NZ624189B2 - Pharmaceutical compounds for use in the therapy of clostridium difficile infection - Google Patents

Pharmaceutical compounds for use in the therapy of clostridium difficile infection Download PDF

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NZ624189B2
NZ624189B2 NZ624189A NZ62418912A NZ624189B2 NZ 624189 B2 NZ624189 B2 NZ 624189B2 NZ 624189 A NZ624189 A NZ 624189A NZ 62418912 A NZ62418912 A NZ 62418912A NZ 624189 B2 NZ624189 B2 NZ 624189B2
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compound
independently
formula
carbon
group
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NZ624189A
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NZ624189A (en
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Bastien Castagner
Mattias Ivarsson
Jeanchristophe Leroux
Anna Pratsinis
Gisbert Schneider
Jean Christophe Leroux
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Eth Zurich
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Priority claimed from PCT/EP2012/004088 external-priority patent/WO2013045107A1/en
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Publication of NZ624189B2 publication Critical patent/NZ624189B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/20—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/093—Polyol derivatives esterified at least twice by phosphoric acid groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins

Abstract

Provided are poly-phosphate, polysulfate or mixed polyphosphate/sulfate derivatives of six-membered cyclic polyol compounds, of general formulae (1) and (15), wherein the variables are as defined in the specification. The compounds are analogues of inositol hexakisphosphate (IP6)/phytic acid. An example of the compounds is myo-inositol-pentakisphosphate-2-PEG(400). The compounds are enteric activators of Clostridium difficile toxin. The compounds are useful in the treatment of Clostridium difficile infection. mple of the compounds is myo-inositol-pentakisphosphate-2-PEG(400). The compounds are enteric activators of Clostridium difficile toxin. The compounds are useful in the treatment of Clostridium difficile infection.

Description

Pharmaceutical Compounds for use in the therapy of Clostridium difficile Infection Description The present invention s to enteric activators of Clostridium difi‘icile toxin, particularly poly- phosphate derivatives, polysulfate derivatives or mixed polyphosphate/sulphate derivatives of six— membered cyclic polyols.
C/ostridium difficile is a species of Gram-positive bacteria that causes severe diarrhoea in human patients. C. difficile ion (CDI) typically affects patients under antibiotic treatment since the bacterium is only able to ze the colon of patients with depleted bacterial flora. The emergence of otic-resistant strains of C. difficile causes increasingly severe ity and mortality due to the spread of new, more virulent s, with recent outbreaks in North America and Europe.
C. difficile asymptomatically colonizes 2-5% of the human adult population. The bacteria form spores, which are difficult to neutralize by common methods of disinfection. As a result, C. difficile infections are a common result of prolonged stays in hospitals; the pathogen is considered the leading cause of hospital-associated diarrhoea in the USA.
Current therapy of choice is oral application of metronidazole or, in case of e of the former, vancomycin. Since clinical symptoms of CDI are caused by two toxic proteins ed by C. difficile in the colon, rather than by the presence of the ia itself, efforts have been made recently to target these toxins (e.g. employing polymeric binders), but have so far failed in clinical trials.
C. le enterotoxin (toxin A, Tch) and cytotoxin (toxin B, Tch) are the main contributors to the symptoms of disease (for a toxin biology review, see Voth and Ballard, Olin/ca! Microbiology Reviews 2005, 18, 247-263). In brief, both toxins are composed of four domains, a first domain mediating the attachment of the toxin to cells; a second one facilitating translocation into the cytosol; a third domain causing the cleavage of the toxic domain by autoproteolysis, and finally the toxic domain or “warhead” itself, which causes the physiological effects of the toxin in the affected cell.
Reineke et al. (Nature 2007, 446, 415) identified myo-inositol hexakisphosphate (IP6) as the natural trigger of TodA/Tch ocessing in the cell l. Egerer et al. (PLoS Pathog. 2010, 6, 42) and Shen et al. (Nat. Struct. Mol. Biol. 2011, 18, 364) suggested targeting the IP6-induced autoprocessing mechanism as a means of therapeutic intervention against toxin—mediated enicity.
Kreimeyer et al. suggested using IP6 pharmaceutically to intervene in CDI (Naunyn-Schmiedeberg's Arch. Pharmacol. 2011 , 383, 253). However, this ch is not feasible as the presence of high calcium concentrations in the colon precipitates lP6 and ts it from being active.
Thus, the objective of the present invention is to provide improved ent options for patients suffering from CDI, or at least to provide a useful ative to known treatments for patients suffering from CDI. This objective is attained by the subject-matter of the independent claims.
Definitions The term alkyl or alkyl group in the context of the present invention signifies a saturated hydrocarbon moiety, which may be , branched, cyclic or cyclic with linear or branched side chains. The term alkyl includes partially unsaturated hydrocarbons such as propenyl. Examples are methyl, ethyl, n- or isobutyl, n- or cyclohexyl. The term alkyl may extend to alkyl groups linked or d by hetero atoms.
Hetero atoms in the context of the present invention are nitrogen (N), sulfur (S) and oxygen (0).
