FI59995C - FRUIT PROCEDURE FOR PHARMACOLOGICAL PROPERTIES OF VARIABLE 2- (PHENOXIALKYLSULPHINYL ELLER-SULPHONYL) -IMIDAZOLER - Google Patents

Description

F5S51 M (11) KUIJ ».UTUS] ULKAISU ς gggr jSTä lJ '' utlAggningsskrift o ^ yyo C (45) * i- at ·· nt '" ^' "'·' 11 s' 11 1 ^ ^ (51) Kv.ik? /Inco.3 C 07 D 233/92, 233/84 FINLAND-FINLAND (21) P * t * nttlh «k« mui - Patamameknlng 792728 (22) Hikumtoplivl - AmMuiIngadag 03 · 09 · 79 '' ( 23) Alkupllvt — Gikifhttadaf 21.01.jh (41) Tullut JulkiMlul - Bllvlt offuMlIg 03 · 09 · 79

Patent and Registration Office · .... ........... ,, .....

Pktant · och regi * ter * tyr * lf * n * ^ AmMcm uttoJTJh 31-07 · 81 (32) (33) (31) Requested «uoikuus — Bugird Priority 22.01.73 USA (US) 325223 (71) G.D. Searle & Co., P.O. Box 5110, Chicago, Illinois 60680, USA (72) Robert Christopher Tveit, Wilmette, Illinois, USA (7 ^) Leitzinger Oy (5 * 0 Method for the determination of pharmacologically valuable 2- (phenoxyalkylsulfinyl or sulfonyl) imidazoles 2- (phenoxyalkylsulfinyl or sulfonyl) -imidazoler (62) Divided by application 159 / jh (Publication 59992) -Avdelad fr & n trap 159/7 ^ (subject of the present invention) prepare pharmacologically valuable 2- (phenoxyalkylsulfinyl or sulphonyl) imidazoles,

CH

whose general formula is,

OF

X '-S - Z-Alk-O-Phyl (i)

-OF

wherein X 'is hydrogen or nitro »Z is sulfinyl or sulfonyl» Alk is alkylene of 1 to 7 carbon atoms »and Ph is phenyl or a radical of formula χ1 wherein X" is halogen, nitro, cyano or carboxy.

The compounds of the formula I are prepared according to the invention by oxidizing the thio group in the compound of the formula (I) in which Z is thio and X ', Alk and Ph have the same meaning as above, mainly perha-polla.

2 59995

Equivalents with the above compounds of formula I include the corresponding non-toxic pharmaceutically acceptable acid addition salts of the formula CH_ I *

OF

X '-II- Z-Alk-O-Ph 1 -N-OH (II) wherein X', Ph and Alk have the same meaning as above and T represents one equivalent of anion - for example chloride, bromide, iodide, nitrate, phosphate, sulphate , sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, or the like - which, in combination with the cationic portion of the aforementioned salt, is not either biologically or otherwise undesirable. These salts are prepared by mixing the corresponding bases with an equivalent amount of the various inorganic or strong organic acids indicated above by the abbreviation HT. Conversely, it is, of course, possible to obtain compounds of formula (I) by neutralizing the corresponding salts of formula (II).

Alkylene groups denoted by Alk include methylene, ethylene, trimethylene, propylene, tetramethylene, 1,1-dimethylethylene, pentamethylene, 2,2-dimethyltrimethylene, and similar divalent, saturated, acyclic, straight-chain or branched-chain hydrocarbon groups having wherein n is 1-7.

The halogens referred to in group X "are fluorine, chlorine, bromine and / or iodine, of which bromine is preferred.

Preferred compounds of the invention are those having the general formula CH 2 F 3. N.

0o-S N-SO-Alk-O-Ph

IL-N

wherein Alk and Ph are as defined above, and their non-toxic pharmaceutically acceptable acid addition salts.

3,59995

The compounds of the invention are useful due to their valuable biological properties. They are antibacterial against Erwinia sp. antiprotozoal for Trichomonas vaginalis and Tetrahymena pyriformis and antifungal for Trichophyton mentagrophytes and Verticillium albo-atrum.

