Abstract:
The new 2-phenoxyacetamido-5-nitro-thiazole represented by the formula: ##SPC1## 
     In which one of the symbols R 1 , R 2 , R 3 , R 4  and R 5  represents a halogen, preferably chlorine, bromine or fluorine, or a lower alkyl radical containing preferably 1 to 3 carbon atoms, or a trifluoromethyl radical, the remaining symbols representing hydrogen are interesting parasiticides, bacteriostatic agents and fungistatic agents.

Description:
SUMMARY OF THE INVENTION 
     This invention relates to new 2-phenoxyacetamido-5-nitro-thiazoles, as well as the preparation and use of said compounds in the pharmaceutical dield. 
     The new compounds according to this invention may be represented by the following general formula: ##SPC2## 
     In which at least one of the symbols R 1 , R 2 , R 3 , R 4  and R 5  represents a halogen or a lower alkyl or trifluoromethyl radical, the remaining symbols representing hydrogen. 
     This invention relates also to a process for preparing the new compounds of formula (I), as well as to compositions containing at least one of said compounds, as active parasiticidal, bacteriostatic and/or fungistatic ingredient. 
     DETAILED DESCRIPTION OF THE INVENTION 
     Among the new compounds according to this invention, the following may be cited by way of examples: 
     2-(3&#39;-chlorophenoxyacetamido)- 5 -nitrothiazole; 
     2-(1&#39; ,3&#39;-dichlorophenoxyacetamido)-5-nitrothiazole; 
     2-(3&#39;-bromophenoxyacetamido)-5-nitrothiazole; 
     2-(1&#39;-isopropyl-3&#39;-chloro-4&#39;-methyl-phenoxyacetamido)-5-nitrothiazole; 
     2-(3&#39;-fluoro-phenoxyacetamido)-5-nitrothiazole; 
     2-(2&#39;-trifluoromethyl-4&#39;-trifluoromethyl-phenoxyacetamido)-5-nitrothiazole; 
     2-(1&#39; ,2&#39; ,3&#39; ,4&#39; ,5&#39;-pentafluoro-phenoxyacetamido)-5-nitrothiazole; 
     2-(1&#39;-chloro-3&#39; ,4&#39;-dimethylphenoxyacetamido)-5-nitrothiazole; 
     2-(2&#39;-trifluoromethyl-3&#39;-methylphenoxyacetamido)-5-nitrothiazole; 
     2-(2&#39;methyl-3&#39;-chlorophenoxyacetamido)-5-nitrothiazole; 
     2-(2&#39; ,4&#39;-dichloro-phenoxyacetamido)-5-nitrothiazole. 
     The new compounds of formula (I) are prepared, according to this invention, by reacting 2-amino-5-nitrothiazole of the formula: ##SPC3## 
     With a phenoacetyl halide of the formula: ##SPC4## 
     In which Hal represents a halogen atom, preferably a chlorine atom, whereas R 1 , R 2 , R 3 , R 4  and R 5  have the above meanings, in the presence of triethylamine. 
     The reaction between the 2-amino-5-nitrothiazole of formula (II) and the phenoxyacetyl halide of formula (III) is preferably carried out at room temperature by adding slowly triethylamine to a stirred solution of the compounds of formulae (II) and (III) in a solvent, such as anhydrous tetrahydrofuran, by stirring the reaction mixture and by pouring it in distilled water, the stirring being continued until the desired product crystallizes. 
     It has been found that the compounds of formula (I) may be used as parasiticides, namely for the control of Trichomonas vaginalis, Entomoeba dysenteriae, Syphacia obvelata and Hymenolepis nana. 
     It has also been found that the compounds of formula (I) may be used as bacteriostatic and fungistatic agents, namely for the control of the following bacteria and fungi: 
     
                           Abbreviation______________________________________BacteriaStaphylococcus      209 P   Sta. or S.   209 PStaphylococcus       ATCC    12715   Sta. or S.                              ATCC  12715Staphylococcus      8006    Sta. or S.   8006Staphylococcus      101     Sta. or S.   101Escherichia coli       IPA     223     E. Coli                              IPA   223Escherichia coli       OIII B  4       E. Coli                              OIII B                                    4Streptococcus faecalis       ATCC    9790    S.faec.                              ATCC  9790Shigella dysenteriae               3410    S.           3410Shigella sonnei     8025    S.           8025Pseudomonas         8194    Pseudo.      8194aeruginosaProteus vulgaris    8181    P. vulg.     8181Proteus morganii       IP      53185   P. morg.                              IP    53185Enterococcus        504     E.           504Enterococcus        8043    E.           8043Enterococcus        9790    E.           9790FungiTrichophyton mentagrophytes               T.m.Trichophyton rubrum T.r.Microsporum felineum               M.f.Microsporum audouini               M.a.Epidermo flocosum   E.f.______________________________________ 
    
     This invention relates therefore also to compositions to be used for the control of parasites, bacteria or fungi, said compositions containing at least one compound of formula (I), together with a suitable pharmaceutical carrier. 
    
