Alkylation of 2-Methyl-5-nitroimidazole. - ACS Publications

(2-me t h yl-5-ni tro- 1-imidazol yl) ethyl ] sulfone (1) (tini- dazole) a more potent drug than metronidazole with- out a demonstrable difference in ...
0 downloads 0 Views 452KB Size
Journal of Medicinal Chemistry, 1970, Vol. 13, 'Vo. 5 849

ANTIPROTOZOAL AGENTS

Alkylation of 2-Methyl-5-nitroimidazole. Some Potent Antiprotozoal Agents' MAXW. MIL LEI^, HAROLD L. HOWES,JR.,ROBERT V. KASUBICK, AND ARTHURR. ENGLISH P j z c r .Tfedical Research Laboratories Groton, Connecticut 06'840 Received J a n u a r y 26, 1970 The contending forces influencing the alkylation of 2-methyl-5-nitroimidazole are discussed. A method is described which yields principally the 1-alkylated 2-methyl-5-nitroimidazole isomers preferred for their superior efficacy in the chemotherapy of certain protozoan infections. A series is reported, bearing short aliphatic side chains which incorporate electronegative groups. Several sulfones in this series are potent, well-tolerated, orally effective antiprotozoal agents. One of these agents is in clinical trial, and has been assigned the nonproprietary name, tinidazole.2

A real advance in the chemotherapy of protozoan infections was made about a decade ago with the introduction of metronidazole. It was the first orally eff ective treatment for trichomonia~is,~t~ and, a t higher dosage levels it proved to be the most efficacious and best tolerated treatment for amebiasis.; While welltolerated relative to earlier drugs for the same purpose (e.g., emetine for amebiasis) over the years a considerable clinical literature has accumulated on troublesome side-eff ects, which occur in significant percentages of patients The low toxicity of metronidazole seemed to allow margin for improvement of efficacy. An effort to do so produced ethyl [a(2-met h yl-5-ni tro- 1-imidazolyl) ethyl ] sulfone (1) (tini-

and, due to its symmetry, yields a single product, 2methyl-4(5)-nitroimidazole, which can exist in the tautomeric forms 4a and b. Alkylation can then be accomplished on either the 1- or the 3-nitrogen atom to yield 1-substituted 2-methyl-hitroimidazoles 5 or 1-substituted 2-methyl-4-nitroimidazoles 6, or a mixture of these isomers.

3

J 6

dazole) a more potent drug than metronidazole without a demonstrable difference in t o ~ i c i t y . ~It was welltolerated in clinical trials, and it is reasonable to expect that the lower dosage regimen required will reduce the incidence of undesirable side effects. While the use of tinidazole probably will be limited to the treatment of trichomoniasis and amebiasis, some broadening of the spectrum beyond that of metronidazole was noted, perhaps due to the higher potency. Chemistry.-Commercially available, inexpensive 2methylimidazole 31° can be nitrated conventionally," (1) Some of the results of the biological evaluation of these materials were reported a t the 9th Interscience Cohference on Antimicrobial Agents a n d Chemotherapy in Washington, D. C., Oct 27-29, 1969, and will be recorded in the Proceedings of that meeting. (2) F a s i g y n s (3) C . Cosar, T. Julou, and M. Bonazet, Ann. Inst. Pasteur. 96, 238 (1959). (4) H. Beckman, Year B . Drug Ther.. 1963-1964, 383 (1965). ( 5 ) S. J. Powell, J. MacLeod, A. J. Wilmot, and R. Elsdon-Dew, Lancet, 1329 (1966). ( 6 ) R . McG. Harden, C. J. S.Chisholm, a n d J. S.C a n t , Metub. Clin. Exp.. 16. 890 (1967). ;7) S.'J. Powell, Amer. J . T r o p . Med. Hyg., 16, 447 (1967). ( 8 ) J. M. C. Holden a n d A. Keskiner, J . Clin. Pharmacol., 8, 333 (1968). (9) H. Howes, J. Lynch, and J. Kivlin, Antimicrob. Ag. Chemother. 1969 (in press). (10) Houdry Process Chemical Co.. Philadelphia, P a . ; BASF AG, West Germany: a n d Toyo Rayon Co., Ltd., Tokuahima, Japan are producers of this chemical. (11) h I p 248' has been reported for this substance: R. G . Fargher and F. L. Pyman, J. Chem. Soc., 115, 217 (1919). As previously described this nitration takes a violent course. Maintenance of a high temperature from the outset and gradual addition of the nitric acid permits nonhazardous operation on a large scale.