A C1-C3 alkyl in the context of the present invention signifies a saturated linear or ed hydrocarbon having 1, 2, or 3 carbon atoms, wherein one -carbon bond may be unsaturated and one CH2 moiety may be exchanged for oxygen (ether bridge). Non-limiting examples for a C1-C3 alkyl are methyl. ethyl, propyl, prop—Z-enyl and prop—Z-inyl.
A 01—05 alkyl in the context of the present invention signifies a saturated linear or ed hydrocarbon having 1, 2, 3, 4 or 5 carbon atoms, wherein one or two carbon~carbon bond may be unsaturated and one CH2 moiety may be ged for oxygen (ether bridge). Non—limiting examples for a 01-05, alkyl include the examples given for C1—C3 alkyl above, and additionally l, 2- methylpropyl, tent-butyl, 3-methylbut—2-enyl, 2-methylbut—3-enyl, 3-methylbutenyl, n-pentyl, 2- methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2—dimethylpropyi, but-S—enyl, but- 3-inyl and pentinyl.
A Ca-Cw alkyl in the context of the present invention signifies a saturated linear or branched hydrocarbon having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, wherein 1, 2 or 3 carbon-carbon bonds may be unsaturated and one CH2 moiety may be exchanged for oxygen (ether bridge).
A ccharide in the context of the present invention signifies a sugar sing three, four. five. six or seven carbon atoms. Examples are glyceraldehyde (C3), erythrose or threose (C4), arabinose, ribose or xylose (05) glucose, mannose, galactose or fructose (C6) or sedoheptulose (C7). The sugar alcohols and amino sugars of CS, C4, CS, C6 and C7 ccharides are ed in the group of monosaccharides according to the definition used .
An oiigosaccharide is a molecule consisting of two to ten of the same or different monosaccharides according to the above definition. A polysaccharide comprises more than ten monosaccharides.
A r of a given group of monomers is a homopolymer (made up of a multiple of the same monomer); a copolymer of a given selection of monomers is a heteropolymer constituted by monomers of at least two of the group.
The ion is based on a novel design of small—molecule analogues of lP6 that are provided as an oral therapy to trigger the cleavage of the toxin in the colon lumen, thereby detaching the warhead before it reaches its destination, and rendering it harmless. Since |P6 itself cannot be used for this purpose because it is not soluble at the high calcium concentrations found in the colon iumen, the present invention provides new ues of |P6 with improved solubility.
According to a first aspect of the invention, a pharmaceutical compound terized by a general formula (1) is provided, X 1 wherein R1 is or comprises a solubility function R2 selected from the group including - a polyethylene glycol ; - a ccharide, oligosaccharide or polysaccharide, - a ycerol, for example a polyglycerol described by the formula ((Ra-O-(CHg-CHOH- CHzo),.—) with R3 being hydrogen, methyl or ethyl, and n having a value from 3 to 200. or a branched or hyperbranched ycerol, such as may be described by the formula (Ra-O- (CHz-CHORS-CHg-O)n~) with R5 being hydrogen or a glycerol chain and R3 being hydrogen, ’10 methyl or ethyl; - a polymer or copolymer comprising a plurality of any of the monomers hydroxypropyl methacrylate (H PMA), hydroxyethyl methacrylate (HEMA), vinyl alcohol (VA), vinyl pyrroiidone (VP), N-isopropyl acrylamide (NlPAM) and/or PEG methacrylate (PEGMA) o NH 0 o 0% o NH o o \g H VA A 2““ OH OH VP >9 HPMA HEMA NlPAM PEGMA with n and m independently having a value from 3 to 200; — a tyrene-co—maleic acid/anhydride); - a Ca-Cm alkyl comprising at least three tuent functions independently selected from the group including an amine-, hydroxy-, thiol—, carboxylic acid, carboxylic amide, sulfonic acid or sulfonamide function, and each X independently is selected from OPOgQ', ', or 0803’, Z is an alkyl chain comprising 1 to 3 carbon and/or hetero atoms, optionally sing a group X, wherein X has the meaning defined above.
An amine function is a function NR'R”, with R’ and R” selected independently from hydrogen and C1- 05 alkyl. in some embodiments, R‘ and R” are selected from en and 01-03 alkyl. A hydroxy function is OH. A thiol function is SH. A carboxylic acid function is COOH or its anion, 000'. A carboxylic amide is CONR’R”, with R’ and R" independently having the meanings indicated above. A sulfonic acid is SOgH. A sulfonic acid amide is SOzNR’R", with R’ and R” independently having the meanings indicated above.
In some embodiments, said polyethylene glycol is described by a formula (Ra-(O-CHg-CH2)n-) with R3 being hydrogen. methyl or ethyl, and n having a value from 3 to 200. In some embodiments, n has a value from 3 to 20. In some ments, n has a value from 10 to 30. In some embodiments, n has a value from 9 to 45. In some embodiments, said polyethylene glycol is a branched polyethylene .
In some embodiments, R1 comprises an ether, her, carboxylic ester, amine. carboxylic amide, urea, sulfonamide, phosphoramide, phosphate ester, phosphorothioate, alkyl, triazole or ate on, or a combination of any of the preceding groups, which links R2 to the molecule.
