WO2013072903A1 - Composés nitroimidazoxadiazocines - Google Patents

Composés nitroimidazoxadiazocines Download PDF

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Publication number
WO2013072903A1
WO2013072903A1 PCT/IB2012/056546 IB2012056546W WO2013072903A1 WO 2013072903 A1 WO2013072903 A1 WO 2013072903A1 IB 2012056546 W IB2012056546 W IB 2012056546W WO 2013072903 A1 WO2013072903 A1 WO 2013072903A1
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Prior art keywords
nitro
imidazo
dihydro
oxadiazocin
methyl
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PCT/IB2012/056546
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English (en)
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Chitalu Christopher MUSONDA
Christopher David Edlin
Grant Alexander BOYLE
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Ithemba Pharmaceuticals (Proprietary) Limited
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Publication of WO2013072903A1 publication Critical patent/WO2013072903A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to nitroimidazoxadiazocine compounds, to their preparation, and to their use as drugs, effective against Mycobacterium tuberculosis (M.tb), and other microbial infections, either alone or in combination with other treatments.
  • the compounds may also be useful for the treatment of other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.
  • the World Health Organization estimates that about 1/3 of the global population is infected with Mycobacterium tuberculosis (M.tb), the bacterium that causes tuberculosis (TB) (WHO, 2010). According to the WHO report, nearly 8 million of the infected people develop active TB, of which nearly 2 million die annually from the disease.
  • M.tb Mycobacterium tuberculosis
  • TB tuberculosis
  • Multidrug-Resistant TB is defined as resistance to the two most commonly used drugs in the current four-drug (or first-line) regimen, isoniazid and rifampin.
  • the WHO treatment standards require that at least four drugs (rifampin, isoniazid, ethambutol and pyrazinamide) be used to treat TB, and to avoid the development of further resistance.
  • Extensively Drug-Resistant TB also known as Extremely Drug- Resistant TB
  • XDR-TB is emerging as an even more ominous threat.
  • XDR-TB is defined as TB that is resistant to any fluoroquinolone, and at least one of three injectable second-line drugs: capreomycin, kanamycin and amikacin. This makes XDR-TB treatment extremely complicated, with some strains proving to be virtually untreatable. According to the WHO, XDR-TB remains rare. Wherever second-line drugs to treat MDR-TB are being misused, the possibility of XDR-TB exists.
  • novel TB drugs So long as TB is treated with a long, complex, decades-old drug regimen, drug resistance will continue to develop. There is therefore a need for the development of novel TB drugs, and effective processes for producing such drugs.
  • the novel drugs are expected to work through new biological mechanisms of action to effectively tackle drug-susceptible and drug- resistant strains, and therefore allow for shorter regimens, reliably administered, thus minimizing the potential for further resistance.
  • Nitroimidazoles have recently been the subject of significant efforts to optimize anti M.tb activity, for example derivatives of PA-824 (1.1 ) and OPC-67863 (1.2) (Fig. 1 ), both of which are currently in Phase II clinical trials for the treatment of multi-drug resistant M.tb have been synthesized and reported extensively (Patents US 5,668,127, US 6, 087, 358, WO 2007075872 A2 and W0 2009/120789 A1 ; Sasaki, 2006; Palmer , 2010, Sutherland, 2010; Kmentova, 2010). Both PA-824 (1.1 ) and OPC-67863 (1.2) kill multidrug resistant M.tb.
  • PA-824 (1.1 ) Unlike most antimicrobial agents, PA-824 (1.1 ) has been shown to maintain potent antimicrobial activity either under aerobic or anaerobic conditions and works better than isoniazid, a standard regimen for M.tb. The discovery of PA-824 (1.1 ), OPC-67683 (1.2) and other derivatives has thus given new hope to the burden caused by TB. However, PA-824 (1.1 ) and OPC-67863 (1.2) both suffer from extremely low solubility and complicated formulations (Kim, 2009). This results in extremely low bioavailability for these compounds. More recently, new derivatives of PA-824 (1.1 ) aimed at overcoming the solubility issues associated with the parent drug have been reported (Kmentova, 2010).
  • Fused nitroimidazole derivatives such as the nitroimidazopyran PA-824 (1.1 ) and the nitroimidazoxazole OPC-67683 (1.2) are useful as anti- tubercular agents and so on. These derivatives are shown in Figure 1 . Different processes for making the imidazopyran PA-824 (1.1 ) have been reported (see WO 97/01562; US 2006/0063929 A1 ; Marsini, 2010); the original process (WO 97/01562), is shown in Figure 2.
