WO2014195718A1 - Dérivés de 3,4-dihydroxy-pyrroles servant d'agents antibactériens - Google Patents

Dérivés de 3,4-dihydroxy-pyrroles servant d'agents antibactériens Download PDF

Info

Publication number
WO2014195718A1
WO2014195718A1 PCT/GB2014/051744 GB2014051744W WO2014195718A1 WO 2014195718 A1 WO2014195718 A1 WO 2014195718A1 GB 2014051744 W GB2014051744 W GB 2014051744W WO 2014195718 A1 WO2014195718 A1 WO 2014195718A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound according
hydrogen
ring
groups
Prior art date
Application number
PCT/GB2014/051744
Other languages
English (en)
Inventor
Peter William Andrew
Mafalda Pires DAMASO
Mark William DAVIES
Daniel HAMZA
Simon Christopher Hirst
Rana LONNEN
Alan David Borthwick
Premji Meghani
Fritz-Frieder Frickel
Original Assignee
University Of Leicester
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Leicester filed Critical University Of Leicester
Publication of WO2014195718A1 publication Critical patent/WO2014195718A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to compounds which are prodrugs of cytolysin inhibitors and their use in therapy, including in pharmaceutical combinations, especially in the treatment of bacterial, e.g. pneumococcal, infections.
  • Streptococcus pneumoniae (pneumococcus) is one of the most potent human pathogens, affecting over 10 million people worldwide, of all age groups, in particular young children, the elderly and the immunocompromised. It is a leading causative agent of serious, often fatal diseases, such as pneumonia, bacteraemia and meningitis. It is also responsible of other less serious, but nevertheless debilitating diseases such as otitis media and keratitis.
  • pneumococcal products the most important of which is the pneumococcal toxin pneumolysin.
  • This toxin is a major player in pneumococcal virulence and is the primary direct and indirect cause of toxaemia.
  • Pneumolysin belongs to the family of cholesterol dependent cytolysins (CDCs), which bind to cholesterol containing membranes and generate large pores that have lethal and sub-lethal effects on the affected cells.
  • CDCs cholesterol dependent cytolysins
  • the toxin pneumolysin is cytoplasmic and is mainly released from the pneumococcus after its lysis. Consequently, under the effect of lytic antibiotics, a large bolus of toxin is released, compounding the toxaemia.
  • lytic antibiotics a large bolus of toxin is released, compounding the toxaemia.
  • This toxaemia constitutes a substantial unmet medical need that is internationally recognised.
  • pneumolysin constitutes a potential therapeutic target to develop new
  • pneumococcal keratitis and the therapeutic benefit obtained following its inhibition.
  • cholesterol is not considered as a therapeutic agent for the treatment of pneumococcal diseases and has not been clinically used in patients.
  • Another pneumolysin inhibitor, Allicin, a component in garlic extract has been previously found to inhibit the haemolytic activity of pneumolysin in vitro [Toxicon (2011) 57 540-545].
  • This compound is a cysteine inhibitor that irreversibly binds to the reactive thiol group of the toxin. Compounds exhibiting such a property are unfavourable as drug candidates because of their potential unspecific binding to other cysteine-containing proteins in the body.
  • cytolysins such as pneumolysin
  • the present invention provides novel N- substituted pyrrole cytolysin inhibitors.
  • compounds of the present invention are expected to prevent stimulation of host-derived toxic effects induced by pneumolysin and, it may be assumed, other cholesterol dependent cytolysins. Thus these compounds may be used as single agents or as adjunct to antibiotics, to prevent or attenuate pneumolysin-induced toxicity and its anti-host effects seen during infections caused e.g. by S. pneumoniae.
  • R 1 is -C(0)NR 5 R 6 or-C(0)OR 7 ;
  • R 2 is -C(0)NR 5 R 6 or -C(0)OR 7 ;
  • R 3 is an optionally substituted moiety selected from:
  • R 4a and R 4b are independently selected from hydrogen; C C 6 alkyl which alkyl group may optionally be substituted by hydroxyl, COOR 12 or CONR 13 R 14 ; aryl and -C C 3 alkylaryl in which said aryl groups may be optionally substituted;
  • R 5 and R 6 are independently selected from:
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 5 -Ci 0 cycloalkenyl,
  • R 5 and R 6 together with the N to which they are attached may form a 5- or 6-membered heterocyclic ring optionally containing a further heteroatom selected from O, S and NR 9 , in which any of the aforementioned R 5 and R 6 groups may be optionally substituted by a group selected from cyano, C C 6 alkoxy, C C 6 fluoroalkoxy, Ci-C 6 alkyl, C C 6 fluoroalkyl and -C(0)NR a R b , where R a and R b are independently selected from hydrogen and C C 6 alkyl, and any of the aforementioned R 5 , R 6 and R g groups may be optionally substituted by one or more halogen atoms, and
  • R 7 is selected from:
  • Ci-C 6 alkyl C 2 C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyl, C 5 -Ci 0 cycloalkenyl,
  • R 7 groups may be optionally substituted by a group selected from cyano, C C 6 alkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, C C 6 fluoroalkyl and -C(0)NR a R b , where R a and R b are independently selected from hydrogen and C C 6 alkyl, and any of the aforementioned R 7 groups may be optionally substituted by one or more halogen atoms, and
  • R 9 is hydrogen, C C 6 alkyl, -C(0)R 10 or -C(0)OR 11 ;
  • R 10 is Ci-C e alkyl
  • R 11 is Ci-Ce alkyl
  • R 12 is Ci-C e alkyl
  • R 13 is hydrogen or C C 6 alkyl
  • R 14 is hydrogen or C C 6 alkyl
  • the compounds of formula (I) have therapeutic activity.
  • the present invention provides a compound of formula (I) for use as a medicament.
  • R 1 and R 2 may be the same or different.
  • R 1 and R 2 are independently -C(0)NR 4 R 5 , and may be the same or different, preferably the same. In a further embodiment R 1 is -C(0)NR 4 R 5 and R 2 is -C(0)OR 7 .
  • R 3 is an optionally substituted moiety selected from:
  • R 3 is a substituted moiety. In one embodiment R 3 is not a substituted moiety.
  • Example 5- or a 6-membered heteroaromatic ring containing one to three heteroatoms selected from O, N and S that R 3 may represent, which may optionally be substituted, include the following:
  • Example naphthalene rings that R 3 may represent include the following: 9 or 10 membered bicyclic heteroaromatic rings containing one to three heteroatoms selected from O, N and S, one or more of said heteroatoms being present in one or both rings, that R 3 may represent, will be fully aromatic.
  • such rings include a phenyl ring.
  • R represents a 9 or 10 membered bicyclic heteroaromatic rings containing one to three heteroatoms selected from O, N and S, suitably the point of attachment to the pyrrole ring shown in the structure of formula (I) is within a phenyl ring.
  • R 3 examples include the following:
  • R 3 represents a 5- or a 6-membered heteroaromatic ring containing one to three heteroatoms selected from O, N and S fused to a 5-6 membered unsaturated or partially saturated carbocyclic or heterocyclic ring
  • R 3 represents a 6-membered heteroaromatic ring containing one to three heteroatoms selected from O, N and S fused to a 5-6 membered unsaturated or partially saturated carbocyclic or heterocyclic ring.
  • R 3 moieties that may be mentioned, which may optionally be substituted, include the following:
  • R 3 moiety that may be mentioned, which may optionally be substituted, is the
  • Suitable optional substituents for R 3 include 1 or more, e.g. 1 , 2 or 3, substituents (e.g. 1 substituent) independently selected from oxo, halo, cyano, hydroxyl, C C 6 alkoxy, C C 6 alkylthio, C C 6 hydroxyalkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, C C 6 fluoroalkyl, -S(0) 2 NR a R b , - C(0)NR a R b , where R a and R b are independently selected from hydrogen and C C 6 alkyl, and - OAr* wherein Ar*is a phenyl ring or a 5 or 6 membered heteroaryl, which phenyl or heteroaryl may optionally be substituted by CrC 4 alkyl or halogen.
  • substituents e.g. 1 substituent
  • substituents independently selected from oxo, halo, cyano, hydroxyl,