In some embodiments, R1 is 3 CH2. 3 CH2CH2, a CHX, a CHXvCHz, a CHzCHX, a CHX-CHX, CHz-O or a CHX~O group linking R2 to the molecule.
In some embodiments, formula (1) describes a five-membered, six-membered or seven-membered alkyl ring and R1 is ntly attached to one of the carbon atoms forming the ring.
In some embodiments, R1 is ed to a CH group forming the ring. ing to another embodiment, R1 is attached to a CX group forming the ring (that is, a ring carbon can be represented by CXR‘, wherein X and FE1 have the meanings indicated above).
In some embodiments, R2 is a C3, C4, C5, 05, C7, or Cg alkyl group comprising three. four, five, six, seven or eight substituent functions ndently selected from the group including an amine-, hydroxy-, thioI-, carboxylic acid, carboxylic amide, sulfonic acid or sulfonamide function.
In some embodiments, R2 is a polyglycerol described by the formula ((Ra-O-(CHz-CHOH-CHZO)n-) with R3 being hydrogen, methyl or ethyl. and n having a value from 3 to 200. In some alternatives of these embodiments, n has a value from 3 to 20. In some alternatives of these embodiments, n has a value from 10 to 30. In some alternatives of these embodiments, n has a value from 9 to 45.
In some embodiments, R2 is a branched polyglycerol described by the formula (Ra-O~(CH2-CHOR5~ CH2-0)n—) with R5 being hydrogen or a linear glycerol chain described by the a (RS-O—(CHZ- CHOH~CH2-O)n-) and R3 being hydrogen, methyl or ethyl.
In some embodiments, R2 is a hyperbranched polyglycerol described by the formula (R3-O-(CH2- CH2—0)n—) with R5 being hydrogen or 3 ol chain described by the formula (R3~O-(CH2~ CHORs-CHz—O),,~), with R6 being hydrogen or a glycerol chain described by the a (Ra-O-(CHZ- CHOR7-CH2-O)n-), with R7 being hydrogen or a linear glycerol chain described by the formula (Ra-O- HOH~CH2-O)n-) and R3 being hydrogen. methyl or ethyl.
Hyperbranched glycerol and methods for its synthesis are described in Oudshorn et al., Biomaterials (2006), 27, 5471-5479; Wilms et aI., Acc. Chem. Res. (2010) 43, 129-41, and references cited therein.
In some embodiments, R2 is a polymer or copolymer comprising a plurality of any of the monomers hydroxypropyl methacrylate , hydroxyethyl methacrylate (HEMA), vinyl alcohol (VA), vinyl pyrrolidone (VP), N-isopropyl acrylamide (NIPAM) and/or PEG methacrylate (PEGMA) OH N 0 NH 0 o 0 o NH 0 R 017 VA A 2'" OH OH VP ask0 HPMA HEMA NIPAM PEGMA with n having a value from 3 to 200 and m having a value from 3 to 200. in some alternatives of these embodiments, n has a value from 3 to 20 and m has a value from 3 to 200. In some alternatives of these embodiments, n has a value from 10 to 30 and m has a value from 3 to 200. In some alternatives of these embodiments, n has a value from 20 to 50 and m has a value from 3 to 200. in some alternatives of these embodiments, n has a value from 3 to 200 and m has a value from 3 to 20, In some alternatives of these embodiments, n has a value from 3 to 200 and m has a value from 10 to . in some alternatives of these embodiments, n has a value from 3 to 200 and m has a value from to 50. in embodiments n the solubility function is attached to the compound directly, R1 equals (is) R2. in some ments, z is CH2, CHX, CHR‘, CXR1,CH2~CH2, CHz-CHX, CHX-CHX, CHR1-CHX, HX. CHR1—CH2. cxatcnz. CHR1—CHOH. z—CHz, CH2-O~CH2, CHOH—CHz-CHQ, CHOH-CHOH-CHR‘, CHOH-CHR1-CHOH, CHX-CHz—CHZ, CHz-CHX-CHZ, CHX-CHX-CHZ, CHX—CHZ- CHX or R1-CHX.
The solubility function provides for the solubility of the molecule in aqueous solution in the presence of mmol/l Ca2+. The molecule according to the ion has a higher solubility than |P6 in concentrations of calcium higher than 1 mmol/l; according to a preferred embodiment, the solubility of the molecule of the invention is above 10 .
In some embodiments, the pharmaceutical compound according to the invention is characterized by general a (2) wherein X and R1 have the meaning outlined above.
In some embodiments, the compound is characterized by a general formula (3), wherein X and R1 have the meaning outlined above: (3).