  • the reagents and conditions required for the process in Figure 2 are as follows; (i) TBDMSCI, imidazole; (ii) EtOH, heat, 53%; (iii) PTS, DCM, 79%; (iv) TBAF, THF; (v) H 2 0, AcOH, THF, heat, 79%.
  • the intermediate epoxide B obtained from the reaction of enantiopure glycidal A and TBDMSCI is subsequently treated with 2,4-dinitroimidazole C in ethanol.
  • the intermediate tetrahydropyran E is obtained; removal of the silyl-protecting group with TBAF results in the cyclized THP-protected imidazopyran F.
  • Acid catalyzed removal of the THP-protecting group affords the imidazopyran derivative G with a free hydroxyl group, which is elaborated further into PA-824 (1 ).
  • An improved alternative process for synthesizing PA-824 (1.1 ) has been reported in patent US2006/0063929A1 .
  • Figure 3 details the process.
  • the reagents and conditions required for the process in Figure 3 are as follows (i) CsF, rt, neat; (ii) TBDMSCI, imidazole, DCM, rt; (iii) DCC, cat DMAP, rt; (iv) TBAF, THF, rt; (v) Ti(/PrO) 4 , reflux.
  • Glycidal A is reacted with 2,4-dinitroimidazole under basic conditions without the need to protect the hydroxyl function of the epoxide, yielding diol H, which is then selectively mono-protected at the primary alcohol position to give the terf-butysilyl ether I.
  • the secondary alcohol of the tert- butysilyl ether I is then esterified with benzoic acid to the ester J, which upon treatment with TBAF removes the silyl-protecting group.
  • the liberated alkoxide (not shown) simultaneously cyclizes into the nitroimidazolpyran ester K. Treatment of K with base affords G, which is derivatized accordingly into PA-824 (1 ).
  • the enantiomerically enriched diol L is esterified by treatment with 4-methoxybenzoyl chloride M to afford ester N.
  • the 4-trifluoromethylbenzyl alcohol O is converted to P by sequential reaction with benzyltrichloroacetimidate derived from p-(trifluoromethoxy) benzyl alcohol L and stoichiometric trifluoromethanesulfonic acid in dichloromethane, then N to generate P.
  • Ma Mb Mc Md Me R in Formulae lla-llg represents any one or more of H, F, CI, Br, CN, MeO, CF 3 , OCHF 2 , OCF 3 , a carboxamide group C(0)NR 7 R 8 , reversed carboxamide NR 7 C(0)R 8 , carboxyl C(0)R 7 , substituted or unsubstituted alkyl, alkenyl, alkynyl, substituted or unsubstituted alkyl amines, amide, aldehyde, substituted or unsubstituted phenyl, biphenyl, hydrazide, hydrazine, pyridine, dihydropyridine,morpholino, pyrrollidine, piperazine, naphthalene, oxophenyl, aryl sulphonamide, alkyl sulphonamide, cycloalkyl, alkoxy aryl, alkoxy alkyl, indole,
  • R in formula lla or lib is a carboxamide group C(0)NR 7 R 8 or a reversed carboxamide NR 7 C(0)R 8 , or a carboxyl C(0)R 7
  • R 7 and R 8 represents any one of substituted or unsubstituted alkyl, phenyl, pyridiyl, cycloalkyl, piperidine, thiophene, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;
  • Ri and R 2 in Formula lid represent one or two of H, substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, piperidine, piperazine, alkyl sulfone, phenyl, phenylsulfone, alkylphenyl, biaryl, alkyl biaryl, pyridine, naphthalene, indole, pyrimidine, pyridazine, piperidine, imidazole, quinoline, sulfonyl, furan, thiophene, oxazole, benzyl, amide, isoxazole, thiazole, thiadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions.
  • Ri and R 2 together with the nitrogen atom to which they are attached form a morpholine ring, which may be substituted or unsubstituted.
  • R 3 in Formula lie represents OR 4 and NR 5 R 6 , wherein R 4 is any one of tert butyl, ethyl or H, and one of R 5 and R 6 is H, substituted or unsubstituted alkyl, cyclopropyl, methoxyethyl, cyclopropylmethyl, cyclohexylmethyl, morpholinoethyl, cyclobutyl, substituted or unsubstituted phenyl, benzyl, phenethyl, piperazine or piperidine.
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a substituted or unsubstituted pyrrole, piperazine or piperidine ring.
