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  • 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
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/402—1-aryl substituted, e.g. piretanide
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  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Definitions

• the invention relates to compounds which are cytolysin inhibitors and their use in therapy, including in pharmaceutical combinations, especially in the treatment of bacterial, e.g.
• 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 compounds that specifically inhibit the direct toxic effect of pneumolysin and other cholesterol dependent cytolysins that are pivotal in the virulence of their respective hosts.
• the compounds of the invention have no structural similarity to Allicin and do not bind covalently to the reactive thiol groups of the toxins.
• Certain N-phenyl substituted pyrroles are known, however their use as pharmaceuticals in particular for the treatment of bacterial infections had not been suggested.
• diethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2,5-dicarboxylate (CAS 654052-34-3) and diethyl 3,4-dihydroxy-1-phenyl-1 /-/-pyrrole-2,5-dicarboxylate (CAS 55932-13-3) are commercially available.
• the compounds of the present invention also prevent stimulation of host-derived toxic effects induced by pneumolysin and other cholesterol dependent cytolysins.
• 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 and R 2 are independently selected from -C(0)NR 5 R 6 , -C(0)OR 7 , CN, -C(0)R 7 , -
• R 3 is optionally substituted phenyl
• 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, C3-C1 0 cycloalkyl, C5-C1 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 and R 6 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 -C1 0 cycloalkyl, C5-C1 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 8 is Ci-C e alkyl
• R 9 is hydrogen, C C 6 alkyl; -C(0)R 10 or -C(0)OR 1 1 ;
• R 10 is Ci-C e alkyl
• R 11 is Ci-Ce alkyl
• R 12 is Ci-Ce alkyl
• R 13 is hydrogen or C C 6 alkyl
• R 14 is hydrogen or C C 6 alkyl
• R 21 and R 22 are independently selected from C C 6 alkyl and C C 6 hydroxyalkyl
• the compounds of formula (I) including the compounds which are the subject of provisos a) to i) have therapeutic activity.
• the present invention provides a compound of formula (I) without provisos a) to i) for use as a medicament.
• Figure 1 shows the in vitro inhibition of pneumolysin-induced LDH release by the compound UL1-012 using A549 human lung epithelial cells.
• Figure 2A shows the effect of the compound UL1-012 in inhibiting pneumolysin from damaging the ciliary function of ependymal cells in an ex vivo meningitis efficacy assay.
• Figure 2B shows the effect of the compound UL1-012 in inhibiting a bacterial lysate from damaging the ciliary function of ependymal cells in an ex vivo meningitis efficacy assay.
• Figure 3 shows the effect of the compound UL2-001 in inhibiting pneumolysin from damaging the ciliary function of ependymal cells in an ex vivo meningitis efficacy assay.
• Figure 4 shows the experimental design for an in vivo mouse pneumonia model efficacy assay using the compound UL1-012.
• Figure 5 shows the survival of infected control mice and treated groups administered with 4 mg/kg of the compound UL1-012 in an in vivo mouse pneumonia model efficacy assay.
• Figure 6 shows the survival of infected control mice and treated groups administered with 16 mg/kg of the compound UL1-012 in an in vivo mouse pneumonia model efficacy assay.
• Figure 7 shows a comparison of the signs of disease between an infected/non-treated control group and an infected/ treated group that received 16 mg/kg of the compound UL1-012 in an in vivo mouse pneumonia model efficacy assay.
• Figure 8 shows the experimental design for an in vivo mouse pneumonia model efficacy assay using the compound UL2-001.
• Figure 9 shows the survival of infected control mice and treated groups administered with 8 mg/kg of the compound UL2-001 in an in vivo mouse pneumonia model efficacy assay.
• R 1 and R 2 may be independently selected from -C(0)NR 5 R 6 , -C(0)OR 7 , CN, -C(0)R 7 , - C(0)NHC(0)R 7 , -N0 2 , -SO 3 R 7 , -SO 2 R 7 , -SOR 7 , -S0 2 NR 5 R 6 , -S0 2 NH-C(0)OR 8 and optionally substituted phenyl or heteroaryl; for example R 1 and R 2 may be independently selected from - C(0)NR 5 R 6 , -C(0)OR 7 , CN, -C(0)R 7 , -C(0)NHC(0)R 7 , -SO 3 R 7 , -S0 2 R 7 , -SOR 7 , -S0 2 NR 5 R 6 , - S0 2 NH-C(0)OR 8 and optionally substituted phenyl or heteroaryl.
