Further advances in the chemistry of mannich bases

Method, compounds and compositions are provided for inhibiting the growth of pathogenic microbes in vitro and of treatment of pathogenic bacterial infections, such as mycobacterial, Clostridium, Cryptosporidium and Helicobacter infections, in vivo using bicyclic nitroimidazole compounds. The methods, compounds and compositions are particularly useful for inhibiting the growth of Mycobacterium tuberculosis, Clostridium difficile, Cryptosporidium parvum, and Helicobacter pylori, and may be used alone, or in combination with other antimicrobial agents.

Nitroimidazole antibacterial compounds and methods of use thereof

During the last two decades, or, more precisely, ever since the introduction of metronidazole into therapy, nitroimidazoles as a class of compounds have attracted much attention. Nevertheless, no adequate review of this chemical class has appeared in literature, even though a large number of reviews on the chemotherapy of protozoal diseases refer to the various nitroimidazoles in clinical use.

Nitroimidazoles as chemotherapeutic agents

The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5 and R6 are as defined herein. The compounds of the present invention have been found to be useful as 17a-hydroxylase/C17,20-lyase inhibitors.

17α-HYDROXYLASE/C17,20-LYASE INHIBITORS

The nitroimidazole scaffold has attracted great interest in the last decade, which ultimately led to the discovery of the successful drug Delamanid for multi-drug resistant tuberculosis (MDR-TB). Herein, we report medicinal chemistry on a 6-nitro-2,3-dihydroimidazooxazole (NHIO) scaffold with SAR on the novel series of triazolyl- and isoxazolyl-based NHIO compounds. In the present study, 41 novel triazolyl- and isoxazolyl-based NHIO compounds were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The active compounds with MIC of 0.57–0.13 μM were further screened against dormant, as well as against resistant strains of MTB. Based on the overall in vitro profile, five compounds were studied for in vivo oral pharmacokinetics, wherein two compounds: 1g and 2e showed a good PK profile. In in vivo efficacy studies in the intra-nasal model of acute infection, 1g showed 1.8 and 1 log CFU reduction with respect to the untreated and early control, respectively. The lead compound 1g also showed an additive to synergistic effect in combination studies with first line-TB drugs and no CYP inhibition. From the present studies, the compound 1g represents another alternative lead candidate in this class and needs further detailed investigation.

Synthesis of new generation triazolyl- and isoxazolyl-containing 6-nitro-2,3-dihydroimidazooxazoles as anti-TB agents: in vitro, structure–activity relationship, pharmacokinetics and in vivo evaluation

A variety of nitroimidazoles, mostly 1,2-disubstituted-5-nitroderivatives were examined for in vitro activity against E. histolytica and in early hepatic infection of infected golden hamsters. Many preparations carried a functionalised N atom at position 2. In vivo activity was found widely among 1-alkyl-5-nitroimidazoles carrying a substituted imidazolidinone (1) or imidazole (2). Out of these derivatives, l-methyl-sulphonyl-3-(1-methyl-5-nitro-2-imidazolyl)-2-irnidazolidinone(la;C 10213-Go) was found to be the best and to be superior to marketed nitroimidazoles against hepatic and caecal infections of E. histolytica ip the golden hamster and T. foetus infections in mice, and has been developed as a drug for treatment of amoebiasis, giardiasis and trichomoniasis.

Nitroimidazoles: Part XIX. Structure-activity relationships

A novel transformation of 2-dichloracetamido-1-methyl-5-nitroimidazole to 5-dichloroacetylimino-tetrahydroimidazo (4,5-c) pyrazoles.