  • R in formula llf is a carboxyl group 0(0 ⁇ , represents any one of substituted or unsubstituted alkyl, phenyl, benzyl, phenethyl, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;
  • X is CH 2 and Y is a compound of formula lie, wherein R 3 is OR 4 and R 4 is ethyl or tert butyl; X is CH 2 and Y is a compound of formula lie, wherein R 3 is 0R 4 and R 4 is H.
  • the phenyl or pyridine rings are substituted with one or more of Br, OMe, CF 3 , OCF 3 , OCH 2 , OCHF2, -C(0)NR 1 R 2 or NR 1 C(0)R 2 , where Ri and R 2 are as defined above.
  • X is CH 2 and Y is a substituted or unsubstituted biaryl.
  • X is CH 2 and Y represents formula lla and R is selected from substituted or unsubstituted phenyl, pyridine, pyrimidyl, indole or a five- membered heterocycle.
  • X is CH 2 and Y represents formula lib, wherein R is a substituted phenyl.
  • the biaryl may be an ⁇ / ⁇ /70-substituted biaryl, mefa-substituted biaryl or para-substituted biaryl.
  • the biaryl may be substituted with one or more of CF 3 , NHBoc, C0 2 Et, CN, OCF 3 , furan, N0 2 , C0 2 H, F, isoxazole, OMe, OCH 3 , pyrrole, a carboxamide group C(0)NR ! R 2 , where Ri and R 2 are as defined above, or C(0)OR 4 , where R is ethyl.
  • X is CH 2 and Y is a compound of formula lie, wherein R 3 is NR 5 R 6 , and R 5 or R 6 is one of H, NH, an aromatic or alkyl group;
  • R 5 and R 6 represent H and any one or more of substituted or unsubstituted alkyl, cyclopropyl, methoxyethyl, cyclopropylmethyl, cyclohexylmethyl, morpholinoethyl, cyclobutyl, substituted or unsubstituted aniline, phenyl, benzyl, phenethyl, piperazine or piperidine.
  • X represents a substituted pyrimidine and Y is absent.
  • the pyrimidine is substituted in the 4-position with CI, or an amine such as pyrrolidine, morpholine, tetrahydropyridine, cyclohexylmethanamine, substitutued or unsubstituted: aniline, benzylamine, phenethylamine, or piperazine.
  • X represents a N-substituted piperidine and Y is absent.
  • the piperidine is substituted as shown in formula llf with a substituted or unsubstituted alkyl group or substituted or unsubstituted carboxyl group C(0)Ri .
  • R in formula llf is a carboxyl group C(0)Ri
  • Ri represents any one of substituted or unsubstituted alkyl, phenyl, benzyl, phenethyl, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, triazole, pyrrole or pyrazole at any one or more of the available ring positions;
  • X is CH 2 and Y represents a substituted phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with a substituted or unsubstituted carboxamide group.
  • X is CH 3 or H and Y is absent; or X is CH 2 and
  • Y is pyridine or pyridine substituted with Br.
  • X is CH 2 and Y is a substituted or unsubstituted biphenyl group, wherein when substituted the biphenyl is substituted with C0 2 Et, F, CN or -N(0)-0-C(CH 3 ) 3 .
  • X is CH 2
  • Y represents formula I la
  • R is unsubstituted or substituted pyridine, wherein when substituted the pyridine is substituted with -C(0)-0- C(CH 3 ) 3 .
  • the substitution occurs on the nitrogen atom of the pyridine ring.
  • X is CH 2
  • Y is formula I la and R is substituted isoxazole, wherein the isoxazole is substituted with CH 3 at one or more of the ring positions or R is unsubstituted or substituted indole, wherein the indole group is substituted with CH 3 .
  • the substitution occurs on the nitrogen atom of the indole ring.
  • X is CH 2
  • Y is formula lib and R is substituted phenyl, wherein the phenyl group is substituted with C0 2 Et, CF 3 , CN or F.
  • R is substituted on the meta position of Formula lla or lib.
  • X is CH 2
  • Y is formula lla and R is unsubstituted or substituted phenyl.
  • the phenyl may be substituted with C0 2 Et, OMe, OCH 3 , CF 3 , OCF3, NHBoc, CN, F or N0 2 at any of the available ring positions.
  • X is CH 2
  • Y is formula lla and R is substituted or unsubstituted indole, furan or triazole.
  • the triazole is substituted with CF 3 and the indole is substituteded with CH 3 .
  • X is CH 2
  • Y is formula lla and R is substituted or unsubstituted pyridine.