4b

40

AI kylation with R +

5

Distinctions can be subtle, but generally the 4-nitro isomers are less basic,12 less soluble in common organic solvents, and have uv absorption maxima which lie a few millimicrons on the blue side from those of the 5nitro isomers 5, although this generalization is not entirely dependable. Hydrogen atoms of the CH, groups attached to the 1-N atom in 5 show nmr signals measurably downfield from those of 6. This is due to the deshielding effect of the KO2 group attached a t the C-5 of 5. Diagnostic differences have been reported recently, too, in the chemical shifts of the NH proton in the conjugate acids of 1-substituted 5 and 6, depending on the position of the X02group.I3 Finally, a t least within the range of our study, the 5 class proved to be more potent antitrichomonals than the 6. Alkylation of 4 by alkyl halides or sulfates under nllraline conditions yields principally 6 since in the anion (conjugate base) of 4a the 3-5 atom is the more basic and the more n~cleophi1ic.l~The substituent effects on the degrees of nucleophilic character of the two S atoms of the imidazole ring in 4 seem to involve induction (a electrons) rather than conjugation ( T electrons), and there is evidence that in polysubstituted imid(12) The higher hasicity of t h e 5-NOz isomers permits their selective removal from mixtures by salt formation as described later. (13) J. S. G. Cox, C. Fitemaurice, A. R . Katritzky, and G. J. T. Tiddy, J . Chem. Sac., 1251 (1967). (14) A good analysis of the kinetic a n d mechanistic factors controlling the alkylation of imidazole, 4 (5)-nitroimidazole and related systems over a pH range is incorporated in t h e following series of publications: (a) A. Grimison and J. H. Ridd, Chem. I n d . , 983 (1956): (b) A . Grimison, J. H. Ridd and B. V. Smith, J . Chem. Soc., 1352 (1960): (c) J. H. Ridd a n d B. V. Smith, ibid., 1363.

azoles t,he clcctroiiic iiifluerictbs of tlie siibstitucrits u t ' essentially additive. Under neutral or mildly acidic conditions :t more complex kinetic mechanism is operative. Two tautomeric forms of 4 are possible, but it has been iri imidazoles permitting reversible 1&sh S H proton, the t'aut'omeric system will predominantly assume the form in which the S H bond is stronger.':' Thus in 4 the less acidic prot,onated form should prevail. Contributing to formation of the desired 5riitroimidazoles, perhaps. is the "principle of least' mot i ~ i i . " ' ~Operative even in urisubstituted imidazole, the eff'ect of this principle would be intensified by t h c polarizing influence of t'he substituents in 4. Subst,itutiori must occur at :in uiiprotonated nitrogen atom. so that in this instance the tautomer present in I o ~ w r coricei~trat~ionwould have the higher rate coefficient for this mechanism of substit~ution. liniill)., in ver)- strong acidic solutions t h e coiijugnti' :tcid vvould form at the more nucleophilic 3-Sin 4 , rt'moving it from competition for the electrophilic idI;\-latirig agent. X pH-independent f a t o r favoring furmihioil of the undesired 4x0, isomers is the considerable steric hiridrarice of the ?->le, iiiid .i-SOng r o u p 011 the intermediate S atom. I.'riSioIl Of'4 with alkyl toSy1:ites (Jfti'll, thol~glltIl(Jtr i l l vLrriably, gives t h e desired isomer 5 . l-ields tend to bc, lo\\., but this method has been w e d to prepare marly of t,lir, tqxrimental drugs reported to date, li-I9and 1 1 , j J (i, (;. Gallo, c'. It. I ' H ~ ~ ~ ~ I1'.~ liadaelli, I ~ I C ~ ~id I , G . C'. I.anvini, .I. O r g . ( ' h e m . 29, 862 (1Hti.i).

(llj) (a) .J. Hine, iiizd.. 31, 12% 1I9661; 11,) E'. 0 . Kire and E:. Tpller, .I. ibid., 7 , 1Y9 ( 1 Y 3 Y ) ; ( e ) J.-A. Muller, Bull. S u r . Cliim. Fr., 46, 438 (1886); J.-.4. hIullerandE. Peytrsl, C. R . Acad. Sci., 179, 831 (1921). (17) ('. Coear, C . Crisan, K. Horclois, K..\I. Jacob, J. Rohert. S.Tchelit,lirti. uric1 I+. \'auuIP, . 1 I - 3 ) i i i , ~ . - F U I . \ c I I . , 16, 23 flR61i). 118) I I I < ~ I I;,t i i ~ lI J . I