  • Ar* is a phenyl ring which may optionally be substituted by C C 4 alkyl or halogen and is preferably unsubstituted.
  • R 3 More suitable optional substituents for R 3 include 1 or more, e.g. 1 , 2 or 3, substituents (e.g. 1 substituent) independently selected from halo, cyano, hydroxyl, C C 6 alkoxy, C C 6 alkylthio, Ci-C 6 hydroxyalkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, C C 6 fluoroalkyl, -S(0) 2 NR a R b and - C(0)NR a R b , where R a and R b are independently selected from hydrogen and C C 6 alkyl.
  • substituents e.g. 1 substituent
  • substituents independently selected from halo, cyano, hydroxyl, C C 6 alkoxy, C C 6 alkylthio, Ci-C 6 hydroxyalkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, C C 6 fluoroalkyl, -S(0) 2 NR a R b and -
  • Optional substituents may, for example, be selected from halogen, C C 4 alkyl and C C 4 alkoxy.
  • R 3 moieties that may be mentioned include the following:
  • R 3 represents a phenyl ring fused to a 5-6 membered saturated heterocyclyl ring, the point of attachment to the pyrrole ring in the structure of formula (I) being elected from:
  • R 4a and/or R 4b are substituted by hydroxyl, COOR 12 or CONR 13 R 14 , examples of R 4a and/or R 4b groups include -CH 2 COOt-butyl, CH 2 CONH 2 and CH 2 CH 2 OH.
  • R 4a and R 4b may be independently selected from hydrogen; C C 6 alkyl which alkyl group may optionally be substituted by hydroxyl, COOR 12 or CONR 13 R 14 ; and -C C 3 alkylaryl in which said aryl groups may be optionally substituted.
  • R 4a and R 4b are preferably independently selected from hydrogen, C C 6 alkyl, aryl and -CrC 3 alkylaryl in which aryl may be optionally substituted.
  • R 4a and R 4b are preferably independently selected from hydrogen, C C 6 alkyl and - C1-C3 alkylaryl in which aryl may be optionally substituted.
  • R 4a and R 4b are more preferably hydrogen or -C1-C3 alkylaryl, e.g. benzyl. Most preferably R 4a and R 4b are hydrogen.
  • R 5 and R 6 are preferably independently selected from hydrogen, C C 6 alkyl e.g. methyl, ethyl, or propyl, aryl e.g. phenyl, or C1-C 3 alkylaryl, e.g. benzyl in which said aryl may be optionally substituted, or R 5 and R 6 together with the N to which they are attached may form a 5- or 6- membered heterocyclic ring optionally containing a further heteroatom selected from O, S and NR 9 , e.g. morpholine, piperidine or piperazine (optionally N substituted with an R 9 group).
  • one of R 5 and R 6 is hydrogen.
  • at least one of R 5 and R 6 is not hydrogen, more preferably both of R 5 and R 6 are not hydrogen.
  • R 9 is not hydrogen.
  • R 6 groups of interest include NMe 2 , NHethyl, -N-morpholinyl and N-piperidinyl, especially NMe 2 .
  • R 7 is preferably C C 6 alkyl e.g. methyl, ethyl, propyl or butyl, such as / ' so-propyl or te/f-butyl.
  • R 9 is preferably hydrogen, methyl, COCH 3 or -CO-t-butyl.
  • R 10 is preferably methyl.
  • R 11 is preferably methyl.
  • R 12 is preferably methyl.
  • R 13 is preferably H or methyl.
  • R 14 is preferably H or methyl.
  • Prodrug derivatives of compounds of the invention will break down after administration to a subject to form an active compound of formula (I) (sometimes herein after referred to as "parent active compound”) in vivo.
  • Prodrug derivatives of compounds of the invention may have some intrinsic biological activity (e.g. as pneumolysin inhibitors) however typically they have little or no such intrinsic activity.
  • Prodrug derivatives of the compounds of formula (I) include ester prodrug derivatives.
  • Ester prodrug derivatives include carboxylate ester, sulfamate ester, phosphate ester and carbamate ester derivatives, preferably carboxylate ester, sulfamate ester or phosphate ester derivatives, more preferably carboxylate ester or phosphate ester derivatives, even more preferably carboxylate ester derivatives.
  • ester prodrug derivatives thus include compounds of formula (I) wherein one or both of R 4a and R 4b are independently selected from -C(0)R 16 , - SO2NH2 , -PO(OR 19 )(OR 20 ), -CHR 26 -OPO(OR 19 )(OR 20 ) (where R 26 is hydrogen or C C 6 alkyl), and -C(0)NR 17 R 18 , wherein R 16 , R 17 , R 18 , R 19 and R 20 are independently selected from:
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C1 0 cycloalkyl, C5-C1 0 cycloalkenyl,
  • R 17 and R 18 together with the N to which they are attached may form a 5- or 6-membered heterocyclic ring optionally containing a further heteroatom selected from O, S and NR 25a R 25b where R 25a is hydrogen, C C 6 alkyl, -CH 2 -OPO(OR 19 )(OR 20 ) or a 5- or 6-membered heterocyclic ring, and R 25b is absent or C C 6 alkyl; and in which any of the aforementioned R 16 , R 17 or R 18 groups may be optionally substituted by one or more groups, e.g.
  • each z which may be the same or different, represents 2 or 3, r represents an integer selected from 1 to 20, e.g.
  • R 24 is hydrogen, C1-C 3 alkyl or - PO(OR 19 )(OR 20 )), Ci-Ce alkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, C C 6 fluoroalkyi and - C(0)NR a R b , where R a and R b are independently selected from hydrogen and C C 6 alkyl, and any of the aforementioned R 16 , R 17 or R 18 groups may be optionally substituted by one or more halogen atoms; and
  • R 18 , R 19 and R 20 may independently represent hydrogen.
  • Optional substituents for phenyl, aryl and heteroaryl groups within the definitions of R 1 , R 2 , R 4a , R 4b , R 5 , R 6 , R 7 , R 16 , R 17 , R 18 , R 19 and R 20 are suitably selected from hydroxyl, halo, cyano, - (CHR 26 ) q -OPO(OR 19 )(OR 20 ) wherein q represents 0 or 1 (said group not being substituted by another R 19 or R 20 containing group), C C 6 alkoxy or C C 6 fluoroalkoxy, e.g.
  • C1-C3 alkoxy or C1-C3 fluoroalkoxy such as methoxy, ethoxy or trifluoromethoxy
  • C C 6 alkyl or C C 6 fluoroalkyi e.g. C1-C3 alkyl or C1-C3 fluoroalkyi such as methyl or trifluoromethyl
  • -C(0)NR a R b where R a and R b are independently selected from hydrogen and C C 6 alkyl e.g. C1-C3 alkyl such as methyl; and also when two adjacent hydroxyl substituents are present they may optionally be connected by a methylene group to form an acetal.
  • Another possible optional substituent is - SF 5 .
  • Said aryl and heteroaryl groups, if substituted, may be substituted by 1 , 2 or 3, preferably 1 or 2, more preferably 1 substituent.
  • Optional substituents for the C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, heterocyclyl, -C1-C3 alkyl-C 3 -Ci 0 cycloalkyl, -C1-C3 alkyl-C 5 -Ci 0 cycloalkenyl, -C C 3 alkylheterocyclyl or heterocyclic ring groups of R 5 , R 6 , R 7 , R 16 , R 17 , R 18 , R 19 and R 20 include substituents selected from cyano, -OPO(OR 19 )(OR 20 ) (said group not being substituted by another R 19 or R 20 containing group), C C 6 alkoxy or C C 6 fluoroalkoxy, e.g.
  • C1-C3 alkoxy or C1-C3 fluoroalkoxy such as methoxy, ethoxy or trifluoromethoxy
  • C C 6 alkyl or C C 6 fluoroalkyi e.g. C1-C3 alkyl or C1-C3 fluoroalkyi such as methyl or trifluoromethyl
  • -C(0)NR a R b where R a and R b are independently selected from hydrogen and C C 6 alkyl e.g. C1-C3 alkyl such as methyl.
  • Optional substituents for the groups R 5 , R 6 and R 7 also include one or more (e.g. 1 , 2, or 3) halogen atoms e.g. F or CI atoms (especially F atoms).
  • R 16 preferably represents C C 6 alkyl or C3-C10 cycloalkyl in which either of the aforementioned groups may be optionally substituted (and is preferably substituted) by a group selected from - OPO(OR 19 )(OR 20 ) and -(0(CH 2 ) z ) r OR 24 , where each z, which may be the same or different, represents 2 or 3, r represents an integer selected from 1 to 20, e.g. 7 to 12, and R 24 is hydrogen, C C 3 alkyl or -PO(OR 19 )(OR 20 ).
  • R 16 preferably represents phenyl optionally substituted (and is preferably substituted) by -(CHR 26 ) q -OPO(OR 19 )(OR 20 ) wherein q represents 0 or 1.
  • R 17 preferably represents C C 6 alkyl e.g. methyl.
  • R 18 preferably represents C C 6 alkyl e.g. methyl.
  • R 17 and R 18 together with the N to which they are attached may form a 5- or 6-membered heterocyclic ring optionally containing a further heteroatom selected from O, S and NR 25a where R 25a is hydrogen, C C 6 alkyl, -CH 2 -OPO(OR 19 )(OR 20 ) or a 5- or 6-membered heterocyclic ring.