  • the substituents include MeO, CI, F.
  • X is CH 2 , Y is formula lla, R is substituted or unsubstituted pyrimidine.
  • the substituents are prefereably, OMe, CI or F.
  • X is CH 2 , Y is lib and R is substituted or unsubstituted phenyl.
  • the substituents include, C0 2 Et, CN, CF 3 or F.
  • R is substituted on the para position of Formula Ma or lib.
  • X is CH 2
  • Y is formula I la and R is substituted or unsubstituted phenyl.
  • the preferable substitutents include C0 2 Et, CN or F.
  • R is substituted on the ortho position of Formula lla.
  • X is CH 2
  • Y is formula lla and R is substituted phenyl, wherein the phenyl is substituted with any one of the amides as disclosed in compounds 8.5.1 - 8.5.6 and 8.6.1 -8.6.5 in Table 5.
  • X is CH 2 , Y is lla and R is substituted phenyl, wherein the phenyl is substituted with F and any one of the amides as disclosed in compounds 8.7.1 -8.7.6 and 8.8.1 -8.8.5 in Table 6.
  • the phenyl may be substituted at any of the available ring positions.
  • X is CH 2
  • Y is formula lib and R is substituted phenyl, wherein the phenyl is substituted with F and any one of the amides as disclosed in compounds 8.7.7-8.7.12, 8.7.14, 8.8.6-8.8.12, 8.9.1 -8.9.12 and 8.10.1 - 8.10.6 in Table 6.
  • the phenyl may be substituted at any of the available ring positions.
  • X is CH 2 , Y is lib and R is substituted phenyl, wherein the phenyl is substituted with F and C(0)OH.
  • the substitution can take place at any of the available ring positions.
  • X is CH 2
  • Y is formula lie
  • R 3 is NR 5 R 6
  • R 5 and R 6 are both CH 3 or R 5 is H and R 6 is CH 2 CH 3 .
  • X is CH 2 , Y is lie, R 3 is NR 5 R 6 , R 5 is H and R 6 is selected from any one of the following groups, a methoxyethyl group, -CH(CH 3 ) 2 , a cyclopropyl group, a cyclopropylmethyl group, a cyclohexylmethyl group, a morpholonoethyl group, a oxopyrrolpropyl group, or a cyclobutyl group.
  • R 5 and R 6 together with the nitrogen atom to which they are attached from a pyrole group, or a piperazine group or a piperadine group.
  • the piperazine group may be optionally substituted with a phenyl group, which phenyl group may be further substituted with F, C0 2 Et or CN.
  • the piperidine group may be optionally substituted with a phenyl group.
  • R 5 is H and R 6 is a substituted phenyl, wherein the phenyl is substituted with Br, CF 3 , OCF 3 or -C(0)CH 3 .
  • R 5 is H and R 6 is CH 2 substituted with a substituted phenyl, wherein the phenyl is substituted with Br, OMe, CF 3 , OCF 3 , or OCHF 2 , or wherein the CH 2 is substituted with a biphenyl group, which may be further substituted with OCF 3 .
  • R 5 is H and R 6 is CH 2 CH 2 substituted with a substituted phenyl, wherein the phenyl is substituted with a CF3.
  • R 5 is H and R 6 is a substituted piperidine group.
  • the piperidine group may be substituted with a substituted alkyl group, preferably substituted with a phenyl group.
  • Y is formula lie, wherein R is CH 2 CH 3 or wherein R is a substituted indole, preferably the indole is substituted with a phenyl group, more preferably the indole and phenyl groups are fused.
  • R is a substituted thiazole group, wherein the thiazole is substituted with phenyl.
  • R may also be cyclobutyl.
  • R is a phenyl group.
  • the phenyl group is fused with formulae lla or lib.
  • X is S0 2
  • Y is CH 3
  • imidazole which is preferably substituted with a methyl group
  • Y is a substituted or unsubstituted phenyl group, wherein the phenyl is substituted with CN, CI, CH 3 or OCH 3 .
  • X is pyrimidine
  • Y is an amine group selected from any one of the amines in compounds 15.1 .2-15.1 .1 1 as set out in Table 12.
  • X is pyrimidine and Y is a dihydropyridine, morpholino, pyrrolidine, or piperazine group.
  • the piperazine group is substituted with a phenyl group.
  • the phenyl group may be further substituted with CN, F, C(0))CH 2 CH 3 .
