungal agents (such as Natamycin, Rimocidin, Filipin, Nystatin, Amphotericin B or Candicin), azole antifungal agents (such as miconazole, ketoconazole, clotromazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, seraconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole terconazole, or abafungin), allylamine antifungal agents (such as Terbinafme, Amorolfine, Naftifme or Buten
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation.
  • the individual components of such combinations may be administered either sequentially or simultaneously/concomitantly in separate or combined pharmaceutical formulations by any convenient route.
  • administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof) or the further therapeutic agent(s) may be administered first.
  • administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions.
  • the two or more compounds When combined in the same formulation, it will be appreciated that the two or more compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation.
  • the subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal).
  • the subject/patient is a mammal.
  • the subject/patient is a human (e.g., a male human or a female human) or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig).
  • the subject/patient to be treated in accordance with the invention is a human.
  • Treatment of a disorder or disease, as used herein, is well known in the art.
  • Treatment of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject.
  • a patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).
  • the “treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only).
  • the ''treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease.
  • the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease.
  • Such a partial or complete response may be followed by a relapse.
  • a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above).
  • the treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
  • a patien t/su bject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease.
  • the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
  • a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators.
  • a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/su bject does not show any clinical or pathological symptoms).
  • the term ''prevention comprises the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
  • the present invention further encompasses non-therapeutic uses of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a disinfectant comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disinfectant of the present invention is preferably an aqueous disinfectant formulation or an alcohol-based disinfectant formulation, preferably an ethanol-based disinfectant formulation.
  • the disinfectant of the present invention further comprises a surfactant.
  • the surfactant allows for the creation of a “foaming effect” when the disinfectant solution is applied to a surface to be treated. The creation of a foam allows for the disinfectant solutions to remain in contact with the surface to be treated for longer periods of time.
  • the aqueous disinfectant formulation of the present invention in certain embodiments is capable of generating a foam when applied to a surface to be disinfected.
  • the foam adheres to the surface to be disinfected for a time sufficient to ensure eradication of the non-indigenous and/or pathogenic bacterial, microbial, fungal and/or viral population.
  • the disinfectant formulations of the present invention may be applied onto a surface to be disinfected (i.e. cleaned) by means of a variety of spraying techniques.
  • the disinfectant of the present invention is applied using a diffuser or a mist blower.
  • the disinfectant formulations of the present invention can also be formulated into aerosol formulations.
  • the disinfectant of the present invention may be applied to the surface to be disinfected by using a foamer.
  • the disinfectant of the present invention preferably exhibits antibacterial properties, antifungal properties and/or antiviral properties. More preferably, the disinfectant of the present invention exhibits antibacterial properties and/or antifungal properties.
  • the present invention relates to non-therapeutic use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the disinfectant of the present invention, for disinfecting or sterilizing an inanimate object.
  • the present invention relates to a method of disinfecting or sterilizing an inanimate object.
  • the said method of the present invention comprises applying a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the disinfectant of the present invention, to said inanimate object.
  • the inanimate object is not particularly limited, as any object can in principle be disinfected according to the present invention.
  • the inanimate object is a technical device, e.g., a catheter, a medical implant, a surgical instrument, contact lenses, or a food-processing device.
  • HPLC-UV-HRMS analysis was conducted on an UltiMate 3000 system (Thermo Fisher) coupled to an Impact II qTof mass spectrometer (Bruker) either equipped with an ACQUITY UPLC BEH C18 column (130 A, 2.1 mm * 100 mm, 1.7 pm particle size, Waters) at a flow of 0.4 mL/min (5-95% acetonitrile/water with 0.1% formic acid, v/v, 16 min, UV detection wavelength 190-800 nm), oran ACQUITY UPLC BEH Amide column (130 A, 2.1 mm x 50 mm, 1.7 pm particle size, Waters) at a flow of 0.4 mL/min (5-50% water/acetonitrile with 0.1% formic acid, v/v, 5 min, 90% water/acetonitrile with 0.1% formic acid, v/v, 2.1 min, UV detection wavelength 190-800 nm).
  • HPLC purification was performed on preparative and semipreparative Agilent 1260 systems coupled to a DAD and a single quadrupole detector with a C18 ZORBAX Eclipse XDB column (9.4 mm x 250 mm, 5 pm, 3 mL/min; 21.2 mm x 250 mm, 5 pm, 20 mL/min; 50 mm x 250 mm, 10 pm, 40 mL/min). Freeze drying was performed by BUCHI LyovaporTM L-300 Continuous. NMR experiments were acquired on a Bruker AVANCE 500, 600, or 700 MHz spectrometer equipped with a 5 mm cryoprobe.
  • Wild-type strains and the mutants thereof and E. coli were cultivated on lysogeny broth (LB) agar plates at 30 oC overnight and were subsequently inoculated into liquid LB culture at 30 oC with shaking at 200 rpm.
  • LB lysogeny broth
  • the overnight LB culture was transferred into 5 mL LB, XPP 15 , or Sf-900TM II SFM medium (1:100, v/v) with 2% (v/v) of AmberliteTM XAD-16 resins, 0.4 % of L-arabinose as the inducer (for mutants with a P BAD promoter), and selective antibiotics such as ampicillin (Am, 100 ⁇ g/mL), kanamycin (Km, 50 ⁇ g/mL), or chloramphenicol (Cm, 34 ⁇ g/mL) at 30 oC for 72 h with shaking at 200 rpm.
  • ampicillin Am, 100 ⁇ g/mL
  • Km kanamycin
  • Cm chloramphenicol
  • a 500— 800-bp upstream of the target gene (rdb1A) was amplified with a corresponding primer pair listed in Table 1.
  • the resulting fragments were cloned using Hot Fusion (Fu, C. et al., PLoS One 9, e115318 (2015)) into pCEP_kan or pCEP_cm backbone that was amplified by pCEP_Fw and pCEP_Rv.
  • Hot Fusion Fu, C. et al., PLoS One 9, e115318 (2015)
  • a wildtype strain (X budapestensis DSM 16342) or a deletion mutant (X. budapestensis ⁇ hfq, X. budapestensis ⁇ rdb1P, X. budapestensis ⁇ rdb1P ⁇ hfq, X. budapestensis ⁇ rdb1H, or X budapantsis ⁇ rdb1H ⁇ hfq) was used as a recipient strain.
  • the recipient strain was mated with E. coli S17-1 A pir (donor) carrying a constructed plasmid. Both strains were grown in the LB medium to an OD 600 of 0.6 to 0.7, and the cells were washed once with the fresh LB medium.
  • the donor and recipient strains were mixed on an LB agar plate in ratios of 1 :3 and 3: 1 , and incubated at 37oC for 3 h followed by incubation at 30oC for 21 h.
  • the bacterial cell layer was harvested with an inoculating loop and resuspended in 2 mL fresh LB medium. 200 ⁇ L of the resuspended culture was spread out on an LB agar plate with Am/Km or Am/Cm incubated at 30oC for 2 days.
  • Individual insertion clones were cultivated and analyzed by HPLC-UV-HRMS, and the genotype of all mutants was verified by plasmid- and genomespecific primers.
  • a ⁇ 1 ,000-bp upstream and a ⁇ 1 ,000-bp downstream fragments of hfq in X. budapestensis DSM 16342 were amplified using primer pairs listed in Table 1.
  • the amplified fragments were fused using the complementary overhangs introduced by primers and cloned into the pCKcipB vector or pEB17 (both were linearized with Pstl and Bglll) by Hot Fusion (Fu, C. et al., PLoS One 9, e115318 (2015)). Transformation of E.
  • Example 1 HPLC-MS analysis of (pre-)rhabdobranins in the promoter exchange mutants ofX. budapestensis
  • Fig. 6b shows BPCs of the (i) non-induced and (ii) induced promoter exchange mutants of the X. budapestensis P BAD rdb1A ⁇ rdb1P ⁇ hfq.
  • ⁇ hfq mutant is a strain wherein the production of other natural products beyond the one originating from the induced BCG is lost due to deletion of Hfq, a bacterial RNA chaperone that modulates BCG expression through small RNA / messenger RNA interactions.
  • Example 3 Antimicrobial activity of rhabdobranins and pre-rhabdobranins presented by using the promoter exchange mutants of X. budapestensis DSM 16342
  • the antimicrobial activity of rhabdobranins and pre-rhabdobranins was evaluated by using the following indicator organisms: Bacillus subtilis B168, Escherichia coli MG 1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2.
  • Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2 A 1 mL culture of Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2 with an OD 600 of 1 .0 was spread on LB or YPD agar plates using a sterile cotton swab. The inventors inoculated a 2 mL pre-culture of the X.
  • budapestensis wild-type strain X. budapantsis P BAD rdb1A, X. budapantsis ⁇ rdb1P P BAD rdb1A, X. budaptersis ⁇ hfq P BAD rdb1A, X. budaptersis A hfq ⁇ rdb1P P BAD rdb1A, X. budaptersis ⁇ rdb1H P BAD rdb1A mutants to a 100 mL LB media separately with/without induction by 0.4% L-arabinose, followed by shaking at 120 rpm at 30 oC for 72 h.
  • the whole cultures were lyophilized and the resulting extract was resolved in 10 mL methanol.
  • the cell particles were removed by centrifugation at 17.000 x g for 25 minutes and 10 ⁇ L of the supernatant was loaded onto a 3 mm sterile filter disk and dried under a clean bench. Disks were place on the agar plates. After incubation at 30 oC for 16-48 h, the zones of inhibition were determined.
  • a plate covered with selected bacterial or yeast film is inoculated at a single point with a single colony of X. budapestensis wild type (top row) that produces small amounts of rhabdobranins, or with inducible expression of rdb1A (labelled as X. budapestensis P BAD rdb1A), which can produce higher amounts of rhabdobranins.
  • the colonies on the left side were induced with 0.4% L-arabinose (labelled with “+”, as opposed by those labelled with which have not been induced), leading to an increased production of rhabdobranins.
  • the X. budapestensis P BAD rdb1A mutant was cultivated in 12 L of lysogeny broth (LB) medium supplemented with 2% XAD, 0.2% arabinose, and kanamycin (50 ⁇ g mL" 1 ). After production at 30 oC and 180 rpm for 72 hours, the XAD was discarded to decomplex the culture matrix. The culture was centrifugated, filtrated, and freeze-dried. In the next step, 20g of the extract was solved in 500 mL of H 2 O adjusted to pH 11 .5 using triethylamine (TEA).
  • TAA triethylamine
  • a polymeric weak cation exchanger column (Phenomenex 5 g/60 mL XCW-33) was used.
  • the conditioning step was started with 60 mL MeOH, followed by equilibration with 60 mL H 2 O (pH 11 .5 adjusted with TEA).
  • the solved extract was loaded on the single-use plastic tube column.