In some embodiments, the compound of the invention comprises a five— to seven—membered ring, wherein at least four ring members can be described by a formula CH-X, and one ring member can be described by a a Y—R1, with Y being CH or N, and R1 and each X ndently having the meaning defined above. in some embodiments, only one ring member can be described by a formula Y-R‘. in some embodiments, the compound of the invention has a five-membered circular structure, with four members of the ring described by a formula CH-X and one member described by a formula Y-R1, with X, Y and R1 as defined above. in some embodiments, the compound of the invention has a mbered circular structure, with five members of the ring bed by a formula CH-X and one member bed by a formula Y-R‘. with X, Y and R1 as defined above. In some embodiments, the nd of the invention has a seven—membered circular structure, with six members of the ring described by a formula CH-X and one member described by a formula Y-R1, with X, Y and R1 as defined above. in some embodiments, the compound of the invention is described by a formula (4). In some embodiments, it is described by formula (5) or formula (6). in some embodiments, such circular molecule according to the invention can be described by a general formula X X X Y X (4) (5) (6) wherein each X (independently), Y and R1 have the meaning defined above.
In one embodiment, (6) comprises a po|y(ethy|ene glycol) PEG400 as solubility function, with R1 being CH40CHTCHQ¢04 (\o/V \/\oo CPD? 0P0? \/\0/\/0 2- 203m opoa OPOS o/\/ \/\o myo-inositol-pentakisphosphate-Z—PEG(400) (7) is the PEGwo—analogue of myo-inositol hexaklsphosphate. (7) has proved to have an improved ability to cleave Tch CPD in the presence of calcium.
Another embodiment s to the o analogue to (7), Le. a PEG with approximately 45 ethylene glycol monomers.
Another embodiment s to an analogue to -inositol hexakisphosphate as described by formula (8) 0P0? 0P0;- R1 OP0: 03130 CPD; wherein R1 has the same meaning as outlined above. in some embodiments, the compound of the invention can be described by formula (8) and R1 is a poly(elhylene ) moiety.
The solubility function, a poly(ethylene glycol) (PEG) chain shown here as a non-limiting example. is attached to the molecule to render it soluble in the colon lumen, at the concentrations of calcium present therein.
According to a second aspect of the invention, an inositolhexakissulfate (lnositol hexasulfate; lSS) is provided for therapy or prevention of cm. A ularly red embodiment is myo— (11) or say/Io- inositolhexakissulfate (12). 030; i _ _ O!303 :oso; 0803 030; 030; ‘03so -0330%0305 oso; '0380 ( 11) 0303 (12) Although comparable to lP6 in structure and charge density, the t invention surprisingly shows that in the presence of calcium, lSB is much more active than lP6 (see Figure 4). lnositol hexakissulphate is available commercially (CAS No. 28434—25-5; inter alia, Santa Cruz Biotechnology, Santa Cruz, CA, USA). 2012/004088 According to a third aspect of the invention, a ceutical compound characterized by a general formula (15) is provided, (15) wherein each X independently is selected from OPOgZ‘, ', or 0803‘, with the proviso that not all X are opoaz‘ and not all x are 0303'.
According to a fourth aspect of the invention. the compound characterized in the previous paragraph by formula (15) is provided for use as a medicament, particularly for use in the prevention or therapy of infections by Clostridium dificile.
In some embodiments, the compound ing to this third aspect of the invention is characterized by a general formuia (153) or (15b), wherein X has the meaning ed above: XIII“:- (153) (myo) (15b) (scyl/o) in some embodiments, the compound according to this third aspect of the invention is characterized by the general formula (16a) or (16b), (16a) (16b) wherein a) X2 is 0803', and X1, X3, X4, X5 and X6 are independently selected from , OPSOzZ‘ or 080;; b) x‘, x3 and x5 are OPOgZ‘and x2, x4 and x8 are 0303‘ (Compound tea-b or iGb-b), c) x‘, x3 and x5 are 0803' and x2, x“ and x6 are oeoaz' und 16a—c or 16b-c), d) x“, X5 and x6 are 0803' and x1, X2 and X3 are oposz' (Compound 16a-d or 16b—d), e) X“, X5 and X6 are OPOgZ‘ and X1, Xzand X3 are 0803' (Compound iBa-e or 16b-e). r) x2 and x5 are opof‘ and x‘, x3, x“, and x6 are 0303' (Compound 16a—f or 16b-f), g) X2 and X5 are 0803‘ and X1, X3, X4, and X6 are OPO32' (Compound 16a-g or 16b—g), n) x2 and x3 are opof‘ and x‘, x4, x5, and x6 are 0303' (Compound tGa-h or 16b-h), or i) x2 and x3 are 0803‘ and x‘, x4, x5, and x6 are opos‘i‘ (Compound 16a-i or 16b-i).
The compounds d above can be synthesized according to standard methods. The synthesis of compound 16a-b is described in the examples of the present invention. ing to another aspect of the invention, a compound according to any of the above aspects of the ion, in the broadest definition given, or as specified in any of the embodiments, is provided for use as a medicament.
According to yet another aspect of the invention, a compound ing to any of the above aspects of the invention, in the broadest definition given, or as ed in any of the embodiments, is provided for use in the treatment or prevention of C. difi‘icile infection.