• R 1 and R 2 are preferably independently selected from -C(0)NR 5 R 6 , -C(0)OR 7 , CN, -C(0)R 7 , -C(0)NHC(0)R 7 and - S0 2 NH-C(0)OR 8 ; more preferably R 1 and R 2 are independently selected from -C(0)NR 5 R 6 , - C(0)OR 7 and CN; even more preferably R 1 and R 2 are independently selected from -C(0)NR 5 R' and -C(0)OR 7 .
• R 1 is preferably -C(0)NR 5 R 6 .
• R 2 is -C(0)NR 5 R 6 .
• R 2 is -C(0)OR 7 .
• R 1 is -C(0)NR 5 R 6 and R 2 is -C(0)NR 5 R 6 and in another embodiment R 1 is - C(0)NR 5 R 6 and R 2 is -C(0)OR 7 .
• R 1 and R 2 are both -C(0)NR 5 R 6 they may be same or different, preferably they are the same.
• R 1 and R 2 are both -C(0)OR 7 and they may be same or different, preferably they are the same.
• R 3 is preferably substituted phenyl. 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
• R a and R b are independently selected from hydrogen and C C 6 alkyl; -O-R 15 wherein R 15 is -(CH 2 ) X - P(0)(OR 23 ) 2 (where x is 0, 1 , 2, 3 or 4 and R 23 is independently selected from hydrogen and C C 3 alkyl), -(CH 2 )y-S(0) 2 Me (where y is 1 , 2, 3 or 4), -C C 6 alkylheterocyclyl which heterocyclyl group may be optionally substituted e.g.
• C C 3 alkyl -C C 6 alkylphenyl which phenyl group may be optionally substituted e.g. by C C 3 alkoxy, or phenyl or 5- or 6-membered heteroaryl which phenyl or heteroaryl group may optionally be substituted by a group e.g. selected from C1-C4 alkyl and halo; or -(0(CH 2 ) z ) p OR 24 , where each z, which may be the same or different, represents 2 or 3, p represents 1 , 2, 3, 4 or 5 and R 24 is hydrogen or C1-C 3 alkyl; or two adjacent carbon atoms within R 3 may be linked by -0-CH 2 -0-.
• R 15 is -C C 6 alkylheterocyclyl
• particular heterocyclyl groups which may be mentioned include 5- or 6-membered, monocyclic non-aromatic ring systems, containing up to two heteroatoms selected from N, O and S. Such rings are suitably linked to -C C 6 alkyl via an N atom.
• heterocyclic rings include morpholine, piperazine, and the like, which may be optionally substituted e.g. by C1-C 3 alkyl, such as methyl.
• Further examples of heterocyclic rings include piperidine and pyrrolidine.
• a group of suitable optional substituents for R 3 which may be mentioned include 1 , 2 or 3 substituents selected from halo, cyano, C C 6 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 Ci-C 6 alkyl.
• R 3 when R 3 is substituted phenyl, said phenyl may be provided with a single substituent -O-R 15 wherein R 15 is selected from phenyl and 5- or 6-membered heteroaryl which phenyl or heteroaryl group may optionally be substituted by a group selected from C C 4 alkyl and halo.
• Preferred optional substituents for R 3 include 1 or more, e.g. 1 , 2 or 3, substituents (e.g. 1 substituent) independently selected from C C 6 alkoxy; -O-R 15 wherein R 15 is -(CH 2 ) X - P(0)(OR 23 ) 2 , where x is 0, 1 , 2, 3 or 4 and R 23 is independently selected from hydrogen and C C 3 alkyl or R 15 is -(CH 2 ) y -S(0) 2 Me where y is 1 , 2, 3 or 4; and -(0(CH 2 ) z ) p OR 24 , where each z, which may be the same or different, represents 2 or 3, p represents 1 , 2, 3, 4 or 5 and R 24 is hydrogen or C1-C 3 alkyl.
• R 3 When R 3 is substituted phenyl, it preferably has a substituent in the meta or para position relative to the pyrrole ring, more preferably it has a substituent in the para position relative to the pyrrole ring. Alternatively, when R 3 is substituted phenyl it may have a substituent in the ortho position relative to the pyrrole ring. In one embodiment, R 3 is phenyl substituted by a single substituent. In another embodiment, R 3 is phenyl substituted by two substituents. When R 3 is substituted phenyl having 2 substituents, these may, for example, be in the meta and para positions relative to the pyrrole ring. In another embodiment, R 3 is phenyl substituted by three substituents. When R 3 is substituted phenyl having 3 substituents, these may, for example, be in the 3, 4 and 5 positions relative to the pyrrole ring.