  • the column was washed two times with 120 mL H 2 O (pH 11.5 adjusted with TEA) and dried for 5 min.
  • the elution was started by applying 60 mL ACN containing 7% formic acid, followed by 60 mL H 2 O/ACN (v:v 3:2, supplemented with 7% formic acid), then 60 mL H 2 O (supplemented with 7% formic acid) was used. Finally, 3 x 60 mL H 2 O supplemented with 10% formic acid was used for the elution of rhabdobranin, the second and third fractions were collected and freeze-dried, resulting in an extract mass of 117.3 mg.
  • Example 6 Antimicrobial activity of pre-rhabdobranins and rhabdobranin against Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2
  • a disc diffusion assay was performed by applying either 5 ⁇ L (1), 10 ⁇ L (2) or 20 ⁇ L (3) of an aqueous 10 mM pre- rhabdobranins (a mixture in proportion as shown in Figure 6) or rhabdobranin solution. Water was applied as a control (C). The results are shown in Figures 11 A and 11 B. Zones of inhibition were observed for all tested strains, whereby the zones of inhibition against Micrococcus luteus showed the greatest diameters, followed by the zones against Bacillus subtilis B168, Escherichia coli MG1655 and Saccharomyces cerevisiae CEN.PK2.

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Abstract

The present invention relates to novel compounds termed rhabdobranins and pre-rhabdobranins and their medical use, in particular a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to a pharmaceutical composition comprising the compound of formula (I) as defined herein and a pharmaceutically acceptable excipient. The instant compounds and compositions are useful in the treatment or prevention of an infectious disease. The present invention further relates to a disinfectant comprising the compound of formula (I) and to the non-therapeutic use of the instant compounds or disinfectants for disinfecting or sterilizing an inanimate object.

Description

Rhabdobranins and their medical use
The present invention relates to novel compounds termed rhabdobranins and pre-rhabdobranins and their medical use, in particular a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to a pharmaceutical composition comprising the compound of formula (I) as defined herein and a pharmaceutically acceptable excipient. The instant compounds and compositions are useful in the treatment or prevention of an infectious disease. The present invention further relates to a disinfectant comprising the compound of formula (I) and to the non-therapeutic use of the instant compounds or disinfectants for disinfecting or sterilizing an inanimate object.
Antimicrobial (e.g., antibacterial, antifungal and/or antiprotozoan) agents have proved to be important weapons in the fight against pathogenic microorganisms. However, a recognized and increasing problem with respect to the effectiveness of said antibacterial, antifungal and/or anti-protozoan agents relates to the emergence of strains that are highly resistant to such agents. It would therefore be highly desirable to find antibacterial agents that are active against a broad spectrum of bacteria, in particular resistant strains. It would also be advantageous to discover antibacterial agents that demonstrate high activity and selectivity toward their targets and are of low toxicity.
It is thus an object of the present invention to provide novel and/or improved antimicrobial agents, in particular novel and/or improved antibacterial, antifungal and/or antiprotozoan agents.
In the context of the present invention it was surprisingly found that the compounds of formula (I) as described herein below, termed rhabdobranins, are highly potent antibacterial agents, and are therefore particularly well suited for therapeutic use, e.g., for the treatment or prevention of an infectious disease.
Intense research efforts have also been devoted to the characterization of unknown biosynthetic gene clusters (BGCs) for natural product discovery, as well as functional assignments of natural products in the context of bacteria- nematode-insect interactions. The present inventors have identified a previously unknown biosynthetic gene cluster (also referred to as BGC), referred to as rdb (rhabdobranin).
Microorganisms contribute to the biology and physiology of eukaryotic hosts and affect other organisms through natural products. Xenorhabdus and Photorhabdus (XP) living in mutualistic symbiosis with entomopathogenic nematodes produce a myriad of natural products to mediate bacteria-nematode-insect interactions. However, a lack of systematic analysis of the XP biosynthetic gene clusters (BGCs) has limited the understanding of how natural products affect the specific interactions between the organisms.
Interactions between microorganisms (e.g. bacteria) and higher eukaryotes are ubiquitous and have essential medical, environmental, and evolutionary significance (Newman, D. K. & Banfield, J. F. Science 296, 1071-1077 (2002)). Microorganisms supply nutrients (LeBlanc, J. G. et al. Curr. Opin. Biotechnol. 24, 160-168 (2013)), shape immune systems (Hooper, L. V. et al., Science 336, 1268-1273 (2012)), maintain diverse and productive communities (Eisenhauer, N. PLoS One 7, e34517 (2012)), and drive evolution (Rosenberg, E. & Zilber-Rosenberg, I. mBio 7, e01395-01315 (2016)) for higher eukaryotic hosts. Such microbe-host interactions can be relationships ranging from mutualistic/parasitic to pathogenic symbiosis (Newton, A. C. et al., Trends Microbiol. 18, 365-373 (2010)), in which microorganisms sense and respond to environmental changes with diffusible small molecules. These small molecules are also known as natural products or specialized metabolites, which affect not only the microbial host but also neighboring microbes and other organisms (Shi, Y.-M. & Bode, H. B., Nat. Prod. Rep. 35, 309-335 (2018)). However, due to limitations in genetic tractability of microbial species, as well as formidable obstacles to imitating microbial natural habitats (Schmidt, R. et al., The ISME Journal 13, 2656-2663 (2019)), only a few correlations between microbial natural products (e.g. colibactin (Xue, M. et al. Science 365, eaax2685 (2019), Wilson, M. R. eta/., Science 363, eaar7785 (2019)) and tilivalline (Schneditz, G. et a/. Proc. Natl. Acad. Sci. U. S. A. 111, 13181-13186 (2014)) produced by the human gut microbiota) and the function that microbial natural products endow the producers with have been established.
The survey of previously unidentified conserved BGCs has showcased the abilities of XP to produce pervasive and structurally unique natural products. The present inventors have examined the uncharacterized BGCs that only exist in specific species to assess the biosynthetic potential of XP. Eight unknown PKS/NRPS hybrid BGCs from seven Xenorhabdus and one Photorhabdus (see Fig. 1) compose a gene cluster family (GCF), termed rdb (rhabdobranin). The rdb BGCs feature a peptidase encoded gene, suggesting a prodrug activation mechanism similar to the biosyntheses of xenocoumacin/amicoumacin that are potent antibiotics inhibiting mRNA translation (Shi, Y.-M. & Bode, H. B., Nat. Prod. Rep. 35, 309-335 (2018)) and colibactin that is a genotoxin alkylating DNA (Wilson, M. R. et al, Science 363, eaar7785 (2019)). Although the nodes of the rdb GCF are adjacent to those of the rhabdopeptide/xenortide-like BGCs, the rdb BGCs connect neither to amicoumacin and xenocoumacin BGCs (Reimer, D., et al., Nat. Chem. Biol. 7, 888-890 (2011)). These eight highly similar BGCs were classified by the present inventors into three types, rdb1-3, based on the presence/absence of the first A domain in RdbH and the TE domain in Rdbl (see Fig. 2), which might lead to products with distinct numbers of amino acid residues and non-linear biosynthetic assembly line logic, respectively.
To identify products derived from this GCF, the present inventors focused on rdb1 that contains five out of eight BGCs in this GCF, and attempted to activate the rdb1 in Xenorhabdus budapestensis DSM 16342 by inserting a PBAID promoter in front of rdb1A. The X. budapestensis PBADrdblA mutant yielded four N-myristoyl-D-asparagine congeners (see Example 1 , compounds 19-22), as well as a non-XAD-resin-bound hydrophilic compound with a low production level (see Example 1, compound 23; see also Fig. 6). Since an acylated D-asparaginyl capping the N-terminus of xenocoumacin, zwittermicin, and colibactin has been found to be a self-resistance mechanism (Reimer, D. & Bode, H. B. Nat. Prod. Rep. 31, 154-159 (2014)), the detection of N-myristoyl-D-asparagine analogs was consistent with the inventors' hypothesis that a prodrug strategy was involved in the rdb biosynthesis. To accumulate the inactive prodrugs for structural identification, they deleted the peptidase encoded gene, rdb1P, and the X. budapestensis PBAD rdb1A ΔrdblP mutant led to loss of compounds 19-22 and high production of four new peaks with larger masses, designated as pre-rhabdobranins A-D (see Example 1, compounds 24-27; and Fig. 3) with differences in the N- acylated moiety. Pre-rhabdobranin D (compound 27) was purified from the X. budapestensis PBAD rdb1A ΔrdblP Δhfq and its structure was determined by HRMS and NMR spectroscopy (Tables 4 and 5, and Fig. 7). Intriguingly, pre-rhabdobranins are characterized by a proline-serine dipeptidyl side chain that branches off at the N atom of an aminomalonyl building block. This represents a highly uncommon T-shape peptide in contrast to the canonical linear- chain-elongation on thiotemplated assembly lines.
In a first embodiment, the present invention thus relates to a compound of formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof.
In formula (I), R1 is selected from -OH, -NH2, -O-(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl) or a moiety of the formula:
Figure imgf000004_0002
wherein the alkyl in said -O-(C1-6 alkyl), the alkyl in said -NH(C1-6 alkyl), and any alkyl in said -N(C1-6 alkyl)(C1-6 alkyl) are each optionally substituted with one or more -OH and/or one or more -NH2; wherein R4 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C1-6 alkylene)-O-R41, -(C1-6 alkylene)-S- R41, -(C1-6 alkylene)-N(R41)-R41, -(C1-6 alkylene)-CO-R41, -(C1-6 alkylene)-COO-R41, -(C1-6 alkylene)-O-CO-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-CO-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(R41)-O-R41, -(C1-6 alkylene)-O-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-C(=N-R41)-N(R41)-R41, - (C1-6 alkylene)-SO3-R41 , -(C0-6 alkylene)-carbocyclyl, and -(C0-6 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-6 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-6 alkylene)-heterocyclyl are each optionally substituted with one or more groups R42, wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group comprised in any of the aforementioned R4 groups are each optionally substituted with one or more -OH, and further wherein each R41 is independently selected from hydrogen and C1-6 alkyl.
R2 is selected from hydrogen, an amino acid or a peptide. R3 is hydrogen or a moiety of the formula:
Figure imgf000005_0001
wherein R5 is C1-22 alkyl or C2-22 alkenyl.