  • R 19 is preferably hydrogen, methyl or ethyl, especially hydrogen.
  • R 20 is preferably hydrogen, methyl or ethyl, especially hydrogen.
  • R is preferably hydrogen or methyl.
  • R 25b is preferably absent.
  • R 26 is preferably hydrogen or methyl, more preferably methyl.
  • q represents 0. In another embodiment q represents 1.
  • R 4a and R 4b represents a prodrug derivative group as defined above. In another embodiment both of R 4a and R 4b represent a prodrug group as defined above. When only one of R 4a and R 4b represents a prodrug derivative group as defined above the other of R 4a and R 4b is preferably hydrogen.
  • both of R 4a and R 4b are independently selected from -C(0)R 16 , -S0 2 NH 2 , - PO(OR 19 )(OR 20 ), -CHR 26 -OPO(OR 19 )(OR 20 ) where R 26 is hydrogen or C C 6 alkyl, and - C(0)NR 17 R 18 .
  • one of R 4a and R 4b is selected from -C(0)R 16 , -S0 2 NH 2 , -PO(OR 19 )(OR 20 ), -CHR 26 -OPO(OR 19 )(OR 20 ) where R 26 is hydrogen or C C 6 alkyl, and - C(0)NR 17 R 18 ; and the other of R 4a and R 4b is hydrogen.
  • R 4a and R 4b are preferably independently selected from -C(0)R 16 .
  • the prodrug is a carboxylate ester prodrug, e.g. wherein one or both of R 4a and R 4b are - C(0)R 16
  • the carbon atom adjacent to the C(O) moiety is preferably a tertiary or quaternary carbon atom.
  • prodrug derivatives include compounds of formula (I) wherein one or both of R 4a and R 4b are independently selected from -S0 2 NH 2 , -PO(OH) 2 , -CH 2 -PO(OH) 2 , -PO(OEt) 2 , -CON-(4-N-piperidinyl-piperidine), -COt-butyl, -COisopropyl, -CON-(N-methyl)piperazine, -CON- piperazine, -CON(CH 3 ) 2 , COCH 3 , -CO-(CH 2 ) 2 -OMe, -CO(CH 2 ) 2 -(0(CH 2 ) 2 ) p OMe where p is 1 to 12, -CO-CMe 2 -CH 2 -(0(CH 2 ) 3 ) P OMe where p is 1 to 12, -CO-CMe 2 -CH 2 -(0(CH 2 ) 2 ) p OM
  • a group of specific examples of prodrug derivatives include compounds of formula (I) wherein R 4a and R 4b are independently selected from -S0 2 NH 2 , -PO(OH) 2 , -CON-(4- N-piperidinyl-piperidine), -COt-butyl, -COisopropyl, -CON-(N-methyl)piperazine, -CON(CH 3 ) 2 and COCH 3 .
  • preferred compounds of this invention include those in which several or each variable in formula (I) is selected from the preferred, more preferred or particularly listed groups for each variable. Therefore, this invention is intended to include all combinations of preferred, more preferred and particularly listed groups.
  • the molecular weight of the compounds of the invention is preferably less than 2000, more preferably less than 1000, even more preferably less than 800, for example less than 600.
  • Alkyl as used herein refers to straight chain or branched chain alkyl, such as, without limitation, methyl, ethyl, propyl, / ' so-propyl, butyl, and te/f-butyl. In one embodiment alkyl refers to straight chain alkyl in another embodiment alkyl refers to branched chain alkyl. Alkenyl and alkynyl should be interpreted accordingly.
  • Fluoroalkyl groups are as described above for alkyl, but may have one or more hydrogen atoms replaced by fluoro.
  • fluoroalkyl groups include -CH 2 F, -CHF 2 and -CF 3 .
  • CycloalkyI as used herein refers to a cyclic alkyl group, containing 3-10 carbon atoms, optionally branched, for example cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A branched example is 2- methylcyclopentyl.
  • Cycloalkenyl refers to a cyclic alkenyl group containing typically 5-10 carbon atoms, for example cyclopentyl, cyclohexenyl or cycloheptenyl. CycloalkyI and cycloalkenyl groups may for example be monocyclic or bicyclic (including spirocyclic) but are suitably monocyclic.
  • Carbocyclyl as used herein refers to a cycloalkyl or cycloalkenyl group, for example cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl.
  • Alkoxy as used herein refers to straight or branched chain alkoxy, for example methoxy, ethoxy, propoxy, butoxy. Alkoxy as used herein also extends to embodiments in which the oxygen atom is located within the alkyl chain, for example -CH 2 OCH 3 . In one embodiment the alkoxy is linked through oxygen to the remainder of the molecule. In one embodiment the disclosure relates to straight chain alkoxy.
  • Halo includes fluoro, chloro, bromo or iodo, in particular fluoro, chloro or bromo, especially fluoro or chloro.
  • Heterocyclyl as used herein includes 4- to 10-membered mono or bicyclic non-aromatic ring systems, e.g. 4- to 7- membered monocyclic saturated rings, containing up to three heteroatoms selected from N, O and S.
  • heterocyclic rings examples include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine, piperidine, azepane, azocane, [1 ,4]dioxane, oxazolidine, piperazine, and morpholine.
  • Other examples of heterocyclic rings include the oxidised forms of the sulfur- containing rings.
  • tetrahydrothiophene-1 -oxide, tetrahydrothiophene-1 , 1 -dioxide, tetrahydrothiopyran-1 -oxide and tetrahydrothiopyran- 1 , 1 -dioxide are also considered to be heterocyclic rings.
  • Aryl as used herein includes C 6 -Ci 4 mono or bicyclic groups having 1 or 2 rings wherein at least one ring is aromatic, including phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl and the like, such as phenyl and napthyl particularly phenyl.
  • Heteroaryl as used herein includes 5- to 10-membered aromatic mono or bicyclic ring systems comprising one or more, (for example 1 , 2, 3 or 4) heteroatoms independently selected from O, N and S.
  • heteroaryl groups include pyrrole, furan, thiophene, oxazole, thiazole, isothiazole, oxadiazole, tetrazole, imidazole, pyrazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine, benzothiophene, benzofuran, 1 , 2, 3-triazole and 1 , 2, 4-triazole.
  • heteroaryl In a bicyclic ring system the definition of heteroaryl will be satisfied if at least one ring contains a heteroatom and at least one ring is aromatic.
  • the heteroaryl may be linked to the remainder of the molecule through a carbocyclic ring or a ring comprising a heteroatom.
  • salts of the compounds of formula (I) include all pharmaceutically acceptable salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • Salts derived from bases include, for example, potassium and sodium salts and the like.
  • Salts derived from acids include those derived from inorganic and organic acids such as, for example, hydrochloric,
  • solvates include hydrates.
  • the compounds described herein may include one or more chiral centers, and the disclosure extends to include racemates, enantiomers and stereoisomers resulting therefrom.
  • one enantiomeric form is present in a substantially purified form that is
  • the invention also extends to all polymorphic forms of the compounds of formula (I).
  • the invention also extends to isotopically-labelled compounds of formula (I) in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 2 H, 3 H, 11 C, 14 C and 18 F.
  • Isotopically labelled compounds of formula (I) may be prepared by carrying out the synthetic methods described below and substituting an isotopically labelled reagent or intermediate for a non-isotopically labelled reagent or intermediate.
  • the invention extends to all tautomeric forms of the compounds illustrated herein (particularly enol-keto tautomers).
  • formula (I) illustrates in some embodiments (e.g. when R 4a and/or R 4b represents H) an enol form
  • the corresponding keto form is also embraced as part of the invention.
  • R x typically represents d-C 6 alkyl such as methyl or ethyl.
  • R x typically represents CrC 6 alkyl such as methyl or ethyl.
  • Scheme C A method for preparing certain compounds of formula (I) in which R 1 is -C(0)NHR 6 , R 2 is C(0)NR 5 R 6 and R 4a and R 4b represent hydrogen is shown below in Scheme D:
  • Scheme E A method for preparing certain compounds of formula (I) in which R and R represent groups other than hydrogen is shown below in Scheme F:
  • Scheme F where X are independently leaving groups such as halogen, an ester (-OCOR', giving a mixed anhydride), or hydrogen, when used in combination with a suitable coupling agent, such as: 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDC), AyJ ⁇ /'-diisopropylcarbodiimide (DIC) or 1 ,1 '- carbonyldiimidazole (CDI).