• R 3 may represent phenyl bearing a para substituent selected from F, CI, I, cyano, OCH 3 , OCH2CH3, OCH2CH2CH3, CF 3 , OCF3, CON(CH 3 ) 2 , O-phenyl, methyl, ethyl, isopropyl, t- butyl, hydroxyl, -OP(0)(OH) 2 , -(0(CH 2 ) 2 )pOMe where p is 1 , 2, 3 or 4, 3-morpholinopropoxy, 3- (4-methylpiperazin-1-yl)propoxy, 3-(diethoxyphosphoryl)propoxy, -(0(CH 2 ) 3 )-P(0)(OH) 2 , 3- (methylsulfonyl)propoxy, and 4-methoxybenzyloxy.
• a para substituent selected from F, CI, I, cyano, OCH 3 , OCH2CH3, OCH2CH2CH3, CF 3 , OCF3, CON(CH
• R 3 may represent phenyl bearing a para substituent selected from F, CI, I, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , CF 3 , OCF 3 , CON(CH 3 ) 2 , O-phenyl, methyl, ethyl, isopropyl and t- butyl.
• a particular R 3 group which may be mentioned is phenyl bearing a para OCH 3 substituent.
• R 3 may represent phenyl bearing an ortho substituent which is OCH 3 .
• R 3 may represent phenyl bearing a meta substituent which is O-phenyl or OCH 3 .
• R 3 may represent phenyl substituted in the meta position by I and in the para position by OCH 3 , or phenyl substituted in the meta position by OCH 3 and in the para position by OCH 3 , or phenyl linked in the meta and para positions by -0-CH 2 -0-.
• R 3 may represent phenyl substituted in the ortho position by OCH 3 and in the para position by OCH 3 .
• R 3 may represent phenyl substituted in the 3, 4 and 5 positions by OCH 3 , or phenyl substituted in the 3 and 5 positions by F and in the para position by OCH 2 CH 3 .
• a particularly suitable substituent for the phenyl of R 3 is OCH 3 , especially in the para position.
• Further particularly suitable substituents for R 3 include -O-R 15 wherein R 15 is as defined above and -(0(CH 2 ) z ) p OR 24 , where z, p and R 24 are as defined above, especially in the para position.
• R 4a and/or R 4b When an alkyl group or R 4a and/or R 4b is 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 -C1-C3 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-C 3 alkylaryl in which aryl may be optionally substituted.
• R 4a and R 4b are more preferably hydrogen or -C1-C 3 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-C3 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.
• Specific- NR 5 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 8 is preferably methyl.
• 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.
• R 15 is -(CH 2 ) x -P(0)(OR 23 ) 2 or -(CH 2 ) y -S(0) 2 Me.
• R 15 group is optionally substituted phenyl, e.g. unsubstituted phenyl.
• R 15 is-C C 6 alkylheterocyclyl which heterocyclyl group may be optionally substituted e.g. by C1-C3 alkyl.
• R 21 are R 22 are preferably independently selected from C C 6 alkyl, e.g. methyl.
• R 23 is preferably hydrogen, methyl or ethyl.
• R 24 is preferably C1-C3 alkyl, e.g. methyl.
• x is preferably 0, 1 , 2, 3 or 4.
• y is preferably 1 , 2 or 3.
• z is preferably 2.
• p is preferably 2, 3, 4 or 5.
• Prodrug derivatives of compounds of the invention will break down after administration to a subject to form an active compound of formula (I) 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 , - 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 , 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, C3-C10 cycloalkyl, C5-C10 cycloalkenyl,
• heterocyclyl -C1-C3 alkyl-C 3 -Ci 0 cycloalkyl, -C1-C3 alkyl-C 5 -Ci 0 cycloalkenyl or -C1-C3 alkylheterocyclyl, or 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. 7 to 12
• R 24 is hydrogen, C1-C3 alkyl or - PO(OR 19 )(OR 20 )), C C 6 alkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, C C 6 fluoroalkyi and -
• 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;
• 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 3 , 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 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 C
• 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.
• 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 25a 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 ) 3 ) p
• a group of specific examples of prodrug derivatives include compounds of formula (I) wherein R 4a and R 4 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 While the preferred groups for each variable have generally been listed above separately for each variable, 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.