Each R42 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OH, -O(C1-6 alkyl), -O(C1-6 alkylene)- OH, -O(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 alkylene)-OH, -(C1-6 alkylene)-O(C1-6 alkyl), -SH, -S(C1-6 alkyl), -S(C1-6 alkylene)-SH, -S(C1-6 alkylene)-S(C1-6 alkyl), -(C1-6 alkylene)-SH, -(C1-6 alkylene)-S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -NH-OH, -N(C1-6 alkyl)-OH, -NH-O(C1-6 alkyl), -N(C1-6 alkyl)-O(C1-6 alkyl), halogen, C1-6 haloalkyl, -O-(C1-6 haloalkyl), -CN, -NO2, -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO-NH(C1-6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(C1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), -SO-(C1-6 alkyl), -(C0-4 alkylene)-carbocyclyl, and -(C0-4 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-4 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C1-6 haloalkyl, -O-(C1-6 haloalkyl), -CN, -OH, -O(C1-6 alkyl), -SH, -S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO-NH(C1-6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(C1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), and -SO-(C1-6 alkyl).
In a further embodiment, the present invention relates to a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The invention likewise relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament. Furthermore, the present invention likewise relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or to a pharmaceutical composition of the invention for use as a medicament.
In a further embodiment, the present invention relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof, or to the pharmaceutical composition of the invention for use in the treatment of an infectious disease.
In a further embodiment, the present invention relates to use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment or prevention of an infectious disease. In a further embodiment, the present invention relates to a method of treating or preventing an infectious disease, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, to a subject (preferably a human) in need thereof. It will be understood that a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof (or of the pharmaceutical composition) is to be administered in accordance with this method.
In a further embodiment, the present invention relates to a disinfectant comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.
In a further embodiment, the present invention relates to the non-therapeutic use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or of the disinfectant of the present invention, for disinfecting or sterilizing an inanimate object.
The present invention is illustrated by the appended figures:
Fig. 1 presents phylogeny and gene organization of the rdb BGCs. The phylogenetic tree is based on protein sequences of BGCs. BGC subclassification is indicated next to the branch.
Fig. 2 presents the domain organization of three types of rdb BGCs with predicted substrates of adenylation and acyltransferase domains. T, thiolation; A, adenylation; C, condensation; E, epimerization; AT, acyltransferase; KS, ketosynthase; KR, ketoreductase; DH, dehydratase; ER, enoyl reductase; cMT, carbon methyltransferase; TE, thioesterase; Ser, serine; Asn, asparagine; Mai, malonyl; Pro, proline; Leu, leucine; Unk, unknown. Presumably inactive domain is labeled with an asterisk.
Fig. 3 presents chemical structures of previously unidentified pre-rhabdobranins A-D (24-27) and rhabdobranin (23) from X. budapestensis DSM 16342, as well as the proposed late-stage biosynthesis involved in a prodrug activation mechanism, similar to xenocoumacin and colibactin. The N-terminus capped acylated D- asparaginyl moiety (19-22) and the dipeptidyl branch are highlighted in grey. The stereocenters were predicted by analyzing the conserved motif in C domain and KR domain that are responsible for stereocontrol.
Fig. 4 presents the proposed first steps in the biosynthesis of rhabdobranins. It starts with an N-capping PCP-bound asparagine in Rdb1 D with one of the four different acyl chains, followed by an arginine extension in Rdb1 F. A fully reduced PKS (Rdb1 G) enrolls a malonyl for a two-carbon extension. RdbU introduces an aminomalonyl unit for chain extension. Without being bound by theory, the aminomalonyl is considered to originate from such a pathway: a free-standing PCP (Rdb1A) is loaded with a serine by a free-standing A domain (Rdb1 C). The hydroxymethyl group of serine is oxidized to carboxyl acid by two oxidases (Rdb1 B and Rdb1 L). The AT domain in RdbU seems to be inactive and it is replaced by a free-standing AT domain (Rdb1E). The Rdb1A bound aminomalonyl is transferred to the AGP of the RdbU by Rdb1E. After that, the chain is further extended with a leucine by Rdb 11. However, the second module of Rdb 11 seems to be inactive.
Fig. 5 presents the proposed biosynthesis of pre-rhabdobranin. The first C domain of Rdb11 functions as a C terminal domain to enroll putrescine for off-loading. In the meantime, a proline-serine dipeptidyl is synthesized by Rdb 1 H and then is off-loaded by nucleophilic attack of the amino group that is catalyzed by the C domain of Rdb1 H to afford a branched peptide.
Fig. 6 presents HPLC-MS analysis of (pre-)rhabdobranins in the promoter exchange mutants of X. budapestensis DSM 16342 in LB medium, a, EICs of the X. budapestensis PBAD rdb1A and X. budapestensis PBAD rdb1A Δrdb1P mutants. Shown are (i) N-(w-7-myristoyl)-D-asparagine (19), N-myristoyl-D-asparagine (20), N-(13- methyl-ω -7-myristoyl)-D-asparagine (21), N-(13-methylmyristoyl)-D-asparagine (22), and rhabdobranin (23); (ii) pre-rhabdobranin A (24), pre-rhabdobranin B (25), pre-rhabdobranin C (26), and pre-rhabdobranin D (27). Intensities in trace (i) are magnified for visualizing tiny peaks. Magnifications are indicated on the right side of traces, b, BPCs ofthe (i) non-induced and (ii) induced promoter exchange mutants of the X. budapestensis PBAD rdb1A ΔrdblP Δhfq. Desired peaks are highlighted in trace (ii). Mutants were induced with L-arabinose. Representative data from three independent experiments are shown, c, LC profile of the HILIC column highlighting rhabdobranin.
Fig. 7 presents the NMR and MS spectral data of pre-rhabdobranin D (27). a, 2D NMR correlations of pre-rhabdobranin D. b, 1H NMR spectrum of pre-rhabdobranin D (27) in DMSO-d6. c, 13C NMR spectrum of pre-rhabdobranin D (27) in DMSO-d6 d, HSQC spectrum of pre-rhabdobranin D (27) in DMSO-d6 e, HMBC spectrum of pre-rhabdobranin D (27) in DMSO-d6 f, 1H-1H COSY spectrum of pre-rhabdobranin D (27) in DMSO-d6 g, HMQC-COSY spectrum of pre-rhabdobranin D (27) in DMSO-d6 h, HSQC-TOCSY spectrum of pre-rhabdobranin D (27) in DMSO-d6 i, HR-ESI-MS of pre-rhabdobranin D (27).
Fig. 8 presents the activity of rhabdobranins and pre-rhabdobranins against B. subtilis B168, E. coli MG1655, M. luteus and S. cerevisiae CEN.PK2. The strain used for inoculation is indicated on the left side for each row of inoculants. In each plate, the colonies on the left side were induced with 0.4% arabinose (column labelled with “+") as opposed to the colonies on the right side (labelled with “-”), which have not been induced.
Fig. 9 presents the NMR spectra of rhabdobranin. a, 1H NMR spectrum of rhabdobranin in D2O. b, 13C NMR spectrum of rhabdobranin in D2O. c, HSQC spectrum of rhabdobranin in D2O. d, HMBC spectrum of rhabdobranin in D2O. e, 1H-1H COSY spectrum of rhabdobranin in D2O.
Fig. 10 presents rhabdobranin mediated inhibition of mRNA translation, a, in vitro translation of E. coli dihydrofolate reductase harboring a coding sequence for the Lumio labelling system in presence of 0 pM to 4000 pM rhabdobranin in triplicates, b, determination of the pixel density (PD) of the detected dihydrofolate reductase in presence of the different rhabdobranin concentrations, c, the determined PD was plotted against the rhabdobranin concentration and a one-site model fit was performed in order to determine the inhibitory concentration for 50% inhibition (IC50) using the GraphPad Prism 9 software (IC50 = 99.81 pM ± 17 pM, R2 = 0.9728).
Fig. 11 presents antimicrobial activity of rhabdobranin and pre-rhabdobranins against Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2. A disc diffusion assay was performed by applying either 5 μL (1), 10 μL (2) or 20 μL (3) of an aqueous 10 mM rhabdobranin solution (a) or an aqueous 10 mM pre-rhabdobranin solution (b). Water was applied as a control (C).
As explained above, the present invention relates to a compound of formula (I)
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof. The compounds of formula (I) may also be referred to as rhabdobranins (if R3 is hydrogen) or pre-rhabdobranins (if R3 is different from hydrogen).
The following detailed description of the compounds of formula (I) relates to all embodiments of the present invention and is also applicable to the pharmaceutically acceptable salts of the compounds of formula (I).
R1 is selected from -OH, -NHZ, -O-(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl) or a moiety of the formula:
Figure imgf000008_0002
wherein the alkyl in said -O-(C1-6 alkyl), the alkyl in said -NH(C1-6 alkyl), and any alkyl in said -N(C1-6 alkyl)(C1-6 alkyl) are each optionally substituted with one or more (e.g., one, two or three) -OH and/or one or more (e.g. , one, two or three) -NHZ.
Preferably, R1 is a moiety of the formula:
Figure imgf000009_0001
R4 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C1-6 alkylene)-O-R41, -(C1-6 alkylene)-S-R41, -(C1-6 alkylene)-N(R41)-R41, -(C1-6 alkylene)-CO-R41, -(C1-6 alkylene)-COO-R41, -(C1-6 alkylene)-O-CO-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-CO-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(R41)-O-R41, -(C1-6 alkylene)-O- CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-C(=N-R41)-N(R41)-R41, -(C1-6 alkylene)-SO3-R41, -(C0-6 alkylene)-carbocyclyl, and -(C0-6 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-6 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-6 alkylene)-heterocyclyl are each optionally substituted with one or more (e.g., one, two or three) groups R42, wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group comprised in any of the aforementioned R4 groups are each optionally substituted with one or more (e.g., one, two or three) -OH, and further wherein each R41 is independently selected from hydrogen and C1-6 alkyl.
Preferably, R4 is selected from hydrogen, C1-6 alkyl, -(C1-6 alkylene)-NH2, -(C1-6 alkylene)-NH-(C1-6 alkyl), -(C1-6 alkylene)-N(C1-6 alkyl)(C1-6 alkyl), -(C1-6 alkylene)-COOH, -(C1-6 alkylene)-COO-(C1-6 alkyl), -(C1-6 alkylene)-CO- NH2, -(C1-6 alkylene)-CO-NH-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(C1-6 alkyl)(C1-6 alkyl), -(C1-6 alkyleneJ-SOaH , and -(C1-6 alkylene)-SO3-(C1-6 alkyl), wherein said alkyl and any alkylene group comprised in any of the aforementioned R4 groups are each optionally substituted with one or more -OH.
More preferably, R4 is selected from -CH2CH2-COOH, -CH2-COOH, -CH2-SO3H, -CH2CH2-CO-NH2, -CH2-CO- NH2, -CH2-NH2, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)4-NH2, -CH(-CH3)-(CH2)2-NH2, -C(-OH)-(CH2)3-NH2, -CH2-C(-OH)- (CH2)2-NH2, and -(CH2)2-C(-OH)-C(-CH2-OH)-NH2.
Even more preferably, R4 is selected from -CH2CH2-COOH and -(CH2)4-NH2.
R2 is selected from hydrogen, an amino acid or a peptide.