    
     EXAMPLES 1 to 12 
     The compounds listed in Table I have been prepared by the following method: 
     To a solution of one mole of a phenoxyacetyl chloride formula (III) and one mole of carefully purified 2-amino-5-nitrothiazole in 200 ml of anhydrous tetrahydrofuran at room temperature, one mole of triethylamine has been slowly added (about 10 minutes), while stirring. The reaction mixture which became slightly warn has been stirred during 45 minutes and then poured, under agitation, into 2 liters of distilled water. The stirring has been continued until the precipitation of the desired compound stopped. The obtained precipitate was dried, washed with water, again dried and recrystallized from ethanol. 
     
                                           TABLE I__________________________________________________________________________                    Melt-                    ing                ANALYSISEx Code  Substituents    point         Mol  CalculatedNr Number    in formula I   °C                       Formula    Weight                                       C   H  N   S   Hal__________________________________________________________________________1  PH 5927    R.sub.1 =R.sub.2 =R.sub.4 =R.sub.5 =H; R.sub.3 =Cl                   231 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SCl.sub.2                                = 313,5                                       42.10                                           2.55                                              13.39                                                  10.20                                                      11.322  PH 6091    R.sub.1 =R.sub.3 =Cl; R.sub.2 =R.sub.4 =R.sub.5 =H                   196 C.sub.11 H.sub.7 N.sub.3 O.sub.4 SCl.sub.2                                = 348  37.93                                           2.01                                              12.06                                                  9.19                                                      20.403  PH 6092    R.sub.1 =R.sub.2 =R.sub.4 =R.sub.5 =H; R.sub.3 =Br                   235 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SBr                                = 358  36.87                                           2.23                                              11.73                                                  8.93                                                      22.344  PH 6099    R.sub.1 =C.sub.3 H.sub.7 ; R.sub.2 =R.sub.5 =H:                   178 C.sub.15 H.sub.16 N.sub.3 O.sub.4 SCl                                = 369,5                                       48.71                                           4.33                                              11.36                                                  8.66                                                      9.60    R.sub.3 =Cl; R.sub.4 =CH.sub.35  PH 6159    R.sub.1 =R.sub.4 =Cl; R.sub.2 =R.sub.3 =R.sub.5 =H                   246 C.sub.11 H.sub.7 N.sub.3 O.sub.4 SCl.sub.2                                = 348  37.93                                           2.02                                              12.06                                                  9.19                                                      20.406  PH 6160    R.sub.1 =R.sub.2 =R.sub.4 =R.sub.5 =H; R.sub.3 =F                   188 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SF                                = 297  44.44                                           2.69                                              14.14                                                  10.77                                                      6.397  PH 6167    R.sub.1 =R.sub.3 =R.sub.5 =H; R.sub.2 =R.sub.4 =CF.sub.3                   207 C.sub.13 H.sub.7 N.sub.3 O.sub.4 SF.sub.6                                = 415  37.59                                           1.68                                              10.12                                                  7.71                                                      27.468  PH 6168    R.sub.1 =R.sub.2 =R.sub.3 =R.sub.4 =R.sub.5 =F                   154 C.sub.11 H.sub.4 N.sub.3 O.sub.4 SF.sub.5                                = 369  35.77                                           1.08                                              11.38                                                  8.67                                                      25.749  PH 6182    R.sub.1 =R.sub.3 =R.sub.5 =H; R.sub.2 =R.sub.4 =                   175 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SCl.sub.2                                = 349  37.82                                           2.29                                              12.03                                                  9.16                                                      20.3410 PH 6305    R.sub.1 =Cl;R.sub.2 =R.sub.5 =H;R.sub.3 =R.sub.4 =CH.sub.3                   185 C.sub.13 H.sub.11 N.sub.3 O.sub.4 SCl.sub.2                                = 340,5                                       45.81                                           3.23                                              12.33                                                  9.39                                                      10.4211 PH 6306    R.sub.1 =R.sub.4 =R.sub.5 =H;R.sub.2 =CF.sub.3 ; R.sub.3    =CH.sub.3      141 C.sub.12 H.sub.6 N.sub.4 O.sub.6 SF.sub.3                                = 391  36.92                                           1.53                                              14.32                                                  8.18                                                      14.5712 PH 6314    R.sub.1 =R.sub.4 =R.sub.3 =H;R.sub.2 =CH.sub.3 ;R.sub.3 =Cl                   177 C.sub.12 H.sub.9 N.sub.3 O.sub.4 SCl                                = 326.5                                       44.10                                           2.75                                              12.86                                                  9.80                                                      10.87__________________________________________________________________________                   Melt-                   ing                 ANALYSISEx Code  Substituents   point          Mol  FoundNr Number    in formula I   °C                       Formula    Weight                                       C   H  N   S   Hal__________________________________________________________________________1  PH 5927    R.sub.1 =R.sub.2 =R.sub.4 =R.sub.5 =H; R.sub.3 =Cl                   231 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SCl.sub.2                                = 313,5                                       42.02                                           2.42                                              13.40                                                  10.18                                                      11.272  PH 6091    R.sub.1 =R.sub.3 =Cl; R.sub.2 =R.sub.4 =R.sub.5 =H                   196 C.sub.11 H.sub.7 N.sub.3 O.sub.4 SCl.sub.2                                = 348  37.84                                           1.92                                              11.95                                                  9.12                                                      20.323  PH 6092    R.sub.1 =R.sub.2 =R.sub.4 =R.sub.5 =H; R.sub.3 =Br                   235 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SBr                                = 358  36.81                                           2.17                                              11.69                                                  8.82                                                      22.294  PH 6099    R.sub.1 =C.sub.3 H.sub.7 ; R.sub.2 =R.sub.5 =H:                   178 C.sub.15 H.sub.16 N.sub.3 O.sub.4 SCl                                = 369.5                                       48.69                                           4.28                                              11.29                                                  8.52                                                      9.54    R.sub.3 =Cl; R.sub.4 =CH.sub.35  PH 6159    R.sub.1 =R.sub.4 =Cl; R.sub.2 =R.sub.3 =R.sub.5 =H                   246 C.sub.11 H.sub.7 N.sub.3 O.sub.4 SCl.sub.2                                = 348  37.87                                           1.97                                              12.04                                                  9.01                                                      20.276  PH 6160    R.sub.1 =R.sub.2 =R.sub.4 =R.sub.5 =H; R.sub.3 =F                   188 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SF                                = 297  44.38                                           2.59                                              14.09                                                  10.69                                                      6.277  PH 6167    R.sub.1 =R.sub.3 =R.sub.5 =H; R.sub.2 =R.sub.4 =CF.sub.3                   207 C.sub.13 H.sub.7 N.sub.3 O.sub.4 SF.sub.6                                = 415  37.48                                           1.62                                              10.06                                                  7.62                                                      27.418  PH 6168    R.sub.1 =R.sub.2 =R.sub.3 =R.sub.4 =R.sub.5 =F                   154 C.sub.11 H.sub.4 N.sub.3 O.sub.4 SF.sub.5                                = 369  35.69                                           1.02                                              11.22                                                  8.60                                                      25.699  PH 6182    R.sub.1 =R.sub.3 =R.sub.5 =H; R.sub.2 =R.sub.4 =Cl                   175 C.sub.11 H.sub.8 N.sub.3 O.sub.4 SCl.sub.2                                = 349  37.76                                           2.19                                              12.05                                                  9.10                                                      20.2810 PH 6305    R.sub.1 =Cl;R.sub.2 =R.sub.5 =H;R.sub.3 =R.sub.4 =CH.sub.3                   185 C.sub.13 H.sub.11 N.sub.3 O.sub.4 SCl.sub.2                                = 340,5                                       45.72                                           3.14                                              12.29                                                  9.31                                                      10.4611 PH 6306    R.sub.1 =R.sub.4 =R.sub.5 =H;R.sub.2 =CF.sub.3 ;R.sub.3 =CH.sub.3    7              141 C.sub.12 H.sub.6 N.sub.4 O.sub.6 SF.sub.3                                = 391  36.83                                           1.47                                              14.26                                                  8.11                                                      14.4912 PH 6314    R.sub.1 =R.sub.4 =R.sub.3 =H; R.sub.2 =CH.sub.3 ;R.sub.3                   177 C.sub.12 H.sub.9 N.sub.3 O.sub.4 SCl                                = 326,5                                       44.07                                           2.69                                              12.78                                                  9.72                                                      10.89__________________________________________________________________________ 
    