• Particular compounds of the invention include the following:
• diethyl 3,4-dihydroxy-1-phenyl-1 /-/-pyrrole-2,5-dicarboxylate (this compound is not novel per se); diethyl 1-(4-fluorophenyl)-3,4-dihydroxy-1 /-/-pyrrole-2,5-dicarboxylate;
• Particular prodrug derivatives of the compounds of the invention include the following:
• prodrug derivatives of the compounds of the invention include the following: ethyl 3,4-bis((diethoxyphosphoryl)oxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole- 2-carboxylate;
• Particular compound of the invention and prodrugs which may be mentioned include those designated as compounds UL1-004, UL1-005, UL1-012, UL1-024, UL1-028, UL1-035, UL1- 049, UL1-070, UL1-089, UL1-098, UL1-106, UL1-109, UL1-11 1 , UL1-114, UL1-115, UL1-116, UL1-117, UL1-118, UL1-120, UL1-121 , UL1-122, UL1-124, UL1-126 and UL2-001 , in Table 1 below.
• 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.
• FluoroalkyI 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 .
• Cycloalkyl 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.
• 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 the like a further example is 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 substantially free of the corresponding enantiomeric form.
• 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.
• the disclaimed compounds are disclaimed in all their tautomeric forms.
• R x typically represents d-C 6 alkyl such as methyl or ethyl.
• R x typically represents CrC 6 alkyl such as methyl ethyl.
• Scheme D A method for preparing certain compounds of formula (I) in which R 1 is -C(0)NR 5 R 6 , R 2 is C(0)NR 5 R 6 and R 4a and R 4b represent hydrogen is shown below in Scheme E:
• Scheme J may be adapted to convert one or both hydroxyl groups to OR and/or OR depending on the molar excess of reagent(s) employed.
• R 4a and R 4b are different, it may be necessary to employ a protection strategy to incorporate one and then the other group. This process is also suitable for preparing prodrug derivatives of compounds of formula (I).
• R 2 is -POR 21 R 22
• R 22 may be prepared by reaction of a compound of formula (XVII) shown above with a compound of formula POR 21 R 22 CI, followed by deprotection.
• Scheme M A method for preparing certain compounds of formula (I) where R 1 is -C(0)OR 7 , R 2 is tetrazole and R 4a and R 4b represent H is shown below in Scheme N:
• Compounds of formula (I) may be converted to different compounds of formula (I) by the above methods and/or by conventional methods.
• 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.
• 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.
• R 1 and R 2 are as defined above for the compounds of formula (I), and R 3 is phenyl substituted by 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 hydroxyalkoxy, C C 6 fluoroalkoxy, C C 6 alkyl, Ci-C 6 fluoroalkyl, -C(0)NR a R b , where R a and R b are independently selected from hydrogen and Ci-C e alkyl; -O-R 15 wherein R 15 is -(CH 2 ) x -P(0)(OR 23 ) 2 , where x is 0, 1 , 2, 3 or 4 and R 23 is independently selected from hydrogen and C C 3 alkyl, -(CH 2 ) y -S(0) 2 Me where y is 1 , 2, 3 or 4, -Ci-C 6 alkylheterocycl
• R 5 or R 6 is optionally substituted aryl
• said aryl is optionally substituted by 1 , 2 or 3 groups selected from hydroxyl, halo, cyano, C C 6 alkoxy or C C 6 fluoroalkoxy, C C 6 alkyl or 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; or when two adjacent hydroxyl substituents are present they may optionally be connected by a methylene group to form an acetal;
• R 5 or R 6 is optionally substituted aryl
• said aryl is optionally substituted by 1 , 2 or 3 groups selected from hydroxyl, halo, cyano, C C 6 alkoxy or C C 6 fluoroalkoxy, C C 6 alkyl or 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; or when two adjacent hydroxyl substituents are present they may optionally be connected by a methylene group to form an acetal;
• Particular compounds of formula (II) include those mentioned in the examples.
• 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.
• 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 comprising a compound of formula (I) without provisos a) to i) optionally in combination with one or more
• 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 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.
• typical 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.
• the compounds of the invention are inhibitors of the cholesterol-dependent cytolysin, pneumolysin, produced by the bacterium Streptococcus pneumoniae. They also inhibit
• Streptolysin O 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.
• 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: Porcine meningitis, septicaemia/bacteraemia and septic shock caused by Streptococcus suis which produces a cholesterol dependent cytolysin, Suilysin, involved in the pathogenesis of diseases by S. suis.