Preferably, R2 is an amino acid or a peptide. For example, R2 may be selected from serine, glycyl-serine and prolylserine. More preferably, R2 is a peptide.
Said amino acid (in R2) is preferably an amino acid selected from serine and threonine, more preferably said amino acid is serine. As shown in formula (I), said amino acid is bound to an amino group forming part of the compound of formula (I). It will be understood that the amino acid is attached via an amide bond formed from its carboxylic acid group (-COOH) and the amino group (which carries R2) in formula (I). The carboxylic acid group of the amino acid, which forms an amide bond with the amino group in formula (I), may be, e.g., the a-amino group (particularly in the case of any of the 20 standard proteinogenic a-amino acids). The amino acid may be present in L-configu ration or D- configuration, preferably in L-configuration. Said peptide (in R2) preferably consists of 2, 3, 4 or 5 amino acids, more preferably of 2 or 3 amino acids, and even more preferably said peptide is a dipeptide (i.e. , a peptide consisting of 2 amino acids). For example, R2 may be a dipeptide consisting of a first amino acid which is serine or threonine (preferably serine) and a second amino acid which is selected from any one of the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai), wherein said dipeptide is attached to the remainder of the compound of formula (I) via the first amino acid. Particularly preferred dipeptides include glycylserine or prolyl-serine (each of which is attached via the serine residue in the respective dipeptide). It will be understood that said peptide is attached to the amino group carrying R2 in the compound of formula (I) via an amide bond formed from a carboxylic acid group (-COOH) of the peptide, preferably the main chain carboxylic acid group (or a-amino group) of its C-terminal amino acid. For example, prolyl-serine is attached to the amino group carrying R2 in the compound of formula (I) by an amide bond formed from the -COOH group of serine. Each of the amino acids comprised in said peptide may be present in L-configuration or D-configuration.
Even more preferably, R2 is selected from glycyl-serine and prolyl-serine. In particular, R2 may be, for example, glycyl- L-serine, L-prolyl-L-serine, or D-prolyl-L-serine. It is particularly preferred that R2 is D-prolyl-L-serine.
R3 is hydrogen or a moiety of the formula:
Figure imgf000010_0001
Preferably, R3 is a moiety of the formula:
R5 is C1-22 alkyl or C2-22 alkenyl.
Figure imgf000010_0002
Preferably, R5 is selected from:
and
Figure imgf000011_0001
Each R42 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OH, -0(C1-6 alkyl), -0(C1-6 alkylene)- OH, -O(C1-6 alkylene)-0(C1-6 alkyl), -(C1-6 alkylene)-OH, -(C1-6 alkylene)-O(C1-6 alkyl), -SH, -S(C1-6 alkyl), -S(C1-6 alkylene)-SH, -S(C1-6 alkylene)-S(C1-6 alkyl), -(C1-6 alkylene)-SH, -(C1-6 alkylene)-S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -NH-OH, -N(C1-6 alkyl)-OH, -NH-O(C1-6 alkyl), -N(C1-6 alkyl)-O(C1-6 alkyl), halogen, C1-6 haloalkyl, -O-(C1-6 haloalkyl), -CN, -NO2, -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO-NH(C1-6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(C1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), -SO-(C1-6 alkyl), -(C0-4 alkylene)-carbocyclyl, and -(C0-4 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-4 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C1-6 haloalkyl, -O-(C1-6 haloalkyl), -CN, -OH, -0(C1-6 alkyl), -SH, -S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO-NH(C1-6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(C1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), and -SO-(C1-6 alkyl).
Preferably, each R42 is independently selected from C1-6 alkyl, -OH, -0(C1-6 alkyl), -0(C1-6 alkylene)-OH, -0(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 alkylene)-OH, -(C1-6 alkylene)-O(C1-6 alkyl), -SH, -S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), halogen, C1-6 haloalkyl, -0-(C1-6 haloalkyl), -CN, -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO- NH(C1-6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(C1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), and -SO-(C1-6 alkyl).
The compounds of formula (I) wherein R3 is not hydrogen may also be referred to as pre-rhabdobranins.
It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments.
In a first specific embodiment of the present invention, R1 is -OH or -NH(C1-6 alkyl), wherein the alkyl in said -NH(C1-6 alkyl) is optionally substituted with one or more -OH and/or one or more -NH2. Particularly preferred C1-6 alkyl groups are ethyl, n-propyl, and n-butyl. Preferably, the alkyl group in said -NH(C1-6 alkyl) is substituted with one group -NH2. Thus, it is particularly preferred that R1 is -OH, -NH-CH2CH2-NH2, -NH-CH2CH2CH2-NH2, or -NH-CH2CH2CH2CH2- NH2. Even more preferably, R1 is -OH or -NH-CH2CH2CH2CH2-NH2.
In a second specific embodiment of the present invention, R1 is -OH.
In a third specific embodiment of the present invention, R1 is -NH-CH2CH2CH2CH2-NH2.
In a fourth specific embodiment of the present invention, R1 is a moiety of the formula: wherein R4 is -CH2CH2-COOH.
Figure imgf000012_0001
In a fifth specific embodiment of the present invention, R1 is a moiety of the formula:
Figure imgf000012_0002
wherein R4 is -(CH2)4-NH2.
In a sixth specific embodiment, R2 is hydrogen.
In a seventh specific embodiment, R2 is an amino acid selected from serine and threonine. Preferably, R2 is serine.
In an eighth specific embodiment, R2 is a peptide. Preferably, R2 is selected from glycyl-serine and prolyl-serine.
In a ninth specific embodiment, R2 is selected from hydrogen, serine, glycyl-serine and prolyl-serine. In a tenth specific embodiment, R3 is hydrogen.
In an eleventh specific embodiment, R3 is a moiety of the formula:
Figure imgf000013_0001
wherein R5 is C1-22 alkyl or C2-22 alkenyl. Preferably, R5 is C13-14 alkyl or C13-14 alkenyl.
In a twelfth specific embodiment, R3 is a moiety of the formula:
Figure imgf000013_0002
wherein R5 is selected from: and
Figure imgf000013_0003
Preferably, R5 is selected from:
and
Figure imgf000014_0001
More preferably, R5 is selected from: and
Figure imgf000014_0002
In a thirteenth specific embodiment of the invention, R1 is -OH
In this thirteenth specific embodiment of the invention, R2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
In a fourteenth specific embodiment of the invention, R1 is -NH-CH2CH2CH2CH2-NH2.
In this fourteenth specific embodiment of the invention, R2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
In a fifteenth specific embodiment of the invention, R1 is a moiety of the formula:
Figure imgf000014_0003
wherein R4 is -CH2CH2-COOH. In this fifteenth specific embodiment of the invention, R2 is selected from hydrogen, serine, glycyl-serine and prolylserine.
In a sixteenth specific embodiment of the invention, R1 is a moiety of the formula:
Figure imgf000015_0001
wherein R4 is -(CH2)4-NH2.
In this sixteenth specific embodiment of the invention, R2 is selected from hydrogen, serine, glycyl-serine and prolylserine. Said serine is preferably L-serine. Said glycyl-serine is preferably glycyl-L-serine. Said prolyl-serine is preferably D-prolyl-L-serine. More preferably, R2 is glycyl-L-serine or D-prolyl-L-serine, even more preferably D-prolyl- L-serine.
In a seventeenth specific embodiment of the invention, R1 is selected from -OH and -NH-CH2CH2CH2CH2-NH2.
In this seventeenth specific embodiment of the invention, R3 is hydrogen.
In an eighteenth specific embodiment of the invention, R2 is hydrogen.
In this eighteenth specific embodiment of the invention, R3 is hydrogen.
In the compound of formula (I), including also in any one of the above-described specific embodiments, the absolute configuration of the carbon atom that carries the group -C(O)R1 is preferably as follows:
Figure imgf000015_0002
Preferably, in the compound of formula (I), including also in any one of the above-described specific embodiments, the absolute configuration of the carbon atom that carries the group -NH-R3 is as follows:
Figure imgf000016_0001
Preferably, in the compound of formula (I), including also in any one of the above-described specific embodiments, the absolute configuration of the two carbon atoms that carry the groups -NH-R2 and -OH, respectively, is as follows:
Figure imgf000016_0002
Thus, preferably, in the compound of formula (I), including also in any one of the above-described specific embodiments, the absolute configuration of the carbon atom that carries the group -NHR3and of the two carbon atoms that carry the groups -NHR2 and -OH is as follows:
Figure imgf000016_0003
More preferably, the compound of formula (I), including also any one of the above-described specific embodiments, has the following absolute configuration:
Figure imgf000017_0001
Preferably, in the compound of formula (I), including also any one of the above-described specific embodiments, the moiety of formula:
Figure imgf000017_0002
has the following absolute configuration:
Figure imgf000017_0003
Preferably, in the compound of formula (I), including also any one of the above-described specific embodiments, the moiety of the formula:
Figure imgf000017_0004
has the following absolute configuration:
Figure imgf000017_0005
A particularly preferred compound of formula (I) in accordance with the present invention is any one of the following compounds or a pharmaceutically acceptable salt thereof:
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
In the compounds depicted above, each R is independently selected from:
and
Figure imgf000021_0001
The compounds of formula (I) can be prepared e.g., in accordance with, or in analogy to, the procedure described in Example 2.
The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.
The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.
As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e. , non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-6 alkyl” denotes an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tertbutyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.
As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-6 alkenyl” denotes an alkenyl group having 2 to 6 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl. As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g. , one or two) carbon-to-carbon double bonds. The term “C2-6 alkynyl” denotes an alkynyl group having 2 to 6 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term ''alkynyl” preferably refers to C2-4 alkynyl.
As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1-6 alkylene" denotes an alkylene group having 1 to 6 carbon atoms, and the term "C0-6 alkylene” indicates that a covalent bond (corresponding to the option "Co alkylene") or a C1-6 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2- CH2-CH2-). Unless defined otherwise, the term "alkylene” preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.
As used herein, the term “carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, “carbocyclyl” preferably refers to aryl or cycloalkyl.
As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl or heterocycloalkyl.
As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl. As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and/or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1 -benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,
1.2.4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5- thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-
1.2.4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5- triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- cjpyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., referto cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred “cycloalkyl" is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).
As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and/or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatomcontaining ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4- yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1 -dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “heterocycloal kyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl" refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term “halogen” refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I).
As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. "Haloalkyl” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3. The terms "bond” and “covalent bond" are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.
As used herein, the terms ''optional”, "optionally" and “may” denote that the indicated feature may be present but can also be absent. Whenever the term ''optional”, ''optionally” or “may" is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y" (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional", the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
Various groups are referred to as being "optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the "optionally substituted" groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.
A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.