A compound according to the invention may be given to a patient already diagnosed with CDi, or to a patient being suspected of suffering from CDI. Alternatively, the nd may be used as a prophylactic for patients that are at risk of contracting the infection, such as ts under antibiotic treatment in hospitai settings. The compounds according to the invention are simple to synthesize, resistant to degradation in the gastro~intestinal tract and unlikely to be absorbed into the bloodstream, thus avoiding potential side effects. The compounds according to the invention do not need to penetrate mammalian or bacterial membranes to be active, which makes them more effective in vivo. in addition, the compounds according to the invention are ly to exert selective pressure on the bacteria and therefore avoid problems related to resistance.
According to yet another aspect of the invention, a pharmaceutical composition for use in a method for the prevention or treatment of C. difficile infection is provided, comprising a compound according to any of the above aspects of the invention.
Preferred ceutical itions comprise from approximately 1% to approximately 95% active ingredient. preferably from imately 20% to approximately 90% active ingredient.
A pharmaceutical composition according to the above aspects of the invention can be administered alone or in combination with one or more other'therapeutic . A combination therapy may take the form of fixed ations of the compound of the invention and one or more other antibiotic agents. Administration may be staggered; alternatively drugs may be given independently of one another, or as a fixed combination.
According to a preferred embodiment, a pharmaceutical composition comprises a compound ofthe invention according to any of the above aspects of the ion, and onally metronidazole, ycin and/or lcin.
According to yet another aspect of the invention, a dosage form is ed comprising a compound according to any of the above aspects of the invention. A perorai formulation, ularly a , syrup, on, capsule or powder is preferred.
According to a preferred embodiment, such a dosage form additionally comprises an antibioticaliy active compound, such as (by way of non-limiting example) metronidazole, vancomycin or fidaxomicin.
According to yet another aspect of the invention a treatment regime is provided for the prevention and treatment of CDI, comprising the administration of a compound according to the invention.
Administration may be effected by any of the means described herein.
Also within the scope of the present invention is a method for the prevention or treatment of CDI, comprising the administration a compound according to the invention to a subject in need thereof.
Similarly, a compound ing to the invention is provided for the manufacture of a medicament for the prevention and treatment of CDl. ments according to the invention are manufactured by methods known in the art, especially by conventional mixing, coating, granulating, dissolving or lyophilizing.
Wherever alternatives for single features such as R1, R2, X etc. are laid out herein as “embodiments”, it is to be understood that such alternatives may be combined freely to form discrete embodiments of the entire molecule ed as such or for use in a method or medical indication herein. Thus, any of the alternative embodiments for R1 may be combined with any of the alternative embodiments of Z or any of the ring structures ed in the formulae mentioned herein.
Short description of the figures Fig. 1 showo the tration dependence of cleavage of Tch cysteine protease domain in the presence of activator compound (7) (empty circles) or lP6 in vitro (1A), and the corresponding kinetics (13) in 10 mM Ca2+.
Fig. 2 shows the concentration dependence of cleavage of Tch cysteine protease domain in the presence of activator compound (7) (empty circles), its PEGZOOO analogue (empty triangles), and its methyl analogue (black squares).
Fig. 3 shows the synthesis of compound 7.
Fig. 4 shows the concentration dependence of cleavage of Tch cysteine protease domain in the presence of 10 mM Ca2+ for activator compound (11); tor data shown as empty circles; 1P6 control as black squares.
Fig. 5 shows the sis of compound (16a-b).
Fig. 6 shows the concentration dependence of cleavage of Tch cysteine protease domain in the presence of 10 mM Caz+ for tor compound (16a-b). 1. Synthesis of compound (7) The synthesis followed the sequence depicted in Fig. 3.
Compound B: To a suspension of sodium hydride (4.3 mmol, 103.7 mg) in 10 mL dimethylformamide (DMF) was added a solution of compound A [Martin, S. F. et at, J. Org. Chem. 1994, 59, 4805} (2.16 mmol, 1363 mg) in DMF (10 mL) dropwise. When the addition was complete the e was stirred for 30 min at room temperature, ed by addition of MeO—PEG-OTs (OTs being toiuenesulfonate) (3.2 mmol, 1.64 g in 10 mL DMF). The reaction was allowed to stir overnight, then quenched with water (5 mL). The mixture was extracted with dichloromethane (DCM). The solvent was evaporated and the residue was chromatographed on silica gel with six 100 mL portions of 20:80; 30:70; 40:60; 60:40; 80:20; 100:0 of ethylacetatezhexanes. The chromatography resulted in the fractionation of product with different PEG sizes, including compound B with an average of9 PEG units. 1H NMR (400 MHz; : 6 7.29—7.13 (m, 25H), 4.83 (d, J = 10.8 Hz, 2H), 4.79 (s, 2H), 4.74 (d, J = 10.8 Hz, 2H), 4.63 (d, J = 11.7 Hz, 2H), 4.59 (d, J = 11.6 Hz, 2H), 3.97-3.88 (m, 5H), 3.64-3.42 (m, 31H), 3.38 (t. J: 9.2 Hz, 1H), 3.29-8.25 (m, 5H).