  • X is CH 2 , and Y is lla, R is amide selected from any of the amides iin compounds 16.1 .1 -16.1 .21 , 16.1 .23, 16.1 .27-16.1 .38 and 16.2.1 - 16.2.3.
  • X is CH 2 , Y is lla and R aldehyde group.
  • the R is the aldehyde as in compounds 16. 1 .22, 16.1 .24 - 16.1 .26.
  • X is CH 2 Y is lib and R is an amide group.
  • X is CHCH 3 and Y is lib, wherein R is a substituted phenyl group, wherein the phenyl is substituted with C(0)-OCH 2 CH 3 , CN, CF 3 , F, OCF 3 or wherein the phenyl group is substituted with F and -C(0)NH-C 4 H 7 .
  • X is CH 2 and Y is lla, wherein R is an amine group.
  • R is an amine group.
  • the amine group is selected from those disclosed in compounds 18.1 .1 -18.1 .4 in Table 17.
  • the process comprises the steps of substituting the N atom of an amino alcohol reactant via alkylation or reductive amination with an X-Y group
  • X is CH, i.e Y wherein LG represents a leaving group and X and Y are as defined above, to produce a tertiary amine; reacting the tertiary amine with 2,4-dinitroimidazole under Mitsunobu reaction conditions to produce an intermediate which is then cyclized to produce the compound of Formula (I).
  • (i) represents TBDMSCI, Imidazole and DCM.
  • the reaction is carried out at room temperature for about 12 hours
  • (ii) represents K 2 C0 3 and acetonitrile and the reaction is carried out at room temperature for about 24 hours
  • (iii) Represents PPh 3 , DIAD and THF and the reaction is carried out for about 18 h.
  • (iv) Represents TBAF and the reactions is carried out at room temperature for about 2 hours.
  • the process comprises the steps of substituting the N-atom of an amino alcohol with an alkyl or allyl group; reacting the substituted amino alcohol with 2,4-dinitroimidazole under Mitsunobu reaction conditions to produce an intermediate which is then cyclized; removing the alkyl or allyl group to form the intermediate; and reacting the intermediate with Y ' LG under basic conditions, wherein LG represents a leaving group and X and Y are as defined above, to produce a compound of Formula (I).
  • the reactants for step (ii) are PPh 3 , DIAD and THF. The reaction is carried out for about 18 hours.
  • the step (iii) reactant is TBAF. The reaction is carried out at room temperature for about 2 h.
  • Step (iv) represents 1 - chloromethyl chloroformate and DCE. The reaction is carried out under reflux for about 12 h.
  • the step (v) reactant is MeOH and the reaction is carried out under reflux for about 4 hours.
  • Step (vi) represents K 2 C0 3 and acetonitrile: water (1 :3). The reaction is carried out at room temperature for about 4 hours.
  • the reactant for step (vii) is sodium triacetoxyborohydride in DCE and the reaction is carried out at room temperature for 12 hours.
  • a compound of Formula I for use in a method of treating tuberculosis or other microbial infections, the method comprising the step of administering to a subject any one of the compounds of the formula I or their mixtures, pharmacologically acceptable salts, optical or geometric isomers, esters or prodrugs thereof.
  • the microbial infection is caused by Mycobacterium tuberculosis. These compounds may be useful for treatment of other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.
  • tuberculosis or other microbial infections comprising the step of administering to the subject any one of the compounds of formula I or their mixtures, pharmacologicallay acceptable salts, optical or geometrical isomers, esters or prodrugs thereof.
  • the microbial infection is caused by Mycobacterium tuberculosis.
  • These compounds may be useful in methods of treating other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.
  • a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds of the formula I or their mixtures, pharmacologically acceptable salts, optical or geometric isomers, esters or prodrugs thereof.
  • the composition may be used in a method of treating tuberculosis in a subject. It may also be useful for treatment of other infectious diseases such as malaria, trypanosomiasis, Chagas' disease, Leishmaniasis and Schistosomiasis.
  • composition may further include a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer or the like.
  • compositions may be in tablet, capsule, powder or liquid form.
  • the compound or composition may be administered in a single dose, or multiple doses.
  • the compound or composition may be administered alone or in combination with other therapeutic agent(s).
  • Figure 1 shows the chemical structure of the prior art
  • Figure 2 shows the original synthesis of the prior art
  • Figure 3 shows the improved synthesis of the prior art
  • Figure 4 shows the recent synthesis of the prior art
  • the invention features novel bicyclic nitroimidazoxadiazocine compounds pharmaceutical compositions containing them, their medical use and methods of synthesising such compounds.