A novel transformation of 6,7-dimethoxy- and 6,7-methylene-dioxy-1-(2-bromo-4,5-methylenedioxy-α-methyl) benzyl-1,2,3,4-tetrahydroisoquinolines to benzoxazepinoisoquinolines

Methylation of 2-chloro-4-nitroimidazole (6), obtained from imidazole in four steps, either with dimethyl sulphate or with diazomethane affords a mixture of 2-chloro-l-methyl-5-nitroimidazole (10) and the 4-nitro-isomer (7). The corresponding dinitro compounds 11 and 8 are formed in the methylation of 2,4-dinitroimidazole (5), 8 being converted to 7 by the action of POCl3. Reaction of 10 with the sodium salt of N-methanesulphonyl-2-imidazolidinone provides the potent amoebicide, 1-methylsulphonyl-3-(1-methyl-5-nitroimidazol-2-yl)-2-imidazolidinone (2). The isomer 14 is synthesised from 7 in low yield. Ethylation of 5 leads to preponderant N-alkylation, providing a mixture of l-ethyldinitroimidazoles (9) and (12), but a small amount of N,C-diethyl derivative 15 is also obtained. The formation of 15 from 5 is rationalised. The diiodination product of imidazole is shown to be 4,5-diiodoimidazole (19), nitric acid transforming it to 4-iodo-5-nitroimidazole (20). Methylation of 20 affords a mixture of isomeric 1 -methyliodonitro derivatives (21) and (22). The structures of 21 and 22 are established by 13C NMR data as well as by conversion into morpholine derivatives 26 and 24 respectively which also arise from 1-methylchloronitroimidazoles (25) and (23). A mechanism is proposed for the reported conversion of 5 into 4-chloro-5-nitroimidazole (32) in boiling 2-chloroethanol.

Nitroimidazoles. part xi. some halonitro- and dinitroimidazoles

Sulphone (5) is condensed with sodium salts of a variety of 1-sulphonyl (7), lrthiocarbamoyl (9) and 1-carbonyl (10)-2-imidazolidinones to give 3-(2-imidazolyl)imidazolidinones (12), (13) and (14) respectively, out of which l-methylsulphonyl-3-(l-methyl-5-nitro-imidazol-2-yl)-2-imidazolidinone (12a) is undergoing clinical trials as an antiamoebic-antitrichomonal agent. 15 and 16 are analogous imidazolidinones, while 17 and 18 are benzimidazolone derivatives. The reaction of 5 with the sodium salt of 2-imidazolidinone gives rise to the mono and bis-condensation products 21 and 22 respectively. Several other minor byproducts, 23-27 have been identified. 23,26 and 27 arise from 21. 24, a transformation product of 5 leads to the ether 25 by a displacement reaction. A second synthesis of 12a involves the nitration of imidazolylimidazolidinone (30) in the terminal step, with 30 becoming available from l-methyl-2-aminoimidazole (28) and chloroethyl isocyanate, and subsequent reaction of resultant 29 with methanesulphonyl chloride. The higher ring homologue, 33 of 12a is synthesised in poor yield from 5 and 1-methylsulphonylhexahydropyrimidinone. Treatment of 12a and 13a with KI in DMF leads to the isomeric 4-nitro derivatives 38a, b and desmethyl derivatives 37a, b. Treatment of 12a with triethyloxonium fluborate affords the quaternary isothiourea (35)whieh is hydrolysed to 36. Treatment of 12a and 13a with aqueous alkali leads to cleavage of imidazolidinone ring to form the ethylenediamines 31a and b. Position isomers 41 and 43 of 12a are respectively obtained by the reaction of l-methyl-4-nitro-5-chloro-(40)-, and l-methyl-5-nitro-4-chloro-(42)-imidazoles with 1-methylsulphonyl-ethylene urea. Treatment of the last compound with various reactive halides, e.g. 2-chlorobenzothiazole, yields several analogues 44a-i of 12a while niridazole (45) and methylsulphonyl chloride affords the nitrothiazole analogue 46.

V. Sudarsanam

Papers

Nitroimidazoles: Part XIX. Structure-activity relationships

A novel transformation of 2-dichloracetamido-1-methyl-5-nitroimidazole to 5-dichloroacetylimino-tetrahydroimidazo (4,5-c) pyrazoles.

A novel transformation of 6,7-dimethoxy- and 6,7-methylene-dioxy-1-(2-bromo-4,5-methylenedioxy-α-methyl) benzyl-1,2,3,4-tetrahydroisoquinolines to benzoxazepinoisoquinolines

Nitroimidazoles. part xi. some halonitro- and dinitroimidazoles

Nitroimidazoles. part iv. 1-sulfonyl(carbamoyl/thiocarbamoyl)-3-(1-methyl-5-nitroimidazol-2-yl)-2-imidazolidinones