Compound C: Compound B was dissolved in a mixture of ydrofuran (THF, 4 mL), methanol (7 mL) and water (3 mL), followed by addition of excess 10% ium on charcoal. The mixture was placed under a hydrogen atmosphere and stirred overnight at room temperature. The reaction mixture was then purged with nitrogen, filtered and the solvent evaporated. The crude mixture was purified on a reverse phase cartridge (Sep-Pak, , 19, C18, Cat.# WAT 036905) by eluting with 10 mL water.
All fractions (1 .5ml) were lyophilized and analyzed by 1H NMR is. 1H NMR (400 MHz; D20): 6 3.96-3.94 (m, 2H), 3.89 (t, J = 2.8 Hz, 1H), 3.78—3.69 (m, 28H), 3.69-3.60 (m, 5H). 3.56 (dd, J = 10.0. 2.8 Hz, 2H), 3.40 (s, 3H), 3.25 (t, J = 9.2 Hz, 1H).
Compound D: nd C (0.2 mmol, 119 mg) was suspended in tetrazole (3.630 mmol, 8.1 mL, 0.45 M in CchN) and DCM (10 mL) then NN—diethyl-t,5-dihydro~2,4,3-benzodioxaphosphepin-3~ amine (1.8 mmol, 434 mg) was added and the mixture was stirred at room temperature overnight. The mixture was then cooled to ~10°C and a solution of meta~ch|oroperoxybenzoic acid (mCPBA, ed over NaZSOA, 4.8mmol, 1189 mg) in DOM (2 mL) was added. The mixture was allowed to stir at -10°C for an additional 10 min, and then it was brought to room temperature and stirred for 1 hour. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layers were dried with Na2804, filtered and concentrated. The residue was chromatographed on silica gel with a gradient of 1-5% methanol in DCM. [H NMR (400 MHz; CDCIg): 6 7.41-7.27 (m, 18H), 7.21 (dd, J = 6.9, 1.7 Hz, 2H), 5.59-5.51 (m, 6H), 5.44 (t. J = 14.2 Hz, 2H), 5.37-5.29 (m, 6H), 5.25-4.95 (m. 10H), 4.74 (ddd, J: 9.9. 7.6, 2.1 Hz, 2H), 4.61 (t, J = 2.2 Hz, 1H), 4.03 (t, J = 4.9 Hz. 2H), 3.68-3.50 (m, 22H), 3.48 (dd, J = 6.1, 4.0 Hz, 2H), 3.40-3.34 (m, 7H). 13C NMR (101 CI3):6135.78, . 135.4, 135.14, 134.99, , 129.27, 129.26, 129.22, 129.14, 129.11, 128.96, 128.95, 77.6, 76.05, 76.01, 73.8, 71.9, 70.67, 70.60, 70.57, 70.54, 70.53, 70.49, 70.38, 70.34, 70.29, 69.46. 69.39, 69.33, 69.24, 69.16. 69.01, 68.95, 59.0 Compound (7): Compound D was dissolved in a mixture of THF (1 mL), methanol (1.5 mL) and water (2 mL), followed by addition of excess 10% palladium on charcoal. the mixture was placed under an hydrogen atmosphere and stirred overnight at room temperature. The mixture was then purged with nitrogen, d and concentrated. The compound was brought at pH 7 by addition of dilute aqueous NaOH (1700i, 0.1M). The residue was purified on a ex column (PD—10, GE Healthcare, Sephadex G-25 M, cat.# 1701) by eluting with 10ml of water. All fractions (1.5 mL) were Iyophilized and analyzed by 1H NMR. The fractions containing product were d further on a reverse phase cartridge (Sep-Pak, Waters, 19, C13, cat.# WAT 036905) by eluting with 10 mL water.
All fractions (1.5ml) were lyophilized and analyzed by 1H NMR analysis. 1H NMR (400 MHz; 020): a 4.44 (q, .I = 9.4 Hz, 2H), 4.20 (s, 1H), .10 (m, 3H), 4.06 (t, r = 4.7 Hz, 2H), 3.83-3.63 (m, 26H), 3.40 (s, 3H). 31P NMR (162 MHz;D20):61.5, 1.2, 0.8 2. ination of EC50 in presence of 10 mM Ca2+ The compound to be tested was added to a recombinant His-tagged cysteine se domain of C. difficile toxin B ofSEQ D 1 in presence of 10 mM Ca2+ in 100 mM Tris pH7.4 and incubated for 2 h at 37°C. Cleaved protein fragments were separated by SDS-PAGE and visualized by Coomassie staining. The extent of cleavage fied from protein band ities using the image.) re package. Signals were normalized to cleavage of positive and negative controls.
The results of this assay for PG and compound (7) are shown in Fig. 1A. These demonstrate that 50 % the cleavage of toxin fragment is achieved at similar concentrations of [PB and (7). The activity of lP6 disappears almost completely at 100 pM whereas (7) retains residual activity. The PEG chain of (7) likely s the molecule with a wider window of solubility. 3. Comparison of cleavage kinetics The compound to be tested was added to the His-tagged cysteine protease domain of C. ile toxin B (same sequence as given above) in ce of 10 mM Ca2+ in 100 mM Tris pH 7.4 and incubated for 24 h at 37°C, with aliquots removed at regular intervals. Cleaved protein fragments were ted, Visualized and analyzed as indicated above. The results of this assay for IP6 and compound (7) are shown in Fig. 18. They demonstrate that the extent of cleavage after 4 h is 5-fold higher with (7)than with IP6. 4. Synthesis of compound “Ga-bi Compound F: A solution of 2,4,6-tri-O-(4-methoxybenzyI)-myo-inositol (E) [0 Lampe, C. Liu, B. V. L.