The term “amino acid” refers, in particular, to any one of the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) but also to non- proteinogenic and/or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., γ-aminobutyric acid, isoglutamine, or statine) and/or 5-amino acids as well as any other compound comprising at least one carboxylic acid group and at least one amino group. Unless defined otherwise, an "amino acid” preferably refers to an a-amino acid, more preferably to any one of the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably present as the L-isomer). The term “amino acid” may also refer to a monovalent or divalent radical derived from an “amino acid” as described herein above, wherein preferably an amino group and/or a carboxylic acid group may serve as point(s) of attachment, preferably through an amide bond. Thus, the term “amino acid” may refer to an amino acyl moiety attached to the rest of the molecule, e.g., through a -CO- group formed from its carboxylic acid group. The term “peptide” refers to a polymer of two or more amino acids linked via amide bonds that are formed between an amino group of one amino acid and a carboxylic acid group of another amino acid. The amino acids comprised in the peptide or protein, which are also referred to as amino acid residues, may be selected from the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) but also from non-proteinogenic and/or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., y- aminobutyric acid, isoglutamine, or statine) and 6-amino acids. Preferably, the amino acid residues comprised in the peptide or protein are selected from a-amino acids, more preferably from the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably all present as the L-isomer). The peptide may be unmodified or may be modified, e.g., at its N-terminus, at its C-terminus and/or at a functional group in the side chain of any of its amino acid residues (particularly at the side chain functional group of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu, and/or Arg residues). Such modifications may include, e.g., the attachment of any of the protecting groups described for the corresponding functional groups in: Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006. Such modifications may also include the covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide), the glycosylation and/or the acylation with one or more fatty acids (e.g., one or more C8-30 alkanoic or alkenoic acids; forming a fatty acid acylated peptide or protein). Moreover, such modified peptides or proteins may also include peptidomimetics, provided that they contain at least two amino acids that are linked via an amide bond (formed between an amino group of one amino acid and a carboxyl group of another amino acid). The amino acid residues comprised in the peptide or protein may, e.g., be present as a linear molecular chain (forming a linear peptide) or may form one or more rings (corresponding to a cyclic peptide). The peptide may also form oligomers consisting of two or more identical or different molecules. The term “peptide” may also refer to a monovalent radical derived from a “peptide” as described herein above, wherein preferably an amino group or a carboxylic acid group, in particular the N-terminal amino group or the C-terminal carboxylic acid group, serves as point of attachment, preferably through an amide bond. Thus, the term “peptide” may refer to a peptidyl moiety attached to the rest of the molecule through a -CO- group (formed from a carboxylic acid group, e.g., from its C-terminal carboxylic acid group).
As used herein, unless explicitly indicated otherwise or contradicted by context, the terms ''a", “an” and “the” are used interchangeably with “one or more” and “at least one". Thus, for example, a composition comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more" compounds of formula (I).
It is to be understood that wherever numerical ranges are provided/disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein. As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.
As used herein, the term “comprising" (or “comprise”, “comprises", “contain”, “contains”, or “containing"), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia”, i.e. , “containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of' and “consisting of'. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C", wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C" (i.e., no other components than B and C are comprised in A).
The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g. , by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.
The present invention also specifically relates to the compound of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.
Moreover, the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.
Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (orcis/trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto/enol tautomers or thione/thiol tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures/racemates and non-racemic mixtures). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.
The scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e., 2H; also referred to as "D"). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H/D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or 1H hydrogen atoms in the compounds of formula (I) is preferred.
The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g., 18F, 11C, 13N, 150, 76Br, 77Br, 120l and/or 124l. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by 18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by 11C atoms, (ill) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by 13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by 15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by 77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 120l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by 124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.
The present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention as defined herein, and a pharmaceutically acceptable excipient. The present invention further relates to the said pharmaceutical composition comprising a compound of formula (I) ora pharmaceutically acceptable saltthereof of the present invention, and a pharmaceutically acceptable excipient for use in therapy.
The compounds and/or chemical entities provided herein may be administered as compounds per se or may be formulated as medicaments. The medicaments/pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyethylene glycol), including polyethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β- cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p- cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-β-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.
The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.
The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in “Remington: The Science and Practice of Pharmacy'1, Pharmaceutical Press, 22nd edition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
The compounds of formula (I) or the pharmaceutically acceptable salts thereof or the above described pharmaceutical compositions comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof may be administered to a subject by any convenient route of administration, whether systemically/peri pherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.
If said compounds or pharmaceutically acceptable salts or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Said compounds or pharmaceutically acceptable salts or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
For oral administration, the compounds, the pharmaceutically acceptable salts or the pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing. The compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as “oral-gastrointestinal” administration.
Alternatively, said compounds, pharmaceutically acceptable salts or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
Said compounds, pharmaceutically acceptable salts or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention or a pharmaceutically acceptable salt thereof.
Said compounds, pharmaceutically acceptable salts or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
It is also envisaged to prepare dry powder formulations of the compounds of formula (I) or the pharmaceutically acceptable salt thereof for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification/spray drying process.
For topical application to the skin, said compounds, pharmaceutically acceptable salts or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2 -octyldodecanol, benzyl alcohol and water.
The present invention thus relates to the compounds, pharmaceutically acceptable salts or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. Preferred routes of administration are oral administration or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).
Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
A proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, e.g., 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
The compound of formula (I) or the pharmaceutically acceptable salt thereof is useful in the treatment or prevention of an infectious disease. Thus, the present invention relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infectious disease.
The compound of formula (I) or the pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the compound of formula (I)).
However, the compound of formula (I), the pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof can also be administered in combination with one or more further therapeutic agents. If the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease or condition, the dose of each compound may differ from that when the corresponding compound is used alone, in particular, a lower dose of each compound may be used. The combination of the compound of formula (I) with one or more further therapeutic agents may comprise the simultaneous/concomitant administration of the compound of formula (I) and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential/separate administration of the compound of formula (I) and the further therapeutic agent(s). If administration is sequential, either the compound of formula (I) according to the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I), or they may be administered in two or more different (separate) pharmaceutical formulations.
In one embodiment, the present invention relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infectious disease. The present invention further relates to the pharmaceutical composition of the present invention comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an infectious disease. Preferably, the said infectious disease is selected from a bacterial infectious disease, a protozoan infectious disease, and a fungal infectious disease.
The present invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a bacterial infectious disease caused by Gram-positive bacteria. Preferably, the said Gram-positive bacteria are selected from: Listeria spp., including e.g. Listeria monocytogenes or Listeria welshimeri; Staphylococcus spp., including e.g. Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus lugdunensis, Staphylococcus schleiferi, or Staphylococcus caprae; Streptococcus spp., including e.g. Streptococcus pneumoniae, Streptococcus viridans, Streptococcus pyogenes, or Streptococcus agalactiae; Enterococcus spp., including e.g. Enterococcus faecalis or Enterococcus faecium; Bacillus spp., including e.g. Bacillus licheniformis, Bacillus subtilis, Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis, or Bacillus larvae’, Mycobacterium spp., including e.g. Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium kanasasii, Mycobacterium avium, Mycobacterium paratuberculosis, Mycobacterium scrofulaceam, Mycobacterium microti, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium intracellulare, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium fortuitum, Mycobacterium chelonei, or Mycobacterium marinum; Nocardia spp., including e.g. Nocardia asteroids; Micrococcus luteus and Rhodococcus spp., including e.g. Rhodococcus equi.
The present invention further relates to the compound of formula (I) or pharmaceutically acceptable salt thereof the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a bacterial infectious disease caused by Gram-negative bacteria. As defined herein, the said Gram-negative bacteria are preferably selected from: Neisseria spp., including e.g. Neisseria gonorrhoeae or Neisseria meningitides; Moraxella spp., including e.g. Moraxella catarrhalis; Hemophilus spp., including e.g. Hemophilus influenzae; Klebsiella spp., including e.g. Klebsiella pneumoniae; Legionella spp., including e.g. Legionella pneumophila; Pseudomonas spp., including e.g. Pseudomonas aeruginosa or Pseudomonas putida; Escherichia spp., including e.g. Escherichia coli; Proteus spp., including e.g. Proteus mirabilis; Enterobacter spp., including e.g. Enterobacter c/oaceae; Serratia spp., including e.g. Serratia marcescens; Helicobacter spp., including e.g. Helicobacter pylori; and Salmonella spp., including e.g. Salmonella enteritidis or Salmonella typhi.
The compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the invention can be combined with one or more anti-bacterial agents. In one embodiment, the said anti-bacterial agent is preferably effective against an infectious disease caused by Gram-positive bacteria. Preferably, the said Grampositive bacteria are selected from: Listeria spp., including e.g. Listeria monocytogenes or Listeria welshimeri; Staphylococcus spp., including e.g. Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus lugdunensis, Staphylococcus schleiferi, or Staphylococcus caprae; Streptococcus spp., including e.g. Streptococcus pneumoniae, Streptococcus viridans, Streptococcus pyogenes, or Streptococcus agalactiae; Enterococcus spp., including e.g. Enterococcus faecalis or Enterococcus faecium; Bacillus spp., including e.g. Bacillus licheniformis, Bacillus subtilis, Bacillus anthracis, Bacillus cereus, Bacillus thuringiensis, or Bacillus larvae; Mycobacterium spp., including e.g. Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium ulcerans, Mycobacterium kanasasii, Mycobacterium avium, Mycobacterium paratuberculosis, Mycobacterium scrofulaceam, Mycobacterium microti, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium intracellulare, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium fortuitum, Mycobacterium chelonei, or Mycobacterium marinum; Nocardia spp., including e.g. Nocardia asteroids; Micrococcus luteus and Rhodococcus spp., including e.g. Rhodococcus equi. In one embodiment, the said anti-bacterial agent is preferably effective against an infectious disease caused by Gramnegative bacteria. The said Gram-negative bacteria are preferably selected from: Neisseria spp., including e.g. Neisseria gonorrhoeae or Neisseria meningitides; Moraxella spp., including e.g. Moraxella catarrhalis; Hemophilus spp., including e.g. Hemophilus influenzae; Klebsiella spp., including e.g. Klebsiella pneumoniae; Legionella spp., including e.g. Legionella pneumophila; Pseudomonas spp., including e.g. Pseudomonas aeruginosa or Pseudomonas putida; Escherichia spp., including e.g. Escherichia coli; Proteus spp., including e.g. Proteus mirabilis; Enterobacter spp., including e.g. Enterobacter cloaceae; Serratia spp., including e.g. Serratia marcescens; Helicobacter spp., including e.g. Helicobacter pylori; and Salmonella spp., including e.g. Salmonella enteritidis or Salmonella typhi.