  • Compounds of the invention are shown in Table 1 below.
  • the target nintroimidazoxadiazocine and its derivatives may be prepared by one of several methods described below:
  • Coupling of 2,4-dinitroimidazole C to the tertiary amine 5 may be achieved under Mitsunobu reaction conditions using, triphenylphosphine in combination with an azodicarboxylate such as diethyl azidodicarboxylate (DEAD), di- te/t-butylazodicarboxylate (DBAD), or di-p-chlorobenzyl azodicarboxylate (DCAD), di-2-methoxyethyl azodicarboxylate (DMEAD), Di-p-nitrobenzyl azodicarboxylate (DNAD), but most preferably diisopropyl azidodicarboxylate (DIAD).
  • DEAD diethyl azidodicarboxylate
  • DBAD di- te/t-butylazodicarboxylate
  • DCAD di-p-chlorobenzyl azodicarboxylate
  • DMEAD di-2-methoxyethyl
  • the Mitsunobu reaction may be carried out in organic solvents such as chloroform, DCM, DCE, NMP, DMF, dioxane, DMSO, or a mixture of these, but most preferably in THF, at temperatures between -10 °C and 70 ⁇ €.
  • organic solvents such as chloroform, DCM, DCE, NMP, DMF, dioxane, DMSO, or a mixture of these, but most preferably in THF, at temperatures between -10 °C and 70 ⁇ €.
  • Steps (iii) and (iv) may be carried out in one-pot or stepwise.
  • the product When the two steps are carried out in one pot, the product may be isolated as the salt of a mineral or organic acid, which upon basification and subsequent purification affords clean product.
  • the intermediate When the reaction is performed in two steps, the intermediate may be selectively isolated from by-products with or without need for chromatographic purification.
  • the protecting group in the intermediate 6 may be removed by treatment with a basic fluoride source such as potassium fluoride or cesium fluoride, but most preferably with tetrabutylammonium fluoride (TBAF) to provide target molecules 7 - 9.
  • a basic fluoride source such as potassium fluoride or cesium fluoride, but most preferably with tetrabutylammonium fluoride (TBAF)
  • the target compounds may be synthesized by way of scheme 5.
  • the /V-atom of the tertiary amine is substituted with either a methyl or allyl group that is later removed to unmask a basic /V-centre.
  • the amino alcohol 5 is reacted with 2,4-dinitroimidazole under the conditions described in Method I to afford intermediate 6, which is then cyclized to 7 as described for Method I above.
  • R 3 H, Allyl bromide, K 2 C0 3 , Acetonitrile, rt, 24 h; (ii) PPh 3 , DIAD, THF, 18 h; (iii) TBAF, rt, 2 h; (iv) 1 -Chloromethyl chloroformate, DCE, reflux, 12 h; (v) MeOH, reflux, 4 h; (vi) K 2 C0 3 , Acetonitrile:water (1 :3), rt, 4 h. (vii) Borohydride
  • the methyl and allyl groups in 7 may be removed by treating the compound with 1 -chloroethyl chloroformate in chloroform, DCM or DCE at temperatures ranging from -10 °Q, to 70 °C, followed by refluxing the residue obtained after evaporation of chlorinated solvent in methanol.
  • the intermediate 7.1.3 may be alkylated with aldehydes under reducing conditions, or with alkyl halides as described earlier.
  • the compounds in the present invention are designed to incorporate inherent solubilising groups within the core structures that improve aqueous solubility, and effectively bioavailability.
  • the compounds of the invention are preferably formulated into pharmaceutical compositions for administration.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer.
  • a "therapeutically effective amount” is to be understood as an amount of a compound of Formula I that is sufficient to show antibacterial or anti-microbial effects.
  • the actual amount, rate and time-course of administration will depend on the nature and severity of the disease being treated. Prescription of treatment is within the responsibility of general practitioners and other medical doctors.
  • the pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer should be nontoxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, such as cutaneous, subcutaneous, or intravenous injection, or by dry powder inhaler.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such as gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • isotonic vehicles such as sodium chloride injection, Ringer's injection, Lactated Ringer's injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included as required.
  • the pharmaceutical composition can further comprise one or more additional anti-infective treatments.
  • These anti-infective treatments can be any suitable treatment available commercially or from other sources that are known to effectively prevent or treat microbial infections, such as Mycobacterium tuberculosis.
  • pharmaceutically acceptable salt used throughout the specification is to be taken as meaning any acid or base-derived salt formed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isoethonic acids and the like, and potassium carbonate, sodium or potassium hydroxide, ammonia, triethylamine, triethanolamine and the like.