Potter, J. Med. Chem. 1994, 37, 907] (0.541 g, 1 mmol, 1 eq.) in dry CH2C|2 (20 ml. 0.05 m) under an atmosphere of nitrogen was treated with tetrazole in acetonitrile 0.45 m (20.0 ml, 9.0 mmol, 9 eq.) and lene-N,N-diethylphosphoramidite (6 mmol, 1.44 g, 6 eq.). The reaction mixture was stirred at r.t. for 2 days. A solution of mCPBA (12 mmol. 2.07 g, 12 eq.) dried over Na2304 was added at -10 °C and the reaction e was stirred at r.t. for an additional 45 min. The mixture was then diluted in EtOAc, washed with a saturated solution of aqueous NaHCOa and with brine. The organic phase was dried over Na2804, filtered and concentrated in vacuo. ation by flash chromatography (SiOz, CHzclziMeOl-i gradually from O % to 4 %, three times) afforded 2,4,6-tri-O-(4-methoxybenzyl)-1,3,5-tri~ O-(o-xylylenephospho)myo-inositol (F) as a white solid (98 %). 1H NMR (400 MHz, CDCI3) 6 (ppm) 7.26-7.36 (12H, m), 7.19-7.22 (2H, m), 7.12-7.17 (4H, m), 6.66 (2H, d, J 8.5 Hz), 6.71 (4H, d, J 6.5 Hz), 5.25 (1H, d, .1 13.6 Hz), 5.21 (1H, d, J 13.6 Hz), 5.15 (1H, d, J 13.7 Hz), 5.11 (1H, d, J 13.7 Hz), 4.91-5.08 (8H, m), 4.83—4.89 (4H, m), 4.69-4.61 (3H, m), 4.57 (1H, q, J92 Hz), 4.38 (2H, ddd, J 2.4, 8.1, 9.5 Hz), 4.10 (2H, t, J 9.5 Hz), 3.78 (3H, s), 3.72 (6H, s); 13C NMR (125 MHZ, CDClg) 6 (ppm) 159.3, 159.1, 135.4, 135.3, 135.2, 130.8, 130.3, 129.7, 129.6, 129.2, 129.13, 129.12, 129.0, 128.9, 1O 128.6, 113.74, 113.57, 80.6 (61, J06 6.0 Hz), 78.1 (dd, Jcp 6.9, 3.2 Hz) 77.6, 77.1 (m), 76.0, 74.9, 68.8, 68.70, 68.68, 66.62, 68.34, 68.28, 55.4, 55.3; 31P NMR (160 MHz, 1H-decoupled, opera) 6 (ppm) 1.10, -1.32.
Compound 6: Compound F (97 mg, 0.089 mmol) was dissolved in 1 mL dichloromethane. Added 6 mL of a 5:1 mixture of oroacetic acid-water. Stirred 25 min and then diluted with 10 mL toluene and concentrated under vacuum. The resulting residue was trlturated with hexane and dichloromethane and then dried under high vacuum. Yielded 68 mg of crude compound G that was used directly in the next step.
Compound H: Compound G (39 mg, 0.054 mmol) was dissolved in 3 mL DMF and SOa~Et3N (195 mg, 2O 1.07 mmol) was added. The solution was stirred overnight at 50°C and concentrated on a rotavap. The residue was dissolved in 6 mL water, filtered and loaded on three Vac Soc 19 tC18 Sep-Pak cartridges (Waters). The columns were eluted with a gradient from 0-40% MeOH/HZO. Yielded 32 mg of H. 1H NMR (400 MHz; MeOD): 6 7.45-7.40 (m, 4H), .33 (m, 4H), .24 (m, 2H), 7.21-7.19 (m, 2H), 5.69-5.60 (m, 4H), 5.47 (dd, J = 13.2, 10.4 Hz, 2H), 5.41 (t, J = 2.9 Hz, 2H), 5.40—5.35 (m, 2H), .16 (m, 1H), 5.11—4.97 (m, 5H), 4.90481 (m, 2H), 3.24 (q, J = 7.3 Hz, 17H), 1.32 (t, J: 7.3 Hz, 25H). 130 NMR (101 MH'z; MeOD/CDCI3)16 131.6, 131.2, 125.26, 125.21, 125.09, 124.93, 124.87, 124.78, 70.25, 70.22, 70.19, 69.95, 69.90, 65.18, 65.11, 65.07, 65.00, 64.85, 64.78, 42.4, 4.2; 31P NMR (162 MHZ; MeOD/CDClg): 6 -7.8, -8.9 Compound PSPSPS ((16a)b): Compound H (32 mg) was dissolved in 3 mL H20. A small scoop of Pd 3O on ted carbon (10%) was added, the mixture was placed under a H2 atmosphere and stirred for 4 h. The mixture was then purged with N2 and a drop of NH4OH was added. The mixture was filtered though celite and ated on a rotavap. The e was dissolved in 1 mL water, loaded on a Vac Soc 19 tC18 Sep-Pak cartridge (Waters) and eluted with water. The eluted fractions were lyophilized and analyzed by 1H NMR. Yielded 16 mg of PSPSPS-ZEt3NH+-XNH4+. 1H—NMR (400 MHz; D20): 6 4.93-4.78 (m, 3H), 4.55-4.39 (m, 3H), 3.13 (q, J = 7.3 Hz, 14H), 1.21 (t, J : 7.3 Hz, 21H). 31P NMR (162 MHz; D20): 6 -0.3, -0.7.