  • EDC 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide)
  • DIC AyJ ⁇ /'-diisopropylcarbodiimide
  • CDI 1 ,1 '- carbonyldiimidazole
  • X is halogen.
  • Scheme J may be adapted to convert one or both hydroxyl groups to OR 4a and/or OR 4b depending on the molar excess of reagent(s) employed.
  • compounds of formula (I) in which R 1 and/or R 2 represents -C(0)NHC(0)R 7 may be prepared by reaction of a compound of formula (I) in which R 1 and/or R 2 represents -C(0)NH 2 with a compound of formula R 7 C(0)L wherein L represents a leaving group, such as halogen.
  • Protecting groups may be required to protect chemically sensitive groups during one or more of the reactions described above, to ensure that the process is efficient. Thus if desired or necessary, intermediate compounds may be protected by the use of conventional protecting groups. Protecting groups and means for their removal are described in "Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons Inc; 4 th Rev Ed., 2006, ISBN-10: 0471697540. Any novel intermediates, such as those defined above, may be of use in the synthesis of compounds of formula (I) and are therefore also included within the scope of the invention.
  • R 4a and R 4b represent H which comprises reacting a compound of formula (II) with a compound of formula ROCOCOOR x in which R x represents C C 6 alkyl.
  • This process is typically performed in a polar protic solvent such as ethanol in the presence of a strong base such as sodium ethoxide.
  • compounds of formula (I) are referred to below as "compounds of the invention”.
  • the compounds of the invention are useful for treatment of bacterial infections caused by bacteria producing pore-forming toxins, such as cholesterol dependent cytolysins.
  • the compounds of the invention are useful for the treatment of toxaemia associated with bacterial infections.
  • the compounds of the invention will generally be administered in the form of a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) optionally in combination with one or more pharmaceutically acceptable diluents or carriers.
  • Diluents and carriers may include those suitable for parenteral, oral, topical, mucosal and rectal administration.
  • compositions may be prepared e.g. for parenteral, subcutaneous, intramuscular, intravenous, intra-articular or peri-articular administration, particularly in the form of liquid solutions or suspensions; for oral administration, particularly in the form of tablets or capsules; for topical e.g. intravitreal, pulmonary or intranasal administration, particularly in the form of eye drops, powders, nasal drops or aerosols and transdermal administration; for mucosal administration e.g. to buccal, sublingual or vaginal mucosa, and for rectal
  • administration e.g. in the form of a suppository.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
  • Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for parenteral administration may be provided in solid form, such as a lyophilised composition, the lyophilised composition may be re-constituted, preferably just before administration.
  • Re- constitution may involve dissolving the lyophilised composition in water or some other pharmaceutically acceptable solvent, for example physiological saline, an aqueous solution of a pharmaceutically acceptable alcohol, e.g. ethanol, propylene glycol, a polyethylene glycol, e.g. polyethylene glycol 300, and the like, or some other sterile injectable.
  • a pharmaceutically acceptable solvent for example physiological saline, an aqueous solution of a pharmaceutically acceptable alcohol, e.g. ethanol, propylene glycol, a polyethylene glycol, e.g. polyethylene glycol 300, and the like, or some other sterile injectable.
  • Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray.
  • excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
  • compositions suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.
  • Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone
  • fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine
  • lubricants such as magnesium stearate, talc, polyethylene glycol
  • Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats
  • emulsifying agents such as lecithin, or acacia
  • vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
  • preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage
  • a dry shell formulation typically comprises of about 40% to 60% concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30% to 40% concentration of water. Other materials such as preservatives, dyes, opacifiers and flavours also may be present.
  • the liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
  • compositions of the invention may optionally include one or more anti-oxidants (e.g. ascorbic acid or metabisulfate and salts thereof).
  • anti-oxidants e.g. ascorbic acid or metabisulfate and salts thereof.
  • Particular pharmaceutical compositions according to the invention include the following:
  • a pharmaceutical composition for parenteral, e.g. intravenous, administration is provided.
  • a pharmaceutical composition for parenteral e.g. intravenous, or oral administration in unit dose form.
  • the compounds of the invention are inhibitors of the cholesterol-dependent cytolysin, pneumolysin, produced by the bacterium Streptococcus pneumoniae. They also inhibit Streptolysin O (SLO) produced by Group A Streptococci and Perfringolysin O (PFO) produced by Clostridium perfringens. They are also expected to inhibit other members of the closely related cholesterol-dependent cytolysins, examples of which include, but are not limited to, Listeriolysin O (LLO) produced by Listeria monocytogenes, Anthrolysin O (ALO) produced by Bacillus anthracis and Suilysin (SLY) produced by Streptococcus suis.
  • SLO Streptolysin O
  • PFO Perfringolysin O
  • LLO Listeriolysin O
  • ALO Anthrolysin O
  • SLY Suilysin
  • the compounds of the invention are useful for the treatment of bacterial infections, e.g.
  • pneumococcal infections including the associated toxaemia where the pneumolysin toxin has been demonstrated to play a pivotal role in the diseases produced.
  • diseases include, but are not limited to, pneumococcal pneumonia, pneumococcal meningitis, pneumococcal septicaemia/bacteraemia, pneumococcal keratitis and pneumococcal otitis media.
  • the compounds of the invention are also useful for the treatment of pneumococcal infections associated with other conditions.
  • Such conditions include (without limitation) cystic fibrosis and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • S pneumoniae has been isolated from patients with COPD and is believed to be an exacerbatory factor in this disease.
  • the compounds of the invention are useful for the treatment of infections caused by group A Streptococci (GAS), including but not limited to, invasive group A Streptococcal diseases, where the toxin Streptolysin O (SLO) has been demonstrated to play a crucial role in the pathogenesis of systemic GAS diseases.
  • GAS group A Streptococci
  • SLO toxin Streptolysin O
  • the compounds of the invention are useful for the treatment of infections caused by Clostridium perfringens including, but not limited to, gas gangrene, characterized by myonecrosis, septic shock and death, where the toxin Perfringolysin O has been demonstrated to be a major virulence factor in the pathogenesis of this disease.
  • the compounds of the invention are useful for the treatment of infections caused by Bacillus anthracis, where the cholesterol dependent cytolysin Anthrolysin O (ALO) plays an essential role in gastrointestinal (Gl) anthrax, and contributes to the pathogenesis of inhalational anthrax.
  • ALO cholesterol dependent cytolysin Anthrolysin O
  • the compounds of the invention are useful for the treatment of other diseases caused by Gram positive bacteria, producing cholesterol-dependent cytolysins, examples of which include, but are not limited to:
  • the compounds of the invention may well also be useful for the inhibition of other bacterial pore-forming toxins, such as the RTX family of toxins, which are essential in the virulence of their host.