The present invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a protozoan infectious disease. Preferably, the said protozoan infectious disease is caused by a protozoan of the phylum Apicomplexa. More preferably, the said protozoan infectious disease is caused by a protozoan selected from: Plasmodium spp., including e.g. Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi; Leishmania spp., including e.g. Leishmania major, Leishmania tropica, Leishmania aethiopica, Leishmania mexicana, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, or Leishmania chagasi; Trypanosoma spp., including e.g. Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma simiae, Trypanosoma avium, Trypanosoma congolense, Trypanosoma equinum, Trypanosoma equiperdum, Trypanosoma evansi, or Trypanosoma suis; Babesia spp., including e.g. Babesia microti or Babesia bigemina; and Toxoplasma spp., including e.g. Toxoplasma gondii.
The compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same of the present invention can be used in combination with an antiprotozoan agent. Preferably, the antiprotozoan agent to be used in combination with the compound of the invention or the pharmaceutical composition of the invention is useful in the treatment and/or prevention of protozoan infectious disease is caused by a protozoan selected from: Plasmodium spp., including e.g. Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi; Leishmania spp., including e.g. Leishmania major, Leishmania tropica, Leishmania aethiopica, Leishmania mexicana, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, or Leishmania chagasi; Trypanosoma spp., including e.g. Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma simiae, Trypanosoma avium, Trypanosoma congolense, Trypanosoma equinum, Trypanosoma equiperdum, Trypanosoma evansi, or Trypanosoma suis; Babesia spp., including e.g. Babesia microti or Babesia bigemina; and Toxoplasma spp., including e.g. Toxoplasma gondii.
Thus, the present invention further relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same for use in combination with an antiprotozoan agent, wherein the antiprotozoan agent is preferably selected from acranil, tinidazole, ipronidazole, ethylstibamine, pentamidine, acetarsone, aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole, and suramin.
The present invention further relates to the compound of formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the compound of formula (I) or the pharmaceutically acceptable salt thereof for use in the treatment or prevention of a fungal infectious disease. The fungal infectious disease may also be, e.g., a yeast infectious disease. Preferably, the said fungal infectious disease is caused by a fungus selected from: Aspergillus spp., including e.g. Aspergillus fumigatus, Aspergillus flavus, or Aspergillus clavatus; Candida spp., including e.g. Candida albicans, Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guilliermondii; Cryptococcus spp., including e.g. Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, or Cryptococcus gattii; Histoplasma spp., including e.g. Histoplasma capsulatum; Pneumocystis spp., including e.g. Pneumocystis jirovecii or Pneumocystis carinii; Stachybotrys spp., including e.g. Stachybotrys chartarum; Basidiobolus spp., including e.g. Basidiobolus ranarum; Blastomyces spp., including e.g. Blastomyces dermatitidis; Coccidioides spp., including e.g. Coccidioides immitis or Coccidioides posadasii; Conidiobolus spp., including e.g. Conidiobolus coronatus or Conidiobolus incongruous; and Madurella spp., including e.g. Madurella mycetomatis or Madurella grisea. The present invention thus also relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a yeast infectious disease, wherein the yeast infectious disease is preferably caused by a yeast selected from: Candida spp., including e.g. Candida albicans, Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guilliermondii; or Cryptococcus spp., including e.g. Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, or Cryptococcus gattii.
The compounds of the formula (I) can be used in combination with one or more other medicaments. Preferably the other medicament will be a further medicament which is useful in treating, ameloriating or preventing a fungal infection, more preferably a further medicament which is useful in treating, ameloriating or preventing a fungal infection that is caused by a fungus selected from Aspergillus spp., including e.g. Aspergillus fumigatus, Aspergillus flavus, or Aspergillus clavatus; Candida spp., including e.g. Candida albicans, Candida stellatoidea, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida parapsilosis, or Candida guilliermondii; Cryptococcus spp., including e.g. Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, or Cryptococcus gattii; Histoplasma spp., including e.g. Histoplasma capsulatum; Pneumocystis spp., including e.g. Pneumocystis jirovecii or Pneumocystis carinii; Stachybotrys spp., including e.g. Stachybotrys chartarum; Basidiobolus spp., including e.g. Basidiobolus ranarum; Blastomyces spp., including e g. Blastomyces dermatitidis; Coccidioides spp., including e.g. Coccidioides immitis or Coccidioides posadasii; Conidiobolus spp., including e.g. Conidiobolus coronatus or Conidiobolus incongruous; and Madurella spp., including e.g. Madurella mycetomatis or Madurella grisea.
Thus, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention comprising the compound of formula (I) ora pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in combination with an antifungal agent.
The compound of the formula (I), the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the same can be used in combination with one or more antifungal agents capable of at least one of: a) inhibiting ergosterol biosynthesis; b) binding to ergosterol; c) inhibiting 1 ,3-P-glucan synthase; d) inhibiting epoxidase; e) inhibiting leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2. Thus, the additional antifungal agent may be for example be selected from the group consisting of polyene antifungal agents (such as Natamycin, Rimocidin, Filipin, Nystatin, Amphotericin B orCandicin), azole antifungal agents (such as miconazole, ketoconazole, clotromazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, seraconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole terconazole, or abafungin), allylamine antifungal agents (such as Terbinafme, Amorolfine, Naftifme or Butenafme) and echinocandins (such as Anidulafungin, Caspofungin or Micafungin).
The compound of formula (I), the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the same may also be useful in treating and/or preventing a fungal infection disease, wherein the said fungal infectious disease cannot be treated in a curable manner by any of the antifungal agents capable of at least one of a) inhibiting ergosterol biosynthesis; b) binding to ergosterol; c) inhibiting 1 ,3-P-glucan synthase; d) inhibiting epoxidase; e) inhibiting leucyl-tRNA synthetase; and/or f) inhibition of elongation factor 2. Thus, the compound of formula (I) of the present invention or the pharmaceutical composition comprising the same may also be useful in treating and/or preventing fungal infectious disease that is resistant to any of the agents selected from the group consisting of polyene antifungal agents (such as Natamycin, Rimocidin, Filipin, Nystatin, Amphotericin B or Candicin), azole antifungal agents (such as miconazole, ketoconazole, clotromazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, seraconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole terconazole, or abafungin), allylamine antifungal agents (such as Terbinafme, Amorolfine, Naftifme or Butenafme) and echinocandins (such as Anidulafungin, Caspofungin or Micafungin).
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously/concomitantly in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof) or the further therapeutic agent(s) may be administered first. When administration is simultaneous, the combination may be administered either in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same formulation, it will be appreciated that the two or more compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately, they may be provided in any convenient formulation.
The subject or patient to be treated in accordance with the present invention may be an animal (e.g., a non-human animal). Preferably, the subject/patient is a mammal. More preferably, the subject/patient is a human (e.g., a male human or a female human) or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig). Most preferably, the subject/patient to be treated in accordance with the invention is a human.
The term “treatment” of a disorder or disease, as used herein, is well known in the art. “Treatment” of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject. A patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).
The “treatment" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only). The ''treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the “treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above). The treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
The term ''prevention'" of a disorder or disease, as used herein, is also well known in the art. For example, a patien t/su bject suspected of being prone to suffer from a disorder or disease may particularly benefit from a prevention of the disorder or disease. The subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition. Such a predisposition can be determined by standard methods or assays, using, e.g., genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/su bject does not show any clinical or pathological symptoms). Thus, the term ''prevention" comprises the use of a compound of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
The present invention further encompasses non-therapeutic uses of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention relates to a disinfectant comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The disinfectant of the present invention is preferably an aqueous disinfectant formulation or an alcohol-based disinfectant formulation, preferably an ethanol-based disinfectant formulation. In certain embodiments of the present invention, the disinfectant of the present invention further comprises a surfactant. The surfactant allows for the creation of a “foaming effect” when the disinfectant solution is applied to a surface to be treated. The creation of a foam allows for the disinfectant solutions to remain in contact with the surface to be treated for longer periods of time.
The aqueous disinfectant formulation of the present invention in certain embodiments is capable of generating a foam when applied to a surface to be disinfected. The foam adheres to the surface to be disinfected for a time sufficient to ensure eradication of the non-indigenous and/or pathogenic bacterial, microbial, fungal and/or viral population.
The disinfectant formulations of the present invention may be applied onto a surface to be disinfected (i.e. cleaned) by means of a variety of spraying techniques. In one embodiment, the disinfectant of the present invention is applied using a diffuser or a mist blower. Alternatively, the disinfectant formulations of the present invention can also be formulated into aerosol formulations. In certain embodiments, the disinfectant of the present invention may be applied to the surface to be disinfected by using a foamer.
The disinfectant of the present invention preferably exhibits antibacterial properties, antifungal properties and/or antiviral properties. More preferably, the disinfectant of the present invention exhibits antibacterial properties and/or antifungal properties.
Further accordingly, in one embodiment the present invention relates to non-therapeutic use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the disinfectant of the present invention, for disinfecting or sterilizing an inanimate object.
In another embodiment, the present invention relates to a method of disinfecting or sterilizing an inanimate object. The said method of the present invention comprises applying a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the disinfectant of the present invention, to said inanimate object.
The inanimate object is not particularly limited, as any object can in principle be disinfected according to the present invention. Preferably, the inanimate object is a technical device, e.g., a catheter, a medical implant, a surgical instrument, contact lenses, or a food-processing device.
The invention is furthermore illustrated by the following examples which are not to be construed as limiting.
EXAMPLES
General experimental procedures
All chemicals were purchased from Sigma-Aldrich, Acros Organics, or Iris BIOTECH. Isotope-labeled chemicals were purchased from Cambridge Isotope Laboratories, Inc. Genomic DNA of selected Xenorhabdus and Photorhabdus strains were isolated using the Qiagen Centra Puregene Yeast/Bact Kit. DNA polymerases (Taq, Phusion, and 05) and restriction enzymes were purchased from New England Biolabs or Thermo Fisher Scientific. DNA primers were purchased from Eurofins MWG Operon. PCR amplifications were carried out on thermocyclers (SensoQuest). Polymerases were used according to the manufacturers' instructions. DNA purification was performed from 1% TAE agarose gel using Invisorb® Spin DNA Extraction Kit (STRATEC Biomedical AG). Plasmids in E. coli were isolated by alkaline lysis. HPLC-UV-MS analysis was conducted on an UltiMate 3000 system (Thermo Fisher) coupled to an AmaZonX mass spectrometer (Bruker) with an ACQUITY UPLC BEH C18 column (130 A, 2.1 mm * 100 mm, 1.7 pm particle size, Waters) at a flow of 0.6 mL/min (5-95% acetonitrile/water with 0.1% formic acid, v/v, 16 min, UV detection wavelength 190-800 nm). HPLC-UV-HRMS analysis was conducted on an UltiMate 3000 system (Thermo Fisher) coupled to an Impact II qTof mass spectrometer (Bruker) either equipped with an ACQUITY UPLC BEH C18 column (130 A, 2.1 mm * 100 mm, 1.7 pm particle size, Waters) at a flow of 0.4 mL/min (5-95% acetonitrile/water with 0.1% formic acid, v/v, 16 min, UV detection wavelength 190-800 nm), oran ACQUITY UPLC BEH Amide column (130 A, 2.1 mm x 50 mm, 1.7 pm particle size, Waters) at a flow of 0.4 mL/min (5-50% water/acetonitrile with 0.1% formic acid, v/v, 5 min, 90% water/acetonitrile with 0.1% formic acid, v/v, 2.1 min, UV detection wavelength 190-800 nm). HPLC purification was performed on preparative and semipreparative Agilent 1260 systems coupled to a DAD and a single quadrupole detector with a C18 ZORBAX Eclipse XDB column (9.4 mm x 250 mm, 5 pm, 3 mL/min; 21.2 mm x 250 mm, 5 pm, 20 mL/min; 50 mm x 250 mm, 10 pm, 40 mL/min). Freeze drying was performed by BUCHI Lyovapor™ L-300 Continuous. NMR experiments were acquired on a Bruker AVANCE 500, 600, or 700 MHz spectrometer equipped with a 5 mm cryoprobe.