The antiprotozoal activity of the present compounds is evident from the results of standard experiments in which the ability of the test compounds to inhibit the growth of Trichomonas vaginalis was determined. These experiments were performed as follows. A modified Diamond medium was prepared by mixing 1200 parts of trypticase, 600 parts of yeast extract, 300 parts of maltose, 60 parts of L-cysteine hydrochloride, 12 parts of L-ascorbic acid, 48 parts of dipotassium hydrogen phosphate, 48 parts of potassium hydrogen phosphate and 54,000 parts of water. The pH is adjusted to 6.8 with 40% sodium hydroxide solution and 30 parts of agar are added. The mixture is boiled for 1 minute to dissolve the agar and then sterilized in an autoclave. To 80 volumes of the medium thus obtained is aseptically added 20 volumes of sterile Dubos serum medium. The resulting medium is inoculated with 1% by volume of a 72-hour culture of Trichomonas vaginalis, followed by mixing 1 ml of uninoculated medium and 10 mg of the test compound. The mixture is incubated anaerobically at 37 ° C for 48 hours and then examined microscopically for the presence of mobile Trichomonades. If detected, the compound is considered inactive. If no mobile trichomonads are detected, 0.1 ml of the incubated mixture is serially diluted and mixed with sufficient amounts of inoculated medium to give test compound concentrations of 1000, 100, 10 and 1 pg per ml. The resulting mixtures are incubated anaerobically as before at 37 ° C for 48 hours, after which they are examined microscopically for the presence of mobile trichomonades. At the same time, for the purpose of comparison, identical incubations are performed except that no test compound is present. For example, a compound of the invention that has been shown to be particularly active in this experiment is 2- {t2- (p-cyanophenoxy) -ethyl] sulfinyl] -1-methyl-5-nitroimidazole.

The antiprotozoic activity of the compound of the invention and the compound of the prior art from Trichomonas vaginalis. 59995 4 is shown in the following table, which shows that the compound of the invention is about 10 times more active than the prior art compound.

Compound Active Dose μς / ml 1- {12- (p-cyanophenoxy) ethyl] sulfinyl] -1-methyl-5-nitroimidazole (e.g. 5) 100 1-methyl-2-benzylsulfonyl-5-nitroimidazole 1000 (e.g. 1, US Pat. No. 3,341,549) (e.g. 1, Britt. Pat. No. 1,077,696)

Because of their pharmacological properties, the compounds of the invention may be combined with pharmaceutical carriers and administered in a variety of known pharmaceutical forms suitable for oral, topical or parenteral administration.

CH of formula III

* 3 X '-S N>! - S-Alk-O-Ph I H (III)

-OF

wherein X ', Alk and Ph are as defined above, the sulfides can be converted to the corresponding sulfoxides and sulfones by oxidation in a known manner. The amount of oxidant used and the length of the reaction time usually determine the quality of the final product. Thus, for example, if the sulfide is contacted in chloroform, dichloromethane or another inert solvent with an equivalent of m-chloroperbenzoic acid at room temperature or below for a short time (e.g. 1 hour), sulfoxides are formed. Using two or more equivalents of peracid, especially if the contact time is extended (e.g. 18 hours), sulfones are obtained. Instead of m-chloroperbenzoic acid, other peracids can also be used, for example periodic acid, perbenzoic acid or peracetic acid. When sulfones are desired, the oxidation may alternatively be performed using excess hydrogen peroxide in acetic acid.

5 59995

Sulfides of formula m in which X 'is hydrogen can be prepared by reacting a mercaptan of formula? H3 fNvirSH ™

I-n

contact with a compound of formula Y-Alk-O-Ph (V) wherein Alk and ph are as defined above and Y is bromine, chlorine, iodine, toluenesulfonyloxy or methanesulfonyloxy. The reaction is best carried out in a solvent such as an alcohol (for example methanol or 2-propanol), dioxane, dimethyl sulfoxide or dimethylformamide. Time and temperature are not critical and will vary depending on the particular reaction components used.

Sulfides of the formula IIIi in which X 'is nitro can be prepared by nitration of the corresponding compounds of formula III in which X' is hydrogen in a manner known per se. Suitable nitrating agents are, for example, nitric acid, nitric acid / sulfuric acid, sodium or potassium nitrate / sulfuric acid and acetic anhydride / nitric acid. Alternatively, the nitration can be accomplished using nitronium salts such as nitronium tetrafluoroborate or nitronium hexafluorophosphate in nitromethane, tetramethylene sulfone, or other inert solvent.

The starting materials of formula v wherein Y is bromine, chlorine or iodine can be prepared by contacting a compound of formula HO-Ph (VI) wherein Ph is as defined above with a compound of formula Y'-Alk-Y 'wherein Alk has the same meaning as above, and Y 'is halogen. The starting materials of formula (V) wherein Y is methanesulfonyloxy or toluenesulfonyloxy can be prepared by contacting a compound of formula (V) with a compound of formula 6 59995 HO-Alk-Br wherein Aik is as defined above and then treating the resulting hydroxyalkyl compound tosyl or mesyl chloride.

The invention is illustrated by the following examples. In these examples, temperatures are given in degrees Celsius and IR absorption maxima are given in inverse values of cm (cm -1). Quantities of substances are given in parts by weight unless otherwise indicated. The ratio between parts by weight and parts by volume is the same as between grams and milliliters.