  • Examples include, but are not limited to, pneumonia and septicaemia/bacteraemia caused by Staphylococcus aureus, which produces the pore-forming toxin staphylococcal a- hemolysis and peritonitis caused by pathogenic Escherichia coli which produces the pore forming toxin a-hemolysin.
  • -A compound of the invention for use in the treatment of bacterial infections caused by bacteria producing pore-forming toxins, wherein the bacterial infection is caused by
  • Streptococcus spp. e.g. Streptococcus pneumoniae, Group A Streptococci or Streptococcus suis
  • Clostridium spp. e.g. Clostridium perfringens
  • Listeria spp. e.g. Listeria monocytogenes
  • Bacillus spp. e.g. Bacillus anthracis
  • -A compound of the invention for the treatment of bacterial infection which is caused by Streptococcus pneumonia
  • -A compound of the invention for use in the treatment of pneumococcal pneumonia, pneumococcal meningitis, pneumococcal septicaemia/bacteraemia, pneumococcal keratitis or pneumococcal otitis media
  • pneumococcal pneumonia pneumococcal meningitis
  • pneumococcal septicaemia/bacteraemia pneumococcal keratitis
  • pneumococcal otitis media pneumococcal otitis media
  • -A compound of the invention for the treatment of conditions selected from gas gangrene, gastrointestinal anthrax, inhalational anthrax, porcine meningitis, encephalitis, septicaemia/bacteraemia and pneumonia which are caused by bacteria other than
  • the compounds of the invention may be used to treat either humans or animals, such as domestic animals or livestock, e.g. pigs, cows, sheep, horses etc, and references to
  • compositions should be interpreted to cover compositions suitable for either human or animal use.
  • the present invention provides a compound of formula (I) for use in the treatment of the above mentioned conditions.
  • the present invention provides a compound of formula (I) for the
  • the present invention provides a method of treatment of the above mentioned conditions which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition thereof.
  • treatment is intended to embrace prophylaxis as well as therapeutic treatment.
  • the compounds of the invention may be used either alone or in combination with further therapeutically active ingredients.
  • compounds of the invention may be administered in combination, simultaneously, sequentially or separately, with further therapeutically active ingredients either together in the same formulation or in separate formulations and either via the same route or via a different route of administration.
  • the compounds of the invention may thus be administered in combination with one or more other active ingredients suitable for treating the above mentioned conditions.
  • possible combinations for treatment include combinations with antimicrobial agents, e.g. antibiotic agents, including natural, synthetic and semisynthetic antimicrobial agents.
  • antibiotic agents include ⁇ -lactams including, but not limited to, penicillin, benzylpenicillin, amoxicillin and all generations thereof; ⁇ -lactams in combination with ⁇ -lactamase inhibitors including, but not limited to, clavulanic acid and sulbactam; cephalosporins including, but not limited to, cefuroxime, cefotaxime and ceftriaxone; fluoroquinolones including, but not limited to, levofloxacin and moxifloxacin; tetracyclines including, but not limited to, doxycycline; macrolides including, but not limited to, erythromycin and clarithromycin; lipopeptide antibiotics including, but not limited to, daptomycin;
  • aminoglycosides including, but not limited to, kanamycin and gentamicin; glycopeptide antibiotics, including but not limited to, vancomycin; lincosamides including, but not limited to, clindamycin and lincomycin; rifamycins including, but not limited to, rifampicin; and
  • chloramphenicol Further combinations include combinations with immunomodulatory agents, such as antiinflammatory agents.
  • Immunomodulatory agents can include for example, agents which act on the immune system, directly or indirectly, by stimulating or suppressing a cellular activity of a cell in the immune system, for example, T-cells, B-cells, macrophages, or antigen presenting cells, or by acting upon components outside the immune system which, in turn, stimulate, suppress, or modulate the immune system, for example, hormones, receptor agonists or antagonists and
  • immunomodulatory agents can include immunosuppressants or immunostimulants.
  • Anti-inflammatory agents include, for example, agents which treat inflammatory responses, tissue reaction to injury, agents which treat the immune, vascular or lymphatic systems or combinations thereof. Examples of anti-inflammatory and
  • immunomodulatory agents include, but are not limited to, interferon derivatives such as betaseron, ⁇ -interferon, prostane derivatives such as iloprost and cicaprost, corticosteroids such as prednisolone, methylprednisolone, dexamethasone and fluticasone, COX2 inhibitors, immunsuppressive agents such as cyclosporine A, FK-506, methoxsalene, thalidomide, sulfasalazine, azathioprine and methotrexate, lipoxygenase inhibitors, leukotriene antagonists, peptide derivatives such as ACTH and analogs, soluble TNF (tumor necrosis factor) -receptors, TNF-antibodies, soluble receptors of interleukines, other cytokines and T-cell-proteins, antibodies against receptors of interleukins, other cytokines and T-cell-proteins.
  • NSAID's non-steroidal anti-inflammatory drugs
  • NSAID's include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors e.g. theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors, leukotriene antagonists, inhibitors of leukotriene synthesis such as montelukast, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists such as adenosine 2a agonists, cytokine antagonists e.g. chemokine antagonists, such as CCR3 antagonists, or inhibitors of cytokine synthesis, and 5-lipoxygenase inhibitors.
  • PDE phosphodiesterase
  • leukotriene antagonists inhibitors of leukotriene synthesis
  • montelukast iNOS inhibitors
  • an aspect of the invention provides a compound of formula (I) in combination with one or more further active ingredients, for example one or more of the active ingredients described above.
  • compositions comprising a compound of formula (I) optionally in combination with one or more pharmaceutically acceptable adjuvants, diluents or carriers and comprising one or more other therapeutically active ingredients.
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier.
  • the combination product may be either a single (combination) pharmaceutical formulation or a kit-of-parts.
  • this aspect of the invention encompasses a pharmaceutical formulation including a compound of the present invention and another therapeutic agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation").
  • kit of parts comprising components:
  • a pharmaceutical formulation including a compound of formula (I) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier;
  • a pharmaceutical formulation including another therapeutic agent, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • components (i) and (ii) are each provided in a form that is suitable for administration in conjunction with the other.
  • Component (i) of the kit of parts is thus component (A) above in admixture with a
  • component (ii) is component (B) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the other therapeutic agent i.e. component (B) above
  • the combination product (either a combined preparation or kit-of-parts) of this aspect of the invention may be used in the treatment or prevention of any of the conditions mentioned above.
  • the compounds of formula (I) may also be provided for use, e.g. with instructions for use, in combination with one or more further active ingredients.
  • the compound of formula (I) for use in this aspect of the invention may be used in the treatment or prevention of any of the conditions mentioned above.
  • Hydrogenations are performed either on a Thales H-cube flow reactor or with a suspension of the catalyst under a balloon of hydrogen. Column chromatography is performed on pre-packed silica (230-400 mesh, 40-63 ⁇ ) cartridges.