     BIOLOGICAL TESTS 
     Biological tests have been performed with a great number of compounds of formula (I) using the following techniques: (1) Test for amoebicidal activity described by R. CAVIER, Ann. pharm. franc., 1960, 18, pages 583-589 and by R. CAVIER, and J. CENAC, Bull. Soc. Path. exot. 1972, 65, pages 399-404. (2) Test for trichomonacidal activity described by R. CAVIER and P. BUOT, Ann. pharm. franc., 1964, 22, pages 211-216 and by R. CAVIER and J. CENAC, Semaine des Hopitaux, 1972, 48, pages 391-394). (3) Tests for anthelminthics described for nematodes (such as Syphacia obvelata) by R. CAVIER, Bull. Soc. Path. exot., 1962, 55, pages 412-417 and, for cestodes (such as Hymenolepis nana), by R. CAVIER, Ann. pharm. franc., 1956, 14, pages 545-552 and by R. CAVIER and M. J. NOTTEGHEM, Ann. pharm. franc. 1968, 28, pages 603-606. 
     (4) Method for determining fungistatic doses: 
     MEDIUM 
     A liquide Sabouraud medium having the following composition is used: 
     
         peptone (Oxoid)    10 gramsanhydrous glucose  20 gramsdistilled water q.s. for              1,000 ml. 
    
     If necessary, the pH is adjusted at 6.4 and the medium is sterilized. 
     Solubilization of the compounds to be tested 
     The compounds are dissolved in dimethylformamide to which polyethylene glycol is sometimes added. From the mother-liquor, successive diluted solutions are prepared in the liquid Sabouraud medium, so as to obtain concentrations of 1, 3, 10, 30 100 and 300 mg per ml. For the first dilution, one should not add more than 10% of the mother-liquor to the Sabouraud medium. Subsequently 9 ml per tube of the various solutions in the liquid Sabouraud medium are distributed. 
     Reference tubes corresponding to the highest solvent concentrations are also prepared. 
     SEEDING 
     For dermatophytes: 
     Cultures of the various dermatophyte strains on Sabouraud gelose medium are prepared. From 1 to 2 months old cultures, homogeneous suspensions of said cultures in the liquid Sabouraud medium are prepared, the obtained suspensions being stirred in the presence of glass pearls having a light transmission of about 40%. 
     One drop of said suspension is introduced in the tubes containing the various concentrations of the compound to be tested. 
     For yeasts: 
     The same method as for dermatophytes is used except that 2 to 3 weeks old cultures on Sabouraud gelose medium are used. 
     INCUBATION 
     at 25°C ± 2°C in the dark 
     READING 
     Direct reading after 
     5 days of incubation for yeasts 
     10 days of incubation for dermatophytes. 
     (5) Method for determining bacteriostatic doses 
     MEDIUM 
     A common gelose medium of the following composition is used. 
     
         ______________________________________Bacteriological peptone (Oxoid)               10 gramsmeat extract (Liebig)               5 gramssodium chloride     5 gramsdistilled water q.s. for               1,000 ml______________________________________ 
    
     The pH is adjusted at 7.2 and the medium is sterilized during 30 minutes at 120°C. 
     Solubilization of the compounds to be tested 
     The same method as for the determination of fungistatic doses is used, except that the various dilutions of each compound are added to the gelose medium, the solvent concentration never exceeding 3%. Tubes containing 1, 3, 10, 30, 100, and 300 mg of the compounds per ml are prepared. 
     SEEDING 
     Cultures of each strain in the liquid medium are prepared and, after 24 hours of incubation at 37°C, dilutions of these cultures in ordinary broth are prepared as follows: 
     
         Staphylococcus aureus 209 P               1 drop in 20 mlEnterococcus 9790   1 drop in 20 mlEscherichia coli OIII B 4               1 drop in 20 mlShigella dysenteriae 3410               1 drop in 10 mlProteus morganii IP 53185               1 drop in 10 mlPseudomonas aeruginosa 8194               1 drop in 20 ml 
    
     By means of these dilutions, scratches of a length of 4 to 5 cm are made on the previously dried surface of the gelose medium to which various amounts of the compound to be tested have been added. 
     INCUBATION 
     at 37°C during 24 hours 
     DIRECT READING 
     after 24 hours. 
     Following Tables II and III give the results of the tests which have been made with various compounds of the formula (I) on a number of parasites, bacteria and fungi. 
     