Example 1

To a solution of 27 parts of 1-methyl-2-t (4-phenoxybutyl) thioimidazole in 375 parts of chloroform was added, at about 5 ° C, 51 parts of 67.5% pure m-chloroperbenzoic acid portionwise with stirring. The resulting mixture was allowed to stand at room temperature for 3 days and then filtered. The filtrate was washed with 5% aqueous sodium carbonate solution and then dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation. The residue was 1-methyl-2 - [(4-phenoxybutyl) sulfonyl] imidazole, melting at 111.5-113.5 ° C after crystallization from acetone.

Example 2

To a solution of 63 parts of 2 - {[2- (p-bromophenoxy) ethyl] thio] -1-methylimidazole in 430 parts of chloroform and maintained at about 5 ° C was slowly added 51 parts of 67.5% m-chloroperbenzoic acid. The solid formed was filtered off. The filtrate was washed with 5% aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was triturated with ethyl ether to give 2 - {[2- (p-bromophenoxy) ethyl] sulfinyl] -1-methylimidazole, m.p. about 83-84.5 ° C.

Example 3

To a solution of 20 parts of 1-methyl-5-nitro-2- (β- (o-nitrophenoxy) heptyl] thio} imidazole in 750 parts of chloroform and kept at 7 59995 with stirring at about 5 ° C was added 13 After addition, the reaction mixture was allowed to stand overnight at room temperature, then washed with 5% aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and finally the solvent was removed by vacuum distillation. 5-nitro-1 - {[7- (o-nitrophenoxy) heptyl] sulfinyl} imidazole.

NMR in dimethyl sulfoxide is ε = 8.0; 7.85; 7.5; 6.95; 4.15; 3.9 and 3.25 ppm.

Example 4

When the amount of m-chloroperbenzoic acid given in Example 3 was doubled and otherwise proceeded as in that example, 1-methyl-5-nitro-2- {C7- (o-nitrophenoxy) heptyl} imidazole was obtained, which was further purified by chromatography on silica gel. and using benzene as the solvent. The first eluate was chlorinated. Evaporation of the solvent from the following eluates gave 1-methyl-5-nitro-2 - {[7- (o-nitrophenoxy) -heptyl] sulfonyl] imidazole as a residue. NMR in dimethyl sulfoxide is δ = 8.82; 7.89; 7,75; 7.52; 7.38 and 4.18 ppm.

Example 5

To a solution of 22 parts of 2- [2- (p-cyanophenoxy) ethyl] thio} -1-methyl-5-nitroimidazole in 375 parts of chloroform and maintained at about 5 ° C was added slowly, with stirring, 19 parts of 67.5% pure m- chloroperbenzoic. The reaction mixture was allowed to stand overnight at room temperature, after which it was filtered. The filtrate was chromatographed on silica gel using chloroform as an eluent. The first eluates containing impurities were discarded. Evaporation of the solvent from the following eluates and recrystallization of the residue from acetone gave 2 - {[2- (p-cyanophenoxy) ethyl] sulfinyl] -1-methyl-5-nitroimidazole, m.p. 159.5 to 161 ° C.

Claims (3)

59995 8 Example 6 3.2 parts of 4-12- (1-methyl-5-nitro-2-imidazolylthio) ethoxy] benzoic acid were dissolved in a solution of 105 parts of acetic acid and 300 parts of chloroform. The solution was cooled and 2 parts of 85% m-chloroperbenzoic acid were added with stirring. After two hours, the solution was removed in vacuo. The residue was slurried in benzene and chloroform, and the mixture was poured onto a chromatography column containing 100 g of silica. The column was washed with 200 parts of benzene and 90 parts of 10% ethyl acetate-benzene, and eluted with 90 parts of 5% ethanol-ethyl acetate. The solution was removed in vacuo and the residue was triturated with hot methanol and filtered to give 4-C2- (1-methyl-5-nitro-2-imidazolylsulfinyl) ethoxy] benzoic acid, melting at 205.5-206 ° C. A process for the preparation of pharmacologically valuable 2- (phenoxyalkylsulfinyl or sulfonyl) imidazoles having the general formula CH-, N 1 - X '- (T 71 -Z-Alk-O-Ph H H (I) 1-N wherein X 'is hydrogen or nitro »Z is sulfinyl or sulfonyl» Alk is alkylene of 1 to 7 carbon atoms »and Ph is phenyl or a radical of formula X" ~ d) wherein X "is halogen, nitro, cyano or carboxy, characterized in that the thio group is oxidized in a compound of formula (I) in which Z is thio and X, Alk and Ph have the same meaning as above, mainly with peracid.