Abstract:
2-Aminomethyl-5-phenyloxazoles and the pharmaceutically acceptable salts thereof have been found to be effective for meliorating inflammation in warm blooded animals.

Description:
BACKGROUND OF THE INVENTION 
     FIELD OF THE INVENTION 
     This invention relates to 2-aminomethyl-5-phenyloxazoles and the pharmaceutically acceptable acid addition salt thereof which exhibit anti-inflammatory and analgesic activity. 
     SUMMARY OF THE INVENTION 
     This invention relates to compounds of the formula (I): ##STR1## wherein R 1  is phenyl or halophenyl; R&#39; is (1) 4-(2-hydroxyethyl)-1-piperazinyl or (2) ##STR2## wherein R 2  and R 3  are selected from the group consisting of hydrogen and C 1  -C 10  alkyl. Also encompassed within this invention are pharmaceutically acceptable salts thereof. This invention also relates to a method of meliorating inflammation in warm blooded animals, particularly mammals, which comprises administering to said animal an anti-inflammatory effective amount of a compound of formula (I). 
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     This invention relates to a group of 2-aminomethyl-5-phenyloxazoles of the formula (I): ##STR3## wherein R 1  is phenyl or halophenyl such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl and the like: R&#39; is (1) 4-(2-hydroxyethyl)-1-piperazinyl or (2) ##STR4## wherein R 2  and R 3  are selected from the group consisting of hydrogen and alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyul, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, hexyl, oxtyl, decyl and the like. Suitable R 1  groups in the above formula (I) are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 4-bromophenyl and the like. 
     Suitable methyl, octyl, ##STR5## groups in the above formula (I) are amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, isubutylamino, dimethylamino, diethylamino and the like. 
     ILLUSTRATIVE OF THE COMPOUNDS OF THIS INVENTION ARE THE FOLLOWING: 
     2-dimethylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-methylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-aminomethyl-5-(4-chlorophenyl) oxazole 
     2-aminomethyl-5-(4-fluorophenyl) oxazole 
     2-methylaminomethyl-5-phenyloxazole 
     2-dimethylaminomethyl-5-phenyloxazole 
     2-aminomethyl-5-phenyloxazole 
     2-ethylaminomethyl-5-phenyloxazole 
     2-propylaminomethyl-5-phenyloxazole 
     2-isopropylaminomethyl-5-phenyloxazole 
     2-butylaminomethyl-5-phenyloxazole 
     2-ethylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-isopropylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-methylaminomethyl-5-(4-fluoropuenyl) oxazole 
     2-ethylaminomethyl-5-(4-fluorophenyl) oxazole 
     2-aminomethyl-5-(2-chlorophenyl) oxazole 
     2-methylaminomethyl-5-(3-chlorophenyl) oxazole 
     2-methylaminomethyl-5-(2-chlorophenyl) oxazole 
     2-ethylaminomethyl-5-(2-chlorophenyl) oxazole 
     2-ethylaminomethyl-5-(4-bromophenyl) oxazole 
     2-ethylaminomethyl-5-(3,4-dichlorophenyl) oxazole 
     2-propylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-propylaminomethyl-5-(3-chlorophenyl) oxazole 
     2-propylaminomethyl-5-(4-fluorophenyl) oxazole 
     2-diethylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-chlorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(3-chlorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(2-chlorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-fluorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-bromophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(3,4-dichlorophenyl) oxazole 
     The pharmaceutically acceptable acid addition salts of the above compounds are, of course, also included within the scope of this invention. 
     It will be understood that the term &#34;pharmaceutically acceptable acid addition salts&#34; as used herein is intended to include non-toxic salts of the compounds of this invention with an anion. 
     Representative of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, acetates, succinates, adipates, propionates, tartrates, maleates, citrates, benzoates, toluenesulfonates, and methanesulfonates. Of the compounds of this invention, it will be understood that the following compounds are most preferred due to their high level of anti-inflammatory and analgesic activity. 
     2-methylaminomethyl-5-phenyloxazole 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-chlorophenyl) oxazole 
     The above compounds are intended only to illustrate the variety of structures which can be used in the process of this invention, and the above listing is not to be construed as limiting the scope of the invention. 
     For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved. 
     The 2-aminomethyl-5-phenyloxazole can be prepared by the condensation of a 2-halomethyl-5-phenyloxazole with at least an equimolar amount of a corresponding primary or secondary amine. 
     The following reaction equation illustrates this method of preparation. ##STR6## In the above formulas, R 1  and R&#39; are as defined herein above and when R&#39; is ##STR7## at least one of R 2  and R 3  is alkyl, and X is halogen. 
     The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, sodium carbonate) for a period of from 1 to 30 hours. 
     The preferred solvents for the condensation includes water, methanol, ethanol, dimethylformamide, tetrahydrofuran and the like. The reaction temperature is not critical, and generally ranges from 0° to 200° C, preferably from 15° to 100° C. 