                                           TABLE II__________________________________________________________________________BIOLOGICAL PROPERTIESPARASITOLOGYCompound Trichomonas            Entomoeba    Syphacia    Hymenolepis vaginalis  dysenteriae  obvelata    nana__________________________________________________________________________Code  starting        lethal            starting                   lethal                         N°                            +  D  %  N°                                        +  D  %number activity        action            activity (5)                   action                         (1)                            (2)                               (3)                                  (4)                                     (1)                                        (2)                                           (3)                                              (4)__________________________________________________________________________PH 5927   1 to 1.25        12.5              1 to 1.25                   25 to 50                         10 0  3  30 10 0  0   0PH 6091 1 to 2     50 to 100    10 0  2  20 10 0  3  30PH 6092 100        100          10 0  1  10 10 0  1  10PH 6099 100        10           10 0  2  20 10 0  4  40PH 6159 50 to 100  5 to 10      10 0  0   0 10 0  2  20PH 6160 50 to 100  5 to 10      10 0  0   0 10 0  0   0PH 6167 50 to 100  100          10 0  4  40 10 0  7  70PH 6168 50 to 100  100          10 0  0   0 10 0  2  20PH 6182 50 to 100  2.5                      10 0  0   0PH 6305 5 to 10    10           10 0  1  10 10 0  0   0PH 6306 5 to 10    5            10 0  0   0 10 0  0   0PH 6314 2.5        10           10 0  0   0 10 0  0   0__________________________________________________________________________ (1) Number of subjects (2) Number of dead subjects (3) Number of subjects from which the parasite has been eradicated (4) Percentage of activity (5) in mμ/ml 
    
     
                                           TABLE III__________________________________________________________________________BIOLOGICAL PROPERTIESDoses in μg/ml.Compound fungi                bacteriaCode                       S.   E.  O.III                                    S.  P.   Pseudonumber T.m   M.f.          M.a.             E.f.  T.r.                      209 P                           9790                               B 4  3410                                        morg.                                             8194__________________________________________________________________________PH 5927 30    00    10       100  0        0   0    0PH 6091 3     30    1        3    0   0    0   0    0PH 6092 100   0     0        10   0   0    0        0PH 6099 0.5 to 1 0.1             0.5 to 1                   2  3    300 0    300 0    0PH 6159 30    --    0        0    0   0    0   0    0PH 6160 4        4  1     4  10   0   0    100 0    0PH 6167 1     0     1        3    10  0    0        0PH 6168 1     -- 3  1        10   10  300  300 300                                        (8181)                                             0PH 6182 1     -- 3  1        10   0   0    0   0    0PH 6305 0     0     0        0    0   0    0   0    0PH 6306 1     10    30       10   100 0    0   0    0PH 6314 0     0     0        3    0   0    0   0    0__________________________________________________________________________ 
    
     The above tests clearly show that the compound of formula (I) may be useful for the treatment of various parasitic diseases, such as trichomoniasis, amoebiasis and oxyurasis, as well as bacteriostatic and fungistatic agents. 
     For the treatment of parasitic diseases, the compound of formula (I) may be used together with usual pharmaceutical carriers in tablets, capsules, syrups and gynaecological ovules. 
     For the treatment of mycoses and bacterial infections, the compounds of formula (I) may be used together with usual pharmaceutical carriers in tablets, capsules, ointment and suppositories. 
     When used as anthelminthics, tablets containing about 500 mg of a compound of formula (I) may be administered to adults at a dose of 2 to 4 tablets per day. 
     It is pointed out that the presence of the R 1 , R 2 , R 3 , R 4  or R 5  substituents (other than hydrogen) in the compounds of formula (I) is critical for the parasitological bacteriostatic and fungistatic activities of the compounds, since tests have shown that 2-phenoxyacetamido-5-nitro-thiazole, which is a known compound of formula (I) wherein R 1 , R 2 , R 3 , R 4  and R 5  represent hydrogen, has no activity against Trichomonas vaginalis and Entomoeba dysenteriae, nor against bacteria and fungi. 
     Toxicity investigations have shown that the compounds of formula (I) have a very low acute toxicity. 
     The acute toxicity of compound PH 5927 is more than 4500 mg/kg (LD 50 ) after intraperitoneal administration to mice, whereas the acute toxicity of compound PH 6099 is of about 200 mg/kg (LD 50 ) after intraperitoneal administration to mice. 
     The LD 50  of compounds PH 6099 and 5927, when orally administered to mice, is of more than 4000 mg/kg.