• 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.
• bacterial pore-forming toxins such as the RTX family of toxins
• 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 use in the treatment of pneumococcal pneumonia, pneumococcal meningitis, pneumococcal septicaemia/bacteraemia, pneumococcal keratitis or pneumococcal otitis media; and
• -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) without provisos a) to i) for use in the treatment of the above mentioned conditions.
• the present invention provides a compound of formula (I) without provisos a) to i) for the manufacture of a medicament for the treatment of the above mentioned conditions.
• 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) without provisos a) to 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
• Further combinations include combinations with immunomodulatory agents, such as anti- inflammatory 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) without provisos a) to i) in combination with one or more further active ingredients, for example one or more of the active ingredients described above.
• Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula (I) without provisos a) to i) optionally in combination with one or more
• compositions comprising:
• 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:
• 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) without provisos a) to i) may also be provided for use, e.g. with instructions for use, in combination with one or more further active ingredients.
• a further aspect of the invention provides a compound of formula (I) without provisos a) to i) for use in combination with one or more further active ingredients, for example one or more of the active ingredients described above.
• the compound of formula (I) without provisos a) to i) for use in this aspect of the invention may be used in the treatment or prevention of any of the conditions mentioned above.
• NMR spectra were recorded using a Bruker Avance III 400 MHz instrument, using either residual non-deuterated solvent or tetra-methylsilane as reference.
• Example A A/ 2 ,A/ 2 ,A/ 5 ,A/ 5 -Tetraethyl-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2,5- dicarboxamide (UL1 -003)
• Example B Ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2- ca
• reaction mixture was stirred at 60°C for 16h and then partitioned between 2 M HCI (aq.) (500 mL), and EtOAc (300 mL), the aqueous phase was extracted with EtOAc (300 mL) and the combined organics were washed successiveively with 2 M HCI (aq.) (2 x 300 mL), water (500 mL), and brine (500 mL), dried (MgS0 4 ), filtered and solvents removed in vacuo to give diethyl 2,2'- ((4-methoxyphenyl)azanediyl)diacetate (4) (180 g, 100 %) as a purple oil: m/z 296 (M+H) + (ES + ).
• Diethyl oxalate (83 ml, 0.61 mol) was added dropwise to a stirred solution of diethyl 2,2'-((4- methoxyphenyl)azanediyl)diacetate (4) (180 g, 0.61 mol) in NaOEt (21 % by wt in EtOH) (506 ml, 1.3 mol), the mixture was stirred at 100°C for 1 h. The reaction was quenched with acetic acid (210 ml, 3.7 mol) and the resulting suspension was poured into iced water (1 L), the resulting off-white solid collected by vacuum filtration.
• Example C A/ 2 -Ethyl-3,4-dihydroxy-1-(4-methoxyphenyl)-/ ⁇ / 5 ,A/ 5 -dimethyl-1 /-/-pyrrole-2,5- dicarboxamide (UL1 -024)
• reaction mixture was partitioned between sat. NH 4 CI solution (aq.) (5 mL) and EtOAc (20 mL) the aqueous was further acidified with 1 M HCI (5 mL). The organic layer was separated and washed with brine (25 mL), dried (MgS0 4 ), filtered and concentrated in vacuo to afford crude product. The residue was purified by silica gel
• Step (ii) A/ 2 -Ethyl-3,4-dihydroxy-1-(4-methoxyphenyl)-/ ⁇ / 5 ,/ ⁇ / 5 -dimethyl-1 /-/-pyrrole-2,5- dicarboxamide (UL1 -024)
• Example D isopropyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2- carboxylate (UL1 -035)
• Example E te/f-Butyl (5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrol-2- yl)sulfonylcarbamate (UL1 -030)
• Example F 5-Cyano-3,4-dihydroxy-1-(4-methoxyphenyl)-/ ⁇ /,A/-dimethyl-1 /-/-pyrrole-2- carboxamide (UL1 -031)
• reaction mixture was partitioned between DCM (50 ml_) and 1 M HCI (aq.) (30 ml_), the organic was washed with 1 M HCI (aq.) (20 ml_), sat. NaHC0 3 (aq.) (30 ml_), and brine (20 ml_), dried (MgS0 4 ), filtered and volatiles removed in vacuo to afford a yellow solid.