  • PBS solutions for solubility and stability studies are prepared by dissolving 1 OxoidTM tablet (obtained from Thermo Scientific) in deionised water (100 ml_). Solubility studies are carried out by charging a vial with 5-10 mg of compound followed by the addition of PBS solution to achieve a concentration of 100 mg/ml. If solubility is not observed the solution is diluted to concentrations of 50 mg/ml, 25 mg/mL and 4 mg/ml consecutively until complete solubility is observed.
  • Stability studies are carried out by dissolving 1-2 mg of compound in DMSO (1 mL) followed by addition of 0.4 mL of the resulting solution to stirred PBS solution (9.6 mL) at 37.5 °C. A sample (ca. 0.5 mL) is immediately taken for HPLC analysis. Further samples are then taken for analysis at various timepoints thereafter. Half-lives are determined from the decrease in concentration of compound with respect to time.
  • Analytical HPLC is carried out using an Agilent Zorbax Extend C18, Rapid Resolution HT 1.8 ⁇ column eluting with a 5-95% gradient of either 0.1 % formic acid in MeCN in 0.1 % aqueous formic acid or a 5-95% gradient of MeCN in 50 mM aqueous ammonium acetate.
  • UV spectra of the eluted peaks is measured using either a diode array or variable wavelength detector on an Agilent 1100 system.
  • Analytical LCMS is carried out using an Agilent Zorbax Extend C18, Rapid Resolution HT 1.8 ⁇ column eluting with a 5-95% gradient of either 0.1 % formic acid in MeCN in 0.1 % aqueous formic acid or a 5-95% gradient of MeCN in 50 mM aqueous ammonium acetate.
  • UV and mass spectra of the eluted peaks is measured using a variable wavelength detector on either an Agilent 1100 with or an Agilent Infinity 1260 LC with 6120 quadrupole mass spectrometer with positive and negative ion electrospray.
  • Preparative HPLC is carried out using an Agilent Prep-C18 5 ⁇ Preparative Cartridge using either a gradient of 0.1 % formic acid in MeCN in 0.1 % aqueous formic acid or a gradient of MeCN in 10 mM Ammonium Bicarbonate, Alternatively, a Waters Xselect CSH C18 5 ⁇ column using a gradient 0.1 % MeCN in 0.1 % aqueous formic acid may be used. Fractions were collected following detection by UV at 254nm. 1 H NMR Spectroscopy:
  • NMR spectra is recorded using a Bruker Avance III 400 MHz instrument, using either residual non-deuterated solvent or tetra-methylsilane as reference.
  • Example B Diethyl 1-(2,3-dihydrobenzo[0][1 ,4]dioxin-6-yl)-3,4-dihydroxy-1 /-/-pyrrole-2,5- dicarboxylate (UL10-002)
  • Diethyl oxalate (0.97 mL, 7.1 1 mmol) was added dropwise to a stirred solution of diethyl 2,2'- ((2,3-dihydrobenzo[ 5][1 ,4]dioxin-6-yl)azanediyl)diacetate (4) (2.3 g, 7.1 1 mmol) in NaOEt (21 % by wt in EtOH) (5.90 mL, 15.65 mmol), the mixture was stirred at reflux for 1 h. The reaction was quenched with acetic acid (2.44 mL, 42.7 mmol) and the resulting suspension was poured into iced water (50 mL), the resulting cream solid collected by vacuum filtration.
  • Example C Diethyl 3,4-dihydroxy-1-(2,3-dihydrobenzofuran-5-yl)-1 /-/-pyrrole-2,5-dicarboxylate (UL10-003)
  • Diethyl oxalate (0.73 mL, 5.34 mmol) was added dropwise to a stirred solution of diethyl 2,2'- ((2,3-dihydrobenzofuran-5-yl)azanediyl)diacetate (6) (1.64 g, 5.34 mmol) in NaOEt (21 % by wt in EtOH) (4.42 mL, 1 1.74 mmol), the mixture was stirred at reflux for 1 h. The reaction was quenched with acetic acid (1.83 mL, 32.0 mmol) and the resulting suspension was poured into iced water (50 mL), the resulting cream solid collected by vacuum filtration.
  • Examples D to I may be prepared using the following methods: Example D: 3,4-dihydroxy-1-(2,3-dihydrobenzofuran-5-yl)- A/ 2 ,A/ 2 ,A/ 5 ,A/ 5 -tetramethyl-1 /-/-pyrrole- 2,5-dicarboxamide (10)
  • This example may be prepared from 5-amino-2,3-dihydrobenzofuran (5) via diethyl 3,4- dihydroxy-1-(2,3-dihydrobenzofuran-5-yl)-1 /-/-pyrrole-2,5-dicarboxylate (UL10-003) as shown in the scheme below:
  • Example E 3,4-dihydroxy-1-(2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)- A/ 2 ,A/ 2 ,A/ 5 ,A/ 5 -tetramethyl-1 H- pyrrole-2,5-dicarboxamide (11 )
  • This example may be prepared from 6-amino-1 ,4-benzodioxane (3) via diethyl 3,4-dihydroxy-1- (2,3-dihydrobenzo[b][1 ,4]dioxin-6-yl)-1 /-/-pyrrole-2,5-dicarboxylate (UL10-002).
  • Example F 3,4-dihydroxy-1-(pyrimidine -5-yl)- N 2 , N 2 , N 5 , A/ 5 -tetram ethyl- 1 /-/-pyrrole-2, 5- dicarboxamide (13)
  • This example may be prepared from 5-aminopyrimidine (12).
  • Example G 3,4-dihydroxy-1 -(naphthylamine -1 -yl)- A/ 2 ,A/ 2 ,A/ 5 ,A/ 5 -tetramethyl-1 /-/-pyrrole-2,5- dicarboxamide (15)
  • This example may be prepared from 1 -naphthylamine (14).
  • This example may be prepared from 5-amino-benzofuran (16).
  • This example may be prepared from 4-aminoisoquinoline (18).
  • Test compound solutions are diluted 1 : 1 in 100% DMSO.
  • the compounds are then two-fold serially diluted in 100% DMSO across 1 1 wells of 96-well round- bottomed microtitre plate.
  • PBS is then added to all the wells to achieve a 1 : 10 (v/v) dilution of the compound in PBS.
  • Pneumolysin is then added at a concentration equal to its LD100. Plates are then incubated at 37°C for 30-40 min. After the incubation period, an equal volume of 4% (v/v) sheep erythrocyte suspension is added to each well and the plates incubated again at 37°C, for at least 30 min.
  • Controls with only erythrocytes in PBS (control for no lysis) or erythrocytes plus pneumolysin (control for lysis) are prepared following the same procedure. Following the incubation with the erythrocytes, the Absorbance at 595 nm of each well is measured and the data used to determine the IC 50 for each test compound. The IC 50 values are determined using non-linear regression curve fitting. For that, the Log of the concentrations of the test compound is plotted against the percentage inhibition, estimated from the A 595 values, followed by fitting a Hill Slope to the data. The results of testing the examples are shown in Table 1.
  • LDH lactate dehydrogenase
  • the LDH assay may be applied to demonstrate the ability of the disclosed compounds to inhibit the cytotoxic effect of pneumolysin on human lung epithelial cells in culture.
  • the use of this assay can provide two main pieces of information on (1) Activity, to demonstrate the inhibition of LDH release from cells exposed to pneumolysin in the presence of inhibitory compounds versus the LDH release from cells exposed to
  • pneumolysin alone (2) Compound toxicity
  • the assay format is designed so it allows, in the control wells, the testing of the LDH release from cells exposed to the compound only.
  • Human lung epithelial cells (A549) are seeded in flat-bottomed 96-well tissue culture plates and grown in RPMI 1640 medium supplemented with Glutamine, at 37°C, 5% C0 2 , for 24h. Before use, the cells are washed with PBS. Test compound dilutions are incubated with pneumolysin as described in Section A, then transferred to wells containing the human lung epithelial cells and the plates are incubated at 37°C, 5% C0 2 , for 30 min.
  • Negative controls called low control (PBS only) to measure the natural release of LDH from the cells in culture
  • positive controls (1 % (v/v) Triton-X in PBS) to measure the maximum release of LDH from the cells
  • Pneumolysin solution only to measure pneumolysin- induced LDH release
  • Test compound solution to assess the toxicity of the compound alone. After incubation, the supernatant is transferred to the wells of round-bottomed 96-well microtitre plates containing a double volume of lactate dehydrogenase assay mixture (TOX7, Sigma) prepared according to manufacturer's instructions.
  • TOX7 lactate dehydrogenase assay mixture
  • the ependymal ciliated cells line the cerebral ventricles of the brain and the central canal of the spinal cord and are covered with cilia responsible for the circulation of the cerebrospinal fluid (CSF) around the central nervous system.
  • CSF cerebrospinal fluid
  • This layer acts as a selective brain barrier to and from the cerebrospinal fluid and plays a role in controlling the CSF volume.