  • pro-drug means a pharmacological substance that is administered in an inactive, or significantly less active, form. Once administered, the pro-drug is metabolised in vivo into an active metabolite.
  • terapéuticaally effective amount means a nontoxic but sufficient amount of the drug to provide the desired therapeutic effect.
  • the amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular concentration and composition being administered, and the like. Thus, it is not always possible to specify an exact effective amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Furthermore, the effective amount is the concentration that is within a range sufficient to permit ready application of the formulation so as to deliver an amount of the drug that is within a therapeutically effective range.
  • Flash, thin layer and preparative thin layer chromatography (TLC) were performed on silica gel and precoated plates purchased from Sigma Aldrich. Flash chromatography was performed using silica gel 60 as a normal phase adsorbent. Thin layer chromatography (TLC) spots were visualized with long-wave ultraviolet light followed by permanganate staining. Preparative thin layer chromatography (TLC) was performed using silica gel (SG) 60 F 254 plates (20 x 20 cm, 2000 microns) and the bands were visualized with long-wave ultraviolet light lamp.
  • Analytical chromatography was performed on an Agilent 1200 HPLC fitted with a Waters XBridge C18 (50 mm x 4.6 mm x 5 microns) that was coupled to a UV detector (280 nm) and an Agilent 6120 Quadrupole mass spectrophotometer in the positive mode. The flow rate was maintained at 1 mL/min on this system.
  • Semi-preparative HPLC was carried out on an Agilent 1200 semi-preparative instrument fitted with a Waters XBridge C18 (100 mm x 19.0 mm x 5 microns) that was coupled to a UV/VIS detector (280 nm) and an automated fraction collector. The flow rate was maintained at 1 mL/min on this system.
  • reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine.
  • the organic layer was separated, dried over sodium sulfate, filtered and evaporated.
  • the residue was submitted through a short column eluting with 20% ethyl acetate/hexane to remove starting materials and by-products followed by washing with methanol (500 mL).
  • the solvent was removed in vacuo to yield 2-((4- methoxybenzyl)amino)ethanol (21 .4 g, 1 18 mmol, 72%) as a light yellow oil.
  • 2,4-Dimethoxybenzaldehyde (54.4 g, 327 mmol) was added to a stirring solution of ethanolamine (20.0 g, 327 mmol) in methanol (400 mL). The resulting solution was allowed to stir for 2 hours at room temperature. Thereafter sodium sulfate (-20 g) was added to the reaction mixture and was allowed to stir for a further 30 minutes. Sodium borohydride (18.6 g, 491 mmol) was added cautiously at 0 ' ⁇ over 15 minutes. The reaction mixture was allowed to stir at room temperature for 18 hours.
  • reaction mixture was filtered, evaporated and taken up into DCM (200 mL) and washed consecutively with saturated sodium carbonate solution (100 mL), water (100 mL) and brine (100 mL).
  • the organic layer was separated, dried over sodium sulfate, filtered and evaporated.
  • the residue was submitted through a short column eluting with 20 % ethyl acetate/hexane to remove starting materials and by-products followed by washing with methanol (1500 mL).
  • the solvent was removed in vacuo to yield 2-((4-methoxybenzyl)amino)ethanol (54.1 g, 256 mmol, 78%) as a light yellow oil.
  • N-(4-(hydroxymethyl)phenyl)-4-(trifluoromethoxy)benzamide (0.45g, 1 .46 mmol) was dissolved in dichloromethane (5 mL) and sodium bromide (2.98 mg, 0.03 mmol) and 2,2,6, 6-tetramethyl-1 -piperidinyloxy (TEMPO) (4.52 mg, 0.03 mmol) were added.
  • the reaction mixture was cooled to 0 °C in an ice-bath.
  • Sodium hydrogen carbonate (0.24 g, 2.89 mmol) was dissolved in water (5 mL) and the resulting solution was mixed with sodium hypochlorite (5mL, 10-13%).
  • N-(4-(hydroxymethyl)phenyl)-3-(trifluoromethoxy)benzamide (1 .20 g, 3.86 mmol) was dissolved in dichloromethane (10 mL) and sodium bromide (7.93 mg, 0.08 mmol) and 2,2,6,6-tetramethyl-1 -piperidinyloxy (TEMPO) (12.0 mg, 0.08 mmol) were added.
  • the reaction mixture was cooled to 0 ' ⁇ in an ice-bath.