Primers (i.e., DNA oligos), strains and plasmids used in this study are summarized in Table 1, Table 2 and Table 3, respectively.
Table 1. Primers used in this study.
Figure imgf000040_0001
Figure imgf000041_0002
Table 2. Strains used in this study.
Figure imgf000041_0001
Strain and culture conditions
Wild-type strains and the mutants thereof and E. coli were cultivated on lysogeny broth (LB) agar plates at 30 ºC overnight and were subsequently inoculated into liquid LB culture at 30 ºC with shaking at 200 rpm. For compound production, the overnight LB culture was transferred into 5 mL LB, XPP15, or Sf-900™ II SFM medium (1:100, v/v) with 2% (v/v) of Amberlite™ XAD-16 resins, 0.4 % of L-arabinose as the inducer (for mutants with a PBAD promoter), and selective antibiotics such as ampicillin (Am, 100 μg/mL), kanamycin (Km, 50 μg/mL), or chloramphenicol (Cm, 34 μg/mL) at 30 ºC for 72 h with shaking at 200 rpm.
Culture extraction and HPLC-UV-MS analysis
Culture for producing pre-rhabdobranins was added with XAD-16 resins. The resins were collected after 72 h and extracted with 5 mL methanol. The solvent was dried under rotary evaporators, and the dried extract was resuspended in 500 μL methanol, of which 5 μL was injected and analyzed by HPLC-UV-MS or HPLC-UV-HRMS with a C-18 column. Unless otherwise specified, HPLC-UV-MS and HPLC-UV-HRMS chromatograms in the figures were shown on the same scale. Culture for producing rhabdobranins was cultivated without XAD-16 resins. 5 μL supernatants were injected and analyzed by HPLC-UV-MS or HPLC-UV-HRMS with an Amide column.
Construction of insertion mutants
A 500— 800-bp upstream of the target gene (rdb1A) was amplified with a corresponding primer pair listed in Table 1. The resulting fragments were cloned using Hot Fusion (Fu, C. et al., PLoS One 9, e115318 (2015)) into pCEP_kan or pCEP_cm backbone that was amplified by pCEP_Fw and pCEP_Rv. After the transformation of a constructed plasmid into E. coli S17-1 λ pir, clones were verified by PCR with primers pCEP-Ve-Fw and pDS132-Ve-Rv. A wildtype strain (X budapestensis DSM 16342) or a deletion mutant (X. budapestensis Δhfq, X. budapestensis Δrdb1P, X. budapestensis Δrdb1P Δhfq, X. budapestensis Δrdb1H, or X budapestensis Δrdb1H Δhfq) was used as a recipient strain. The recipient strain was mated with E. coli S17-1 A pir (donor) carrying a constructed plasmid. Both strains were grown in the LB medium to an OD600 of 0.6 to 0.7, and the cells were washed once with the fresh LB medium. Subsequently, the donor and recipient strains were mixed on an LB agar plate in ratios of 1 :3 and 3: 1 , and incubated at 37ºC for 3 h followed by incubation at 30ºC for 21 h. After that, the bacterial cell layer was harvested with an inoculating loop and resuspended in 2 mL fresh LB medium. 200 μL of the resuspended culture was spread out on an LB agar plate with Am/Km or Am/Cm incubated at 30ºC for 2 days. Individual insertion clones were cultivated and analyzed by HPLC-UV-HRMS, and the genotype of all mutants was verified by plasmid- and genomespecific primers.
Construction of deletion mutants
A ~1 ,000-bp upstream and a ~1 ,000-bp downstream fragments of hfq in X. budapestensis DSM 16342 were amplified using primer pairs listed in Table 1. The amplified fragments were fused using the complementary overhangs introduced by primers and cloned into the pCKcipB vector or pEB17 (both were linearized with Pstl and Bglll) by Hot Fusion (Fu, C. et al., PLoS One 9, e115318 (2015)). Transformation of E. co/i S17-1 λ pir with the resulting plasmid and conjugation with a wild-type strain, as well as the generation of double crossover mutants via counterselection on LB plates containing 6% sucrose, were done as previously described (Brachmann, A. O. et al, ChemBioChem 8, 1721-1728 (2007)). The deletion mutant was verified via PCR using primer pairs listed in Table 1, which yielded a ~2,000-bp fragment for mutants genetically equal to the WT strain and a ~1 ,000-bp fragment for the desired deletion mutant. The same procedure was used to generate Δrdb1P mutants, during which E. co// S17-1 A pir carrying pEB17 rdb1P or pEB 17 rdb1H was mated with X. budapestensis DSM 16342 wild-type and X. budapestensis Δhfq mutant.
Example 1 : HPLC-MS analysis of (pre-)rhabdobranins in the promoter exchange mutants ofX. budapestensis
DSM 16342
Culture extraction and HPLC-MS analysis of (pre-)rhabdobranins in the promoter exchange mutants of X. budapestensis DSM 16342 (induced with L-arabinose) in LB medium was performed as described hereinabove. Obtained extracted ion chromatograms and base peak chromatograms are shown in Fig. 6. In the case of X. budapestensis PBAD rdb1A mutant (Fig. 6a(i)) the presence of N-(w-7-myristoyl)-D-asparagine (19), N-myristoyl-D- asparagine (20), N-(13-methyl-w-7-myristoyl)-D-asparagine (21), N-(13-methylmyristoyl)-D-asparagine (22), and rhabdobranin (23) was confirmed. In the case of X. budapestensis PBAD rdb1A Δrdb1P mutant (Fig. 6a(ii)) the following pre-rhabdobranins were detected: pre-rhabdobranin A (24), pre-rhabdobranin B (25), pre-rhabdobranin C (26), and pre-rhabdobranin D (27). Fig. 6b, shows BPCs of the (i) non-induced and (ii) induced promoter exchange mutants of the X. budapestensis PBAD rdb1A Δrdb1P Δhfq. Δhfq mutant is a strain wherein the production of other natural products beyond the one originating from the induced BCG is lost due to deletion of Hfq, a bacterial RNA chaperone that modulates BCG expression through small RNA / messenger RNA interactions.
The HR-ESI-MS data of the compounds concerned here are summarized in Table 4.
Table 4. HR-ESI-MS data of the compounds 19 to 27.
Figure imgf000043_0001
Example 2: Biosynthesis and isolation of pre-rhabdobranin 27
2% of XAD-16 resins from a 12 L LB culture of the X. budapestensis PBAD rdb1A Δrdb1P Δhfq mutant induced by L- arabinose were harvested after 72 h of incubation at 30 ºC with shaking at 120 rpm, and were washed with water and extracted with methanol (3 * 2 L) to yield a crude extract 15.3 g after evaporation. The extract was subject to a Sephadex LH-20 column eluted with methanol. The fraction (2.8 g) containing pre-rhabdobranins was subjected to preparative HPLC with a C18 column using an acetonitrile/water gradient (0.1% formic acid) 0-20 min, 15-35%, 40 mL/min to afford a fraction (206 mg) mainly containing pre-rhabdobranin D, which was further purified by semipreparative HPLC with a C18 column using an acetonitrile/water gradient (0.1 % formic acid) 0-24 min, 5-53%, 3 mL/min to afford pre-rhabdobranin D (27, 59.1 mg). NMR data concerning compound 27 are presented in Fig. 7 and Table 5.
Figure imgf000044_0001
Table 5 1 1H (700 MHz) and 13C (175 MHz) NMR data assignments for pre-rhabdobranin D (27) in DMSO-d6. The stereochemistry was predicted by analyzing the rdb1 BGC.
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Example 3: Antimicrobial activity of rhabdobranins and pre-rhabdobranins presented by using the promoter exchange mutants of X. budapestensis DSM 16342
The antimicrobial activity of rhabdobranins and pre-rhabdobranins was evaluated by using the following indicator organisms: Bacillus subtilis B168, Escherichia coli MG 1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2. A 1 mL culture of Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2 with an OD600 of 1 .0 was spread on LB or YPD agar plates using a sterile cotton swab. The inventors inoculated a 2 mL pre-culture of the X. budapestensis wild-type strain, X. budapestensis PBAD rdb1A, X. budapestensis Δrdb1P PBAD rdb1A, X. budapestensis Δhfq PBAD rdb1A, X. budapestensis A hfq Δrdb1P PBAD rdb1A, X. budapestensis Δrdb1H PBAD rdb1A mutants to a 100 mL LB media separately with/without induction by 0.4% L-arabinose, followed by shaking at 120 rpm at 30 ºC for 72 h. The whole cultures were lyophilized and the resulting extract was resolved in 10 mL methanol. The cell particles were removed by centrifugation at 17.000 x g for 25 minutes and 10 μL of the supernatant was loaded onto a 3 mm sterile filter disk and dried under a clean bench. Disks were place on the agar plates. After incubation at 30 ºC for 16-48 h, the zones of inhibition were determined.
As shown in Fig. 8, in the top row of plates, a plate covered with selected bacterial or yeast film is inoculated at a single point with a single colony of X. budapestensis wild type (top row) that produces small amounts of rhabdobranins, or with inducible expression of rdb1A (labelled as X. budapestensis PBAD rdb1A), which can produce higher amounts of rhabdobranins. The colonies on the left side were induced with 0.4% L-arabinose (labelled with “+”, as opposed by those labelled with which have not been induced), leading to an increased production of rhabdobranins. Said increased production of rhabdobranins correlates with increased effect against B. subtilis, E. coli, M. luteus and S. cerevisiae (relevant differences are highlighted in white frames). In the second row, it is shown by using X. budapestensis Δrdb1P PBAD rdb1A strain that due to deletion of rdb1P produces only pre-rhabdobranins that said pre-rhabdobranins, similarly to rhabdobranins, show activity against P. luteus.