• Example H Ethyl 5-cyano-1-(4-fluorophenyl)-3,4-dihydroxy-1 /-/-pyrrole-2-carboxylate (UL1 -039)
• reaction mixture was allowed to warm to RT and partitioned between 1 M HCI (aq.) (25 mL) and DCM (50 mL) the organic layer was washed with 1 M HCI (aq.), and sat. NaHC0 3 (aq.) (25 mL), dried (MgS0 4 ), filtered and the volatiles removed in vacuo to afford the crude product.
• Ethyl 3,4-bis(benzyloxy)-5-cyano-1-(4-fluorophenyl)-1 /-/-pyrrole-2-carboxylate (UL1 -060) (102 mg, 0.22 mmol) in THF (5 mL) was passed through a Thales ⁇ -cube' cartridge (10% Pd/C) at a flow rate of 1.5 mL/min at 20°C under H 2 (full H 2 mode). The output was concentrated in vacuo to afford the crude product.
• Example J 2-(Dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4-diyl diacetate (UL1 -044)
• 2-((4-methoxyphenyl)amino)acetic acid (18) 45 g, 0.25 mol
• dimethylamine hydrochloride 40.5 g, 0.5 mol
• DIPEA 174 ml, 0.99 mol
• HATU 99 g, 0.26 mol
• reaction mixture was stirred at RT for 1 h, and then partitioned between EtOAc (1 L) and 5% NaH 2 P0 4 (aq.) (250 mL), the organic layer was washed with sat. NaHC0 3 (aq.) (3 x 300 mL), and 3M HCI (aq.) (4 x 250 mL).
• Example L Diisopropyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2,5-dicarboxylate (UL2- 020) and 2-ethyl 5-isopropyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2,5-dicarboxylate (UL2-021)
• Lithium isopropoxide (2M in THF) (10.4 mL, 20.8 mmol) was added to a mixture of diisopropyl 2,2'-((4-methoxyphenyl)azanediyl)diacetate (21) (2.69 g, 8.32 mmol) [prepared using the same procedure as Example B step (i) using isopropyl 2-bromoacetate] and diethyl oxalate (1.13 mL, 8.32 mmol), the mixture was stirred at 65°C for 16h. A further portion of lithium isopropoxide (2M in THF) (5.2 ml, 10.4 mmol) was added and the reaction stirred at 65°C for 3h.
• Impure fractions were combined and purified by preparative HPLC (C-18, 5 ⁇ , 21.2x50 mm column, 5-95% MeCN in Water 0.1 % Formic Acid) to afford 2-ethyl 5-isopropyl 3,4-dihydroxy-1- (4-methoxyphenyl)-1 /-/-pyrrole-2,5-dicarboxylate (UL2-021) (22 mg, 1 %) as a white solid: m/z 364 (M+H) + (ES + ).
• reaction mixture was stirred at RT for 18h, and partitioned between EtOAc (200 mL) and sat. NaHC0 3 (aq.) (200 mL), the organic layer was separated and washed with sat. NaHC0 3 (aq.) (2 x 200 mL), dried (MgS0 4 ), filtered and solvents removed in vacuo to give a yellow oil.
• HATU 153 mg, 0.40 mmol was added to a stirred solution 2-((4-(benzyloxy)-2,5- bis(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrol-3-yl)oxy)acetic acid (24) (100 mg, 0.20 mmol), DIPEA (176 ⁇ , 1.00 mmol), and NH 4 CI (53.8 mg, 1.00 mmol) in THF (2 mL) at O°C.
• Example O Ethyl 5-(dimethylcarbamoyl)-3,4-bis((dimethylcarbamoyl)oxy)-1-(4-methoxyphenyl)- 1 /-/-pyrrole-2-carboxylate (UL1 -063)
• Dimethylcarbamic chloride 160 ⁇ _, 1.74 mmol was added dropwise to a stirred suspension of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (UL1 - 012) (202 mg, 0.58 mmol) and K 2 C0 3 (240 mg, 1.74 mmol) in MeCN (4 mL). The resulting mixture was stirred at 80°C for 16h then partitioned between sat.
• Example P Ethyl 5-(dimethylcarbamoyl)-4-((dimethylcarbamoyl)oxy)-3-hydroxy-1-(4- methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (UL1 -066)
• Example Q Ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-(sulfamoyloxy)-1 /-/- pyrrole-2-carboxylate (UL1 -068)
• Example R Ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-(phosphonooxy)-1 /-/- pyrrole-2-carboxylate (UL1 -070)
• Perbromomethane (286 mg, 0.86 mmol) and A/-ethyl-A/-isopropylpropan-2-amine (376 ⁇ _, 2.15 mmol) were added successively to a solution of A/,A/-dimethylpyridin-4-amine (8.8 mg, 0.07 mmol) and ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2- carboxylate (UL1 -012) (250 mg, 0.72 mmol) in MeCN (3 mL) at -10°C.