The cleavage induced by compound PSPSPS ((16a-b) was determined in the ce of calcium as bed in example 2 and the result is shown in Fig. 7. The cleavage induced by this derivative was 50% at a tration of 20 pM, which is more efficient than lP6 (601 pM). This result shows that the 40 presence of some sulfate groups enhances the activity of the compound in the presence of calcium.

Claims (15)

Claims
1. A compound described by a general a (1) X 1 wherein R1 is a solubility function R2 selected from the group including - a polyethylene glycol; and — a polyglycerol; each X independently is selected from OPO32', opsof: ‘ or 0503'; and Z is an alkyl chain comprising 1 to 3 carbon and/or hetero atoms, wherein each carbon and/or heteroatom is optionally and independently tuted by a group X as defined above
2. A nd according to claim 1, wherein the compound is described by a general formula and wherein X and R1 have the meaning ed in claim 1.
3. A compound according to claim 1 or 2, wherein the compound is described by a general formula (3), and wherein X and R1 have the meaning outlined in claim 1: (3).
4. A compound according to claim 1, n the compound comprises a five- to seven- membered ring, at least four ring members can be described by a formula CH—X, and one ring member can be described by a formula Y—R‘, with Y being CH or N, and R1 and each X independently having the g defined in claim 1.
5. A compound according to claim 4, wherein the compound is described by a general formula (4), (5) 0r (6), (4) (5) (6) wherein each X independently and R1 have the meaning defined in claim 1, and Y has the meaning defined in claim 4.
6. A compound according to claim 1, which is myo—inositol—pentakisphosphate—Z—PEG(400).
7. A compound described by a l formula (15) (15) wherein each X independently is selected from OPOgZ‘, OPSOZZ', or 0803‘, with the proviso that not all X are CFO? and not ail X are 0803'.
8. A compound according to claim 7, n the compound is described by a general formula (15a) or (15b), (158) (15b).
9. A compound according to claim 7 or 8, wherein the compound is described by the general a (16a) or (16b), (16a) (16b), wherein a) X2 is 0803”, and X1, X3, X4, X5 and X6 are each independently selected from 0P032', OPSOZZ' or 0503‘; b) X, x3 and x5 are OPOf‘and x2, X4 and X6 are 0803‘ c) x‘, X3 and X5 are 0803' and x2, x4 and x6 are opof' d) x4, X5 and x6 are 0803‘ and x1, x2 and x3 are , e) x4, x5 and x6 are oposz' and x‘, x2 and x3 are osog'or f) X2 and x5 are OPO32' and x1, x3, x4, and X6 are 0503‘, g) x2 and x5 are 0803‘ and x‘, x3, x4, and x6 are Opof‘, h) x2 and x3 are opof' and X1, x4, x5, and x6 are 0303‘, or i) x2 and x3 are 0503' and x1, x4, x5, and x6 are 0P032‘.
10. Use of a compound described by a general formula (1) X R1 R1 comprises a solubility function R2 selected from the group comprising a polyethylene glycol or a polyglycerol, each x independently is selected from opof‘, opsof', or 0303‘; and Z is an alkyl chain comprising 1 to 3 carbon and/or hetero atoms, wherein each carbon and/or hetero atom is ally and independently substituted by a group X as defined above, or a compound according to any one of claims 6 to 9, in the manufacture of a ment for the prevention or therapy of C. difficile infection.
11. A dosage form, comprising a compound described by a general formula (1) X 1 wherein R1 comprises a solubility function R2 selected from the group comprising a polyethylene glycol or a polyglycerol, each X independently is selected from OPO32', OPSOgZ‘, or 0803’; and Z is an alkyl chain comprising 1 to 3 carbon and/or hetero atoms, wherein each carbon and/or hetero atom is optionally and independently tuted by a group X as d above, or sing a compound according to any one of the claims 6 to 9.
12. A dosage form according to claim 11, further comprising an antibiotic.
13. A dosage form according to claim 12, wherein the antibiotic is metronidazole, vancomycin or fidaxomicin.
14. A dosage form according to any one of claims 11 to 13 as a tablet, capsule, solution, powder or syrup.
15. The nd according to claim 1, substantially as herein described with reference to any one of the Examples and/or
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