It has thus been demonstrated that the compounds of formula (I), including both the rhabdobranins and the pre- rhabdobranins provided herein, have a potent antimicrobial activity, which renders them highly advantageous for therapeutic use, particularly in the treatment or prevention of infectious diseases.
Example 4: Isolation of rhabdobranin
For the production and isolation of rhabdobranin, the X. budapestensis PBAD rdb1A mutant was cultivated in 12 L of lysogeny broth (LB) medium supplemented with 2% XAD, 0.2% arabinose, and kanamycin (50 μg mL"1). After production at 30 ºC and 180 rpm for 72 hours, the XAD was discarded to decomplex the culture matrix. The culture was centrifugated, filtrated, and freeze-dried. In the next step, 20g of the extract was solved in 500 mL of H2O adjusted to pH 11 .5 using triethylamine (TEA). For the first isolation step, a polymeric weak cation exchanger column (Phenomenex 5 g/60 mL XCW-33) was used. The conditioning step was started with 60 mL MeOH, followed by equilibration with 60 mL H2O (pH 11 .5 adjusted with TEA). The solved extract was loaded on the single-use plastic tube column. The column was washed two times with 120 mL H2O (pH 11.5 adjusted with TEA) and dried for 5 min. The elution was started by applying 60 mL ACN containing 7% formic acid, followed by 60 mL H2O/ACN (v:v 3:2, supplemented with 7% formic acid), then 60 mL H2O (supplemented with 7% formic acid) was used. Finally, 3 x 60 mL H2O supplemented with 10% formic acid was used for the elution of rhabdobranin, the second and third fractions were collected and freeze-dried, resulting in an extract mass of 117.3 mg. The subsequent isolation of the combined fractions was performed by using an Agilent 126011 1 nfinity semi-preparation HPLC with an isocratic gradient H2O/ACN (77:33 with 1% formic acid, 3ml/min, 40ºC) equipped with a Waters HILIC BEH Amide column 10x250mm. Rhabdobranin was detected at a retention time of 25.8 minutes and collected. The unified fractions were freeze-dried and 19.3 mg of rhabdobranin was obtained. NMR data is summarized in Table 6 as well as in Figure 9.
Figure imgf000047_0001
Table 6 1 1H (500 MHz) and 13C (125 MHz) NMR data assignments for rhabdobranin in D2O. The stereochemistry was predicted by analyzing the rdb1 BGC.
Figure imgf000048_0001
Figure imgf000049_0001
Example 5: Determination of mRNA translation inhibition
In order to visualize the impact of rhabdobranin on protein synthesis, a coupled transcription-translation cell-free system was used. Reactions were carried out in 10 μL of the purified components from the PURExpress In Vitro Protein Synthesis Kit (E6800S/L, NEB, Ipswich, Massachusetts) with 0.15 pM DNA encoding an E co// dihydrofolate reductase template, in presence of 0 pM to 4000 pM of rhabdobranin. These reactions were incubated at 37°C for 1 hour. After incubation, sample processing and fluorescent labelling were carried out as described by the Lumio Green Detection Kit (LC6090, ThermoScientific, Waltham, Massachusetts) for in vitro reactions. Finally, 10 μL of labelled samples were loaded into 20% SDS-PAGE gels and visualized under a Blue-light LED transilluminator with orange filter (Cleaver Scientific LTD, Warwickshire, UK). Gel quantification was performed by pixel densitometry analysis using Imaged software. The results are shown in Figure 10.
Example 6: Antimicrobial activity of pre-rhabdobranins and rhabdobranin against Bacillus subtilis B168, Escherichia coli MG1655, Micrococcus luteus, and Saccharomyces cerevisiae CEN.PK2
A disc diffusion assay was performed by applying either 5 μL (1), 10 μL (2) or 20 μL (3) of an aqueous 10 mM pre- rhabdobranins (a mixture in proportion as shown in Figure 6) or rhabdobranin solution. Water was applied as a control (C). The results are shown in Figures 11 A and 11 B. Zones of inhibition were observed for all tested strains, whereby the zones of inhibition against Micrococcus luteus showed the greatest diameters, followed by the zones against Bacillus subtilis B168, Escherichia coli MG1655 and Saccharomyces cerevisiae CEN.PK2. In case of Bacillus subtilis B168, Escherichia coli MG1655 and Micrococcus luteus a zone of inhibition was observed from the lowest applied rhabdobranin concentration, while the inhibition zones against Saccharomyces cerevisiae CEN.PK2 was observed from the second lowest applied rhabdobranin concentration. In case of Bacillus subtilis B168 and Micrococcus luteus a zone of inhibition was observed from the lowest applied pre-rhabdobranin concentration, while the inhibition zones against Escherichia coli MG1655 was observed from the highest applied rhabdobranin concentration.

Claims

1. A compound of formula (I):
Figure imgf000050_0001
wherein R1 is selected from -OH, -NH2, -O-(C1-6 alkyl), -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl) or a moiety of the formula:
Figure imgf000050_0002
wherein the alkyl in said -O-(C1-6 alkyl), the alkyl in said -NH(C1-6 alkyl), and any alkyl in said -N(C1-6 alkyl)(C1-6 alkyl) are each optionally substituted with one or more -OH and/or one or more -NH2; wherein R4 is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(C1-6 alkylene)-O-R41, -(C1-6 alkylene)-S-R41, -(C1-6 alkylene)-N(R41)-R41, -(C1-6 alkylene)-CO-R41, -(C1-6 alkylene)-COO-R41, -(C1-6 alkylene)-O-CO-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-CO-(C1-6 alkyl), -(C1-6 alkylene)-CO-N(R41)-O-R41, -(C1-6 alkylene)-O-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-CO-N(R41)-R41, -(C1-6 alkylene)-N(R41)-C(=N-R41)-N(R41)-R41, -(C1-6 alkylene)-SO3-R41, -(C0-6 alkylene)-carbocyclyl, and -(C0-6 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-6 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-6 al ky lene)-heterocycly I are each optionally substituted with one or more groups R42, wherein said alkyl, said alkenyl, said alkynyl, and any alkylene group comprised in any of the aforementioned R4 groups are each optionally substituted with one or more -OH, and further wherein each R41 is independently selected from hydrogen and C1-6 alkyl; wherein R2 is selected from hydrogen, an amino acid and a peptide; wherein R3 is hydrogen or a moiety of the formula:
Figure imgf000051_0001
wherein R5 is C1-22 alkyl or C2-22 alkenyl; and wherein each R42 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -OH, -O(C1-6 alkyl), -O(C1-6 alkylene)-OH, -O(C1-6 alkylene)-O(C1-6 alkyl), -(C1-6 alkylene)-OH, -(C1-6 alkylene)-O(C1-6 alkyl), -SH, -S(C1-6 alkyl), -S(C1-6 alkylene)-SH, -S(C1-6 alkylene)-S(C1-6 alkyl), -(C1-6 alkylene)-SH, -(C1-6 alkylene)-S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -NH-OH, -N(C1-6 alkyl)-OH, -NH-O(C1-6 alkyl), -N(C1-6 alkyl)-O(C1-6 alkyl), halogen, C1-6 haloalkyl, -O-(C1-6 haloalkyl), -ON, -NO2, -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO-NH(CI.6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(C1-6 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), -SO-(C1-6 alkyl), -(C0-4 alkylene)-carbocyclyl, and -(C0-4 alkylene)-heterocyclyl, wherein the carbocyclyl group in said -(C0-4 alkylene)-carbocyclyl and the heterocyclyl group in said -(C0-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, Ci-B haloalkyl, -O-(C1-6 haloalkyl), -ON, -OH, -O(C1-6 alkyl), -SH, -S(C1-6 alkyl), -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)(C1-6 alkyl), -CHO, -CO(C1-6 alkyl), -COOH, -COO(C1-6 alkyl), -O-CO(C1-6 alkyl), -CO-NH2, -CO-NH(C1-6 alkyl), -CO-N(C1-6 alkyl)(C1-6 alkyl), -NH-CO(C1-6 alkyl), -N(C1-6 alkyl)-CO(C1-6 alkyl), -NH-COO(C1-6 alkyl), -N(C1-6 alkyl)-COO(C1-6 alkyl), -O-CO-NH(C1-6 alkyl), -O-CO-N(C1-6 alkyl)(C1-6 alkyl), -SO2-NH2, -SO2-NH(C1-6 alkyl), -SO2-N(C1-6 alkyl)(Ci-0 alkyl), -NH-SO2-(C1-6 alkyl), -N(C1-6 alkyl)-SO2-(C1-6 alkyl), -SO2-(C1-6 alkyl), and -SO-(C1-6 alkyl); or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R1 is a moiety of the formula
Figure imgf000051_0002
and wherein R4 is selected from -CH2CH2-COOH, -CH2-COOH, -CH2-SO3H, -CH2CH2-CO-NH2, -CH2-CO- NH2, -CH2-NH2, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)4-NH2, -CH(-CH3)-(CH2)2-NH2, -C(-OH)-(CH2)3-NH2, -CH2-C(- OH)-(CH2)2-NH2, and -(CH2)2-C(-OH)-C(-CH2-OH)-NH2; preferably wherein R4 is selected from -CH2CH2-COOH and -(CH2)4-NH2.
3. The compound of claim 1 , wherein R1 is -OH or -NH-CH2CH2CH2CH2-NH2.
4. The compound of any one of claims 1 to 3, wherein R2 is hydrogen.
5. The compound of any one of claims 1 to 3, wherein R2 is selected from an amino acid and a peptide.
6. The compound of any one of claims 1 to 5, wherein R3 is hydrogen.
7. The compound of any one of claims 1 to 5 wherein R3 is a moiety of the formula
Figure imgf000052_0001
wherein R5 is C1-22 alkyl or C2-22 alkenyl, preferably wherein R5 is selected from: and
Figure imgf000052_0002
8. The compound of any one of claims 1 to 7, wherein said compound has the following absolute configuration:
Figure imgf000052_0003
9. The compound of claim 1, wherein said compound is any one of the following compounds or a pharmaceutically acceptable salt thereof:
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
wherein each R is independently selected from:
and
Figure imgf000056_0001
10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9 and a pharmaceutically acceptable excipient.
11. The compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 for use as a medicament.
12. The compound of any one of claims 1 to 9 or the pharmaceutical composition of claim 10 for use in the treatment or prevention of an infectious disease.
13. The compound for use according to claim 12 or the pharmaceutical composition for use according to claim 12, wherein said infectious disease is selected from a bacterial infectious disease, a protozoan infectious disease, and a fungal infectious disease.
14. A disinfectant comprising the compound of any one of claims 1 to 9.
15. Non-therapeutic use of the compound of any one of claims 1 to 9 or the disinfectant of claim 14 for disinfecting or sterilizing an inanimate object.
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