• reaction mixture was allowed to stir for 30 min and bis(phenoxymethyl)phosphine oxide (166 ⁇ _, 0.75 mmol) was added, the reaction was allowed to slowly warm to 0°C and stirred for 1 h.
• the reaction was quenched with 5 % NaH 2 P0 4 (aq.) (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organics were washed with brine (50 mL), dried (MgS0 4 ), filtered and solvents removed in vacuo.
• the crude residue was purified by silica gel chromatography (40 g, 0-4 % MeOH in DCM) to afford an orange oil.
• the compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d. x 100 mm, 5 micron particle size, gradient 5-95 % MeCN in 0.1 % aqueous formic acid over 16 min) to afford ethyl 4-((bis(benzyloxy)phosphoryl)oxy)-5- (dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (26) (228 mg, 51 %) as a pale yellow solid: m/z 609 (M+H) + (ES + ); 607 (M-H) " (ES " ).
• ethyl 3,4-bis(benzyloxy)-5-iodo-1-(4-methoxyphenyl)-1 /-/-pyrrole-2-carboxylate 28) (300 mg, 0.51 mmol) in DMF (5 ml_) was added 2-(tributylstannyl)pyridine (280 ⁇ _, 0.87 mmol), copper(l) iodide (19.6 mg, 0.10 mmol) and dichlorobis(triphenylphosphine)palladium(ll) (36.1 mg, 0.05 mmol).
• Example T Ethyl 5-(4-ethylthiazol-2-yl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2- carboxylate (UL1 -086)
• Example U Ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-1 /-/-0 pyrrole-2-carboxylate (UL1 -087)
• HATU (739 mg, 1.94 mmol) was added to a solution of triethylammonium 3,4-bis(benzyloxy)-5- (ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (5) (325 mg, 0.65 mmol), DIPEA (566 ⁇ _, 3.24 mmol) and acetohydrazide (53 mg, 0.71 mmol) in DMF (5 ml_) at 0°C. The0 mixture was stirred for 30 min and allowed to warm to RT.
• the reaction was partitioned between water (10 ml_) and Et 2 0 (30 ml_) and NH 4 OAc (aq.) (20 ml_) was added, the organic layer was separated and washed with sat. NaHC0 3 (aq.) (20 ml_), brine (20 ml_), dried (MgS0 4 ), filtered and solvents removed in vacuo.
• Example V Ethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-5-(2H-tetrazol-5-yl)-1 /-/-pyrrole-2- carboxylate (UL1 -089)
• the organic layer was separated and washed with water (3 x 15 mL), dried (MgS0 4 ), filtered and solvents removed in vacuo.
• the product was purified by silica gel chromatography (40 g, 0-40 % MeOH in DCM/2.5 %Et 3 N) to afford the triethylammonium salt of (UL1 -090).
• the salt was dissolved in DCM (10 mL) and the organic layer was washed with 1 M HCI (aq.) (10 mL), brine (10 mL), sat.
• Example X Ethyl 3,4-bis((diethoxyphosphoryl)oxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)- 1 /-/-pyrrole-2-carboxylate (UL1 -092)
• the compound was further purified by preparative HPLC (C-18 column, 21.2 mm i.d. x 100 mm, 5 micron particle size, gradient 5-95 % MeCN in 0.1 % aq. formic acid over 16 min) to afford ethyl 3,4-bis((diethoxyphosphoryl)oxy)-5- (dimethylcarbamoyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (UL1 -092) (35 mg, 22 %) as a yellow oil: m/z 621 (M+H) + (ES + ).
• Example Y Ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-hydroxyphenyl)-1 /-/-pyrrole-2- carboxylate (UL1 -100)
• Example Z Ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-(3-morpholinopropoxy)phenyl)-1 /-/- pyrrole-2-carboxylate (UL1 -102)
• 4-(3-chloropropyl)morpholine hydrochloride (19 mg, 0.10 mmol) and K 2 C0 3 (25 mg, 0.18 mmol) in DMF (1 mL) was stirred at 60°C for 18h.