  • a rat ex vivo model of meningitis may be used. This model is based on culturing and differentiating ciliated ependymal cells from neonate rat brains, which recreate the in vivo situation, where cells lining the brain ventricles, are exposed to S. pneumoniae and its toxic products.
  • Ependymal cell cultures are prepared by the method previously described [Microb. Pathog. (1999) 27 303-309]. Tissue culture trays are coated with bovine fibronectin and incubated at 37°C in 5% (v/v) C0 2 for 2h before use.
  • the growth medium is minimum essential medium (MEM) with added penicillin (100 lU/mL), streptomycin (100 ⁇ g/mL), fungizone (2.5 ⁇ g/mL), BSA (5 ⁇ g/mL), insulin (5 ⁇ g/ml), transferrin (10 ⁇ g/mL) and selenium (5 ⁇ g/mL).
  • MEM minimum essential medium
  • Neo-natal (0-1 day old) rats are killed by cervical dislocation, and their brains are removed.
  • the cerebellum is removed along with edge regions of the left and right cortical hemispheres and the frontal cortex.
  • the remaining brain areas are mechanically dissociated in 4 mL of growth medium.
  • the dissociated tissue from one or two brains is added to the wells of the tissue culture trays (500 ⁇ /well), each containing 2.5 mL of growth medium.
  • the cells then are incubated at 37°C in 5% (v/v) C0 2 .
  • the medium is replaced after three days and thereafter the ependymal cells are fed every two days with 2 mL of fresh growth medium supplemented with thrombin.
  • the cells are fully ciliated and ready for experiments.
  • the growth medium is replaced with 1 mL of medium MEM containing 25 mM HEPES, pH 7.4.
  • the tissue culture trays are placed inside a thermostatically controlled incubation chamber surrounding the stage of an inverted light microscope.
  • the cell cultures are allowed to equilibrate until the temperature of the assay medium is 37°C.
  • recombinant purified pneumolysin, with and without test compound, pre-incubated in 1 ml of medium MEM at 37°C for 40 min, is added to the wells containing the ciliated cells.
  • 1 mL of MEM medium is added to the control cells.
  • CBF ciliary beat frequency
  • Outbred MF1 female mice 8 weeks old or more and weighing 25-30 g are used. The animals are maintained under controlled conditions of temperature, humidity and day length. They have free access to tap water and pelleted food.
  • the in vivo experiments are performed using two control groups: Control 1 (infected and not treated), Control 2 (not infected and treated) and one Treatment group (infected and treated). Mice in control group 1 and in the treatment group are infected intranasally with Streptococcus pneumoniae strain D39 (procedure described below). After completing the infections, the viable count of the given dose is determined (as described below).
  • mice in the treatment group and in the control group 2 receive the test compound intravenously, while excipient alone is administered to control group 1.
  • the progress of the signs of disease (Table 2) is assessed every 6h based on the scheme of Morton and Griffiths [Veterinary Record. (1985) 111 , 431-436]. Animals are killed if they became 2+ lethargic and the time is recorded. The survival rates of control and test groups are compared with a log-rank test.
  • mice are lightly anaesthetised with 2.5% (v/v) isoflurane over 1.6-1.8 L 0 2 /min.
  • the confirmation of effective anaesthesia is made by observation of no pedal reflex.
  • a mouse is held by the scruff of the neck in a vertical position with its nose upward.
  • the infectious dose is then administered in sterile PBS, given drop by drop into the nostrils, allowing the animal to inhale it in between drops. Once the dose is given, the mouse is returned to its cage, placed on its back to recover from the effects of anaesthetic.
  • mice are placed inside an incubator at 37°C, for 10 min, to dilate their veins. Each mouse is then individually placed inside a restrainer, leaving the tail of the animal exposed. The tail is disinfected with antimicrobial wipes. The treatment with the drug is administered intravenously every 6h using a 0.5 ml insulin syringe inserted carefully into one of the tail lateral veins. Doses are prepared freshly and administered intravenously to the animals.
  • Viable counting is performed by the method of Miles and Misra [J. Hyg. (1938) 38 732-749).
  • 20 ⁇ _ of the sample are serially diluted in 180 ⁇ _ PBS in round-bottomed 96-wells microtitre plates, up to a dilution of 10 6 .
  • Blood agar plates are divided into six sectors and 60 ⁇ _ of each dilution plated onto an individual sector. The plates are incubated in C0 2 gas jars overnight at 37°C. The following day, colonies are counted in the sector where 30-300 colonies are visible.
  • the concentration of colony forming units (CFU) per millilitre is determined by using the following equation:
  • a prodrug derivative can be incubated with mouse or human plasma at 37°C at 5 time points over a 2h period. The samples are then analysed by LC-MS/MS to obtain the amount of parent active compound appearing and prodrug derivative remaining over time.
  • the mouse plasma assay system is considered to be a good model for human behaviour. Nevertheless data in a human plasma assay system may be obtained in some cases.
  • Prodrug derivatives are assessed in the mouse or human plasma stability assay at a concentration of 10 ⁇ .
  • Test compounds are diluted in DMSO to a final stock concentration of 10 mM.
  • the stocks prepared are further diluted in DMSO to a concentration of 400 ⁇ and 5 ⁇ are added to 195 ⁇ of mouse or human plasma (pH 7.4) and then incubated at 37°C.
  • the final concentration of DMSO in the plate is 2.5% (v/v). Reactions are terminated at 0, 15, 30, 60 and 120 min after incubation by adding 400 ⁇ of acetonitrile containing 0.55 ⁇ metoprolol and 1 % (v/v) formic acid.
  • the plate is then centrifuged at 3000 rpm, for 45 min, at 4°C. 80 ⁇ of supernatant is transferred into a conical bottom 96 well glass coated plate. 40 ⁇ of water is added prior to analysis for prodrug derivative and parent active species by LC-MS/MS.
  • the quantification of the prodrug compound remaining and the parent active compound appearing may be performed as follows:
  • the parent active compound is quantified using a 6 point calibration curve prepared in deactivated mouse or human plasma.
  • the percentage of prodrug compound remaining at each time point relative to 0 min sample is calculated from LC-MS/MS peak area ratios
  • Parenteral delivery is one preferred route of administration of compounds of the invention. Therefore, solubility and chemical stability in aqueous buffers is desirable in order to achieve a readily soluble formulation, with enhanced chemical stability that could be reconstituted at the bed side, at a high concentrations, in safe saline solutions, compatible with intravenous administration.
  • Solubility studies may be performed by charging a vial with 5-10 mg of compound followed by the addition of PBS solution to achieve a concentration of 100 mg/ml. If solubility is not observed, the solution may be diluted to concentrations of 50 mg/ml, 25 mg/ml and 4 mg/ml consecutively until complete solubility is observed.
  • Stability studies may be performed by dissolving 1-2 mg of compound in DMSO (1 ml) followed by addition of 0.4 ml of the resulting solution to stirred PBS (9.6 ml) at 37.5°C. A sample ( ⁇ 0.5 ml) is immediately taken for HPLC analysis. Further samples are then taken for analysis at various time-points thereafter. Half-lives are determined from the decrease in concentration of compound with respect to time.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne, entre autres, des composés de formule (I), où R1, R2, R3, R4a et R4b sont tels que définis dans la description et leur utilisation en thérapie, en particulier dans le traitement d'infections bactériennes (par ex. infection à pneumocoques).
PCT/GB2014/051744 2013-06-06 2014-06-05 Dérivés de 3,4-dihydroxy-pyrroles servant d'agents antibactériens WO2014195718A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1310126.6 2013-06-06
GBGB1310126.6A GB201310126D0 (en) 2013-06-06 2013-06-06 Novel pyrrole derivatives