  • Sodium hydrogen carbonate (0.65 g, 7.71 mmol) was dissolved in water (8 mL) and the resulting solution was mixed with sodium hypochlorite (8 mL, 10-13%).
  • the solvent was evaporated to furnish a thick orange oil which was dissolved in DCM (10 mL) and filtered through a pad of silica (1 1 cm x 7 cm). The solvent was removed in vacuo and the residue redissolved in DCM (300 mL), washed with 15% hydrogen peroxide solution (200 mL) and saturated sodium sulfite solution (200 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated.
  • the reaction mixture was refluxed for 14 h, and evaporated to dryness.
  • the oily residue was purified via flash chromatography, eluting with 65 % DCM: 35 % hexanes; the solvent was removed in vacuo and the residue triturated from hexane.
  • the solids were filtered and dried under reduced pressure and dried to afford as a yellow solid (15.45 g, 59 %). See Table 19 for analytical data.
  • the crude was dissolved in a mixture of ethyl acetate and methanol (95%:5%) and filtered through a pad of silica.
  • the silica was washed a few times with the ethyl acetate and methanol mixture. The washings were combined and the solvent evaporated to yield 4-((6- bromopyridin-2-yl)methyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1 - b][1 ,3,6]oxadiazocine (1 .7 g, 4.6 mmol, 92 %) with 68 % purity.
  • the sample was further purified using prep HPLC. See Table 19 for analytical data.
  • hydrochloride 7.1.3 (2.0 g, 8.52 mmol) was taken up in acetonitrile (4 mL), then added to a solution of potassium carbonate (3.53 g, 25.6 mmol) in water (12 mL). The biphasic mixture was stirred at ambient temperature then tert-butyl 4-(chloromethyl)benzoate (2.32 g, 10.23 mmol) was added in one portion. The resulting mixture was stirred for 48 h at ambient temperature, diluted with water (50 mL) and the product precipitated out of solution.
  • PdCI 2 (dppf) (0.1 eq.) were suspended in ethanol (3 mL). The reaction was degassed with nitrogen for 1 minute and then sodium carbonate (2 eq.) in 1 mL water was added. The reaction mixture was heated at reflux overnight, cooled, filtered through a plug of celite and rinsed with chloroform (5 mL).

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Abstract

Cette invention concerne des composés nitroimidazoxadiazocines ayant la Formule générale I, des compositions pharmaceutiques et des utilisations associées. L'invention concerne également des procédés de fabrication de tels composés nitroimidazoxadiazocines de Formule I.
PCT/IB2012/056546 2011-11-17 2012-11-19 Composés nitroimidazoxadiazocines WO2013072903A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10227362B2 (en) 2015-01-29 2019-03-12 Medshine Discovery Inc. Anti-pulmonary tuberculosis nitroimidazole derivative

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WO1997001562A1 (fr) 1995-06-26 1997-01-16 Pathogenesis Corporation Composes antibacteriens de nitro-imidazole et leurs procedes d'utilisation
US6087358A (en) 1995-06-26 2000-07-11 Pathogenesis Corporation Nitro-[2,1-b]imidazopyran compounds and antibacterial uses thereof
US20060063929A1 (en) 2004-09-17 2006-03-23 Junzo Otera Process for preparing for imidazopyran derivatives
WO2007075872A2 (fr) 2005-12-23 2007-07-05 Novartis Ag Composes de nitroimidazole
WO2009120789A1 (fr) 2008-03-26 2009-10-01 Global Alliance For Tb Drug Development Nitroimidazoles bicycliques liés par covalence à des phényloxazolidinones substituées

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US5668127A (en) 1995-06-26 1997-09-16 Pathogenesis Corporation Nitroimidazole antibacterial compounds and methods of use thereof
US6087358A (en) 1995-06-26 2000-07-11 Pathogenesis Corporation Nitro-[2,1-b]imidazopyran compounds and antibacterial uses thereof
US20060063929A1 (en) 2004-09-17 2006-03-23 Junzo Otera Process for preparing for imidazopyran derivatives
WO2007075872A2 (fr) 2005-12-23 2007-07-05 Novartis Ag Composes de nitroimidazole
WO2009120789A1 (fr) 2008-03-26 2009-10-01 Global Alliance For Tb Drug Development Nitroimidazoles bicycliques liés par covalence à des phényloxazolidinones substituées

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10227362B2 (en) 2015-01-29 2019-03-12 Medshine Discovery Inc. Anti-pulmonary tuberculosis nitroimidazole derivative

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