• Example A1 2-(Dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4- diyl bis(3-methoxypropanoate) (UL1 -104)
• Example B1 2-(Dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4- diyl bis(3-(2-methoxyethoxy)-2,2-dimethylpropanoate) (UL1 -108)
• Example C1 Ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4- ((phosphonooxy)methoxy)-1 /-/-pyrrole-2-carboxylate (UL1 -109)
• Benzyl bromide (3.94 ml_, 33.2 mmol) was added to a stirred suspension of ethyl 5- (dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (UL1 -012) (10.5 g, 30.1 mmol), potassium iodide (5.50 g, 33.2 mmol) and K 2 C0 3 (4.58 g, 33.2 mmol) in DMF (100 ml_). The reaction was allowed to stir at 80°C for 24h.
• reaction mixture was poured into water (200 ml_), washed with Et 2 0 (2 x 200 ml_), and the combined organic layers were washed with 1 M HCI (aq.) (400 ml_), brine (2 x 400 ml_), dried (MgS0 4 ), filtered and concentrated in vacuo.
• a solution of dibenzyl (chloromethyl) phosphate (0.23 g, 0.70 mmol) in DMF (1 mL) was added dropwise to a stirred suspension of ethyl 3-(benzyloxy)-5-(dimethylcarbamoyl)-4-hydroxy-1-(4- methoxyphenyl)-1 /-/-pyrrole-2-carboxylate (41) (0.26 g, 0.58 mmol) and K 2 C0 3 (80 mg, 0.58 mmol) in DMF (4 mL) at 0°C, the reaction was stirred at for 1 h, then allowed to warm to RT over 16 h.
• Example D1 Ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-(3- (methylsulfonyl)propoxy)phenyl)-1 /-/-pyrrole-2-carboxylate (UL1 -110)
• Example E1 2,6-Dimethylcyclohexyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)- 1 /-/-pyrrole-2-carboxylate (UL1 -113)
• Example F1 2-(Dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4- diyl bis(3-(2-(2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)ethoxy)-2,2-dimethylpropanoate) (UL1 ⁇ 117)
• step (i) step (ii)
• Example G1 2-(Dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4- diyl bis(2,2-dimethyl-3-(3-(phosphonooxy)propoxy)propanoate) (UL1 -118)
• Example H1 2-(Dimethylcarbamoyl)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4- diyl bis(25,25-dimethyl-2,5,8, 11 , 14, 17,20,23-octaoxahexacosan-26-oate) (UL1 -119)
• reaction was quenched with water (100 mL) and the aqueous layer was extracted with DCM (2 x 100 mL), the combined organic layers were washed with brine (3 x 100 mL), dried (MgS0 4 ), filtered and concentrated in vacuo.
• Example 11 Ethyl 5-(dimethylcarbamoyl)-4-hydroxy-1-(4-methoxyphenyl)-3- ((phosphonooxy)methoxy)-1 /-/-pyrrole-2-carboxylate (UL1 -115)
• reaction mixture was poured into water (50 ml_), extracted with Et 2 0 (2 x 50 ml_). The combined organic layers were washed with brine (3 x 100 ml_), dried (MgS0 4 ), filtered and concentrated in vacuo.
• Example J1 2,5-Bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4-diyl bis(2,2- dimethyl-3-(2-(2-(phosphonooxy)ethoxy)ethoxy)propanoate) (UL1 -121)
• Example K1 2,5-Bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4-diyl
• Example L1 2,5-Bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1 /-/-pyrrole-3,4-diyl bis(4- ((phosphonooxy)methyl)benzoate) (UL1 -124)
• Example M 1 5-(Dimethylphosphoryl)-3,4-dihydroxy-1-(4-methoxyphenyl)-/V,/ ⁇ /-dimethyl-1 /-/- pyrrole-2-carboxamide (UL1 -125)
• PS-DCC (2.3 mmol/g, 1.25 g, 17.6 mmol) was added to a solution of 3,4-dihydroxy-1-(4- methoxyphenyl)-A/ 2 ,A/ 2 ,A/ 5 ,/ ⁇ / 5 -tetramethyl-1 /-/-pyrrole-2,5-dicarboxarTiide (UL1 -005) (200 mg, 0.58 mmol), DMAP (0.028 g, 0.230 mmol) and (1 R,4R)-4-
• reaction mixture was diluted with EtOAc (50 mL) and washed with 1 M HCI (aq.) (50 mL), sat. NaHC0 3 (aq.) (50 mL), brine (50 mL), dried (MgS0 4 ), filtered and concentrated in vacuo.

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