Publications (1)

Publication Number Publication Date
WO2014195718A1 true WO2014195718A1 (fr) 2014-12-11

Family

ID=48875893

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2014/051744 WO2014195718A1 (fr) 2013-06-06 2014-06-05 Dérivés de 3,4-dihydroxy-pyrroles servant d'agents antibactériens

Country Status (2)

Country Link
GB (1) GB201310126D0 (fr)
WO (1) WO2014195718A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1311336A (en) * 1970-09-07 1973-03-28 Ici Ltd Quaternary salts of pyrolylpyridine derivatives
WO2003078396A1 (fr) * 2002-03-12 2003-09-25 Wyeth Preparation d'acide sulfamique n1-(2'-pyridyl)-1,2-propanediamine et utilisation de celui-ci pour la synthese de piperazines biologiquement actives
EP1403265A1 (fr) * 2002-09-24 2004-03-31 Les Laboratoires Servier Nouveau procédé de synthèse industriel des tétraesters de l'acide 5-[bis(carboxyméthyl)amino] -3-carboxyméthyl-4-cyano-2-thiophènecarboxylique, et application à la synthèse des sels bivalents de l'acide ranélique et de leurs hydrates
WO2009035553A2 (fr) * 2007-09-11 2009-03-19 University Of Tennessee Research Foundation Analogues de l'acide tétramique
EP2486925A1 (fr) * 2009-10-09 2012-08-15 Mitsubishi Tanabe Pharma Corporation Agent thérapeutique de l'infarctus cérébral
WO2013083975A2 (fr) * 2011-12-05 2013-06-13 University Of Leicester Nouveaux dérivés de pyrrole

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1311336A (en) * 1970-09-07 1973-03-28 Ici Ltd Quaternary salts of pyrolylpyridine derivatives
WO2003078396A1 (fr) * 2002-03-12 2003-09-25 Wyeth Preparation d'acide sulfamique n1-(2'-pyridyl)-1,2-propanediamine et utilisation de celui-ci pour la synthese de piperazines biologiquement actives
EP1403265A1 (fr) * 2002-09-24 2004-03-31 Les Laboratoires Servier Nouveau procédé de synthèse industriel des tétraesters de l'acide 5-[bis(carboxyméthyl)amino] -3-carboxyméthyl-4-cyano-2-thiophènecarboxylique, et application à la synthèse des sels bivalents de l'acide ranélique et de leurs hydrates
WO2009035553A2 (fr) * 2007-09-11 2009-03-19 University Of Tennessee Research Foundation Analogues de l'acide tétramique
EP2486925A1 (fr) * 2009-10-09 2012-08-15 Mitsubishi Tanabe Pharma Corporation Agent thérapeutique de l'infarctus cérébral
WO2013083975A2 (fr) * 2011-12-05 2013-06-13 University Of Leicester Nouveaux dérivés de pyrrole

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences, 17th ed.,", 1985, MACK PUBLISHING COMPANY
BIOCHEM. J., vol. 140, 1974, pages 95 - 98
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ELASSAR, ABDEL-ZAHER A.: "Synthesis, characterisation and bioactivity of polysubstituted 1-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole derivatives", XP002727495, retrieved from STN Database accession no. 2012:1056084 *
ELASSAR, ABDEL-ZAHER A.: "Synthesis, characterisation and bioactivity of polysubstituted 1-(4-(1H-pyrrol-1-yl)phenyl)-1H-pyrrole derivatives", JOURNAL OF CHEMICAL RESEARCH , 36(6), 328-332 CODEN: JCROA4; ISSN: 1747-5198, 2012, DOI: 10.3184/174751912X13353579628083 10.3184/174751912X13353579628083 *
INFECT. IMMUN., vol. 65, 1997, pages 4411 - 4418
INFECT. IMMUN., vol. 68, 2000, pages 1557 - 1562
INFECT. IMMUN., vol. 70, 2002, pages 1017 - 1022
INFECT. IMMUN., vol. 72, 2004, pages 6694 - 6698
INVEST. OPHTALMOL. VIS. SCI., vol. 48, 2007, pages 2661 - 2666
J. INFECT, vol. 55, 2007, pages 394 - 399
LANCET, vol. 360, 2002, pages 211 - 218
LEE ET AL: "Synthesis and characterization of polar functional group substituted mono- and bis-(o-carboranyl)-1,3,5-triazine derivatives", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 49, no. 1, 30 October 2007 (2007-10-30), pages 159 - 164, XP022374279, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2007.10.145 *
MICROB. PATHOG., vol. 27, 1999, pages 303 - 309
MILES; MISRA, J. HYG., vol. 38, 1938, pages 732 - 749
MORTON; GRIFFITHS, VETERINARY RECORD., vol. 111, 1985, pages 431 - 436
SUN ET AL: "Influence of N-substituent and solvent on internal conversion in 1-aminonaphthalenes", SPECTROCHIMICA ACTA. PART A: MOLECULAR AND BIOMOLECULAR SPECTROSCOPY, ELSEVIER, AMSTERDAM, NL, vol. 68, no. 2, 29 August 2007 (2007-08-29), pages 220 - 224, XP022219986, ISSN: 1386-1425, DOI: 10.1016/J.SAA.2006.11.017 *
THEODORA W. GREENE; PETER G.M. WUTS: "Protective Groups in Organic Synthesis 4th Rev Ed.,", 2006, JOHN WILEY & SONS INC, ISBN: 0471697540
TOXICON, vol. 57, 2011, pages 540 - 545
TREAT B. JOHNSON ET AL: "Research Article SYNTHESES OF PYRROLE COMPOUNDS FROM IMIDO ACIDS. N-PHENYL-[alpha],[alpha]'-DICARBETHOXY-[beta], [beta]'-DIKETOPYRROLIDINE.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 33, no. 5, 1 May 1911 (1911-05-01), pages 745 - 755, XP055064917, ISSN: 0002-7863, DOI: 10.1021/ja02218a013 *

Also Published As

Publication number Publication date
GB201310126D0 (en) 2013-07-24

Similar Documents

Publication Publication Date Title
JP6567778B2 (ja) Ｇｌｐ−１受容体アゴニスト作用を持つピラゾロピリジン誘導体
JP6419990B2 (ja) ブロモドメイン阻害剤としてのベンゾイミダゾール誘導体
TWI458723B (zh) １，２－雙取代雜環化合物
US9221756B2 (en) Pyrrole derivatives
TW201623295A (zh) 具有ｂａｃｅ１抑制活性之二氫噻及二氫衍生物
JP6226889B2 (ja) 新規抗マラリア薬
KR20170139144A (ko) 6원 헤테로환 유도체 및 그를 함유하는 의약 조성물
CA2961033A1 (fr) Compose heterocyclique
JP2008501732A (ja) Ｃｃｒ５拮抗剤としての化合物
US7176313B2 (en) Anti acid-fast bacterial agent containing pyridonecarboxylic acids as active ingredient
JPH05163244A (ja) ピリドンカルボン酸誘導体
JP6231107B2 (ja) マクロライド誘導体、その製造およびその治療的使用
WO2014195705A1 (fr) Nouveaux dérivés de pyrrole
WO2014195702A1 (fr) Nouveaux dérivés de pyrrole
WO2014195718A1 (fr) Dérivés de 3,4-dihydroxy-pyrroles servant d'agents antibactériens
TW201412749A (zh) 含胺基之吡咯啶酮衍生物
US20160130224A1 (en) Novel Pyrrole Derivatives
CN114746089A (zh) 噻唑甲酰胺化合物及其用于治疗分枝杆菌感染的用途
WO2014195697A1 (fr) Nouveau dérivé de pyrrole
EP1314726A1 (fr) Nouveaux derives esteriques ou amidiques
JPS59199693A (ja) インドリルグリシルセフアロスポリン誘導体
FR2953836A1 (fr) Nouveaux derives (heterocycle-tetrahydro-pyridine)-(piperazinyl)-1-alcanone et (heterocycle-dihydro-pyrrolidine)-(piperazinyl)-1-alcanone et leur utilisation comme inhibiteurs de p75
RU2029771C1 (ru) Оптически активные производные пиридобензоксазина или их соли
AU2007260298A1 (en) Pyrrolidine compounds as renin inhibitors
WO2010012138A1 (fr) Dérivés de l'acide carboxylique de quinoline 7-[4-(aminométhyl)-4-fluoro-3-(alkoxyimino)pyrrolidin-1-yle] et leurs procédés de préparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14732300

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14732300

Country of ref document: EP

Kind code of ref document: A1