     The amount of the primary or secondary amine (III) to be used is generally in the range of 1 to 10 moles per mole of the 2-halomethyl-5-phenyloxazole (II), with from 1 to 3 moles per mole of the 2-halomethyl-5-phenyloxazole (II) being preferred. 
     After the reaction is complete, the reaction mixture is concentrated to remove the solvent and the excess amine. The residue is partitioned between NaOH solution and chloroform, the chloroform layer separated and dried over a suitable drying agent, and then the solvent is evaporated under reduced pressure. The resulting product (I), after having been converted to the acid addition salt by interaction of the product with an acid in an appropriate medium, e.g., methanol or ethanol, can be recrystallized from a suitable solvent, e.g., methanol or ethanol. 
     2-Aminomethyl-5-phenyloxazoles wherein R 2  and R 3  are hydrogen, can be prepared by the reaction of a 2-halomethyl-5-phenyloxazole with potassium phthalimide followed by decomposition of the obtained N-(5-phenyl-2-oxazolyl) methylphthalimide with hydrazine hydrate. 
     The following reaction equation illustrates this method of preparation. ##STR8## In the above formulas, X is halogen. The reaction between the 2-halomethyl-5-phenyl oxazole (II) and potassium phthalimide (IV) is generally effected in a suitable reaction-inert solvent at a temperature of from 15° to 100° C for a period of from 1 to 30 hours. 
     The preferred solvents are dimethylformamide and ethanol. The amount of potassium phthalimide to be used is generally in the range of 1 to 10 moles per mole of the 2-halomethyl-5-phenyloxazole (II), with from 1 to 2 moles per mole of the 2-halomethyl-5-phenyloxazole (II) being preferred. 
     Upon completion of the reaction, the reaction mixture is poured into water to give the precipitate (V) which is filtered and can be purified by recrystallization from a suitable solvent, e.g., ethanol. 
     The decomposition of the N-(5-phenyl-2-oxazolyl)methylphthalimide (V) by the action of hydrazine hydrate is generally effected in an alcohol at a temperature of from 15° to 100° C for a period of from 1 to 10 hours. 
     In general, hydrazine hydrate is used in an amount of 1 to 3 moles per mole of the N-(5-phenyl-2-oxazolyl) methylphthalimide (V). 
     After the reaction is complete, the formed precipitate is filtered off. The filtrate is evaporated to dryness, and the residue, after having been converted to the acid addition salt, can be purified by recrystallization from a suitable solvent, e.g., ethanol. 
     The 2-halomethyl-5-phenyloxazoles (II) starting materials can be prepared by the condensation of a phenacylamine with a haloacetyl halide followed by cyclization of the obtained N-phenacylhaloacetamide. 
     The following reaction equation illustrates this method of preparation. ##STR9## In the above formulas, R 1  and X are as defined herein above. The condensation of the phenacylamine (VII) with the haloacetyl halide (VII) is carried out in a suitable solvent, e.g., benzene-water, in the presence of a base, such as sodium hydroxide at a temperature of 0° to 50° C for a period of 1 to 5 hours. 
     A convenient method of isolation comprises extraction of the product with a water immiscible solvent, e.g., benzene, followed by removal of the solvent. The resultant product can be used in this crude state for the subsequent reaction or can be recrystallized from an appropriate solvent, e.g., ethanol. 
     The cyclization of the N-phenacylhaloacetamide (IX) to the 2-halomethyl-5-phenyloxazole (II) is carried out in a suitable solvent, e.g., benzene or toluene, in the presence of a dehydrating agent, e.g., phosphorous oxychloride, or sulfuric acid at a temperature of 15° to 100° C for a period of 1 to 5 hours. 
     The product is conveniently isolated by pouring the reaction mixture into water followed by extraction with a water immiscible solvent such as chloroform. The organic layer is dried over a suitable drying agent and concentrated in vacuo. The isolated product can be used in this crude state or may be further purified by recrystallization. 
     The 2-aminomethyl-5-phenyloxazoles of this invention form acid addition salts with any of a variety of inorganic and organic acids. 
     The product of the reactions described above can be isolated in the free form or in the form of an acid addition salt. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid. 
     Likewise, treatment of the salts with a base results in a regeneration of the free base. 
     Pharmacological testing of the 2-aminomethyl-5-phenyloxazoles has demonstrated that they are useful as anti-inflammatory agents. Analgesic activity has also been found in the compounds of this invention. 
     The anti-inflammatory activity of the compounds of the present invention was demonstrated in the following test: 
     The anti-inflammatory activity of the 2-aminomethyl-5-phenyloxazoles was compared with that of aminopyrine. 
     Eight male rats of Wistar-King strain, each weighing between 120 to 150 grams, were used for each group. The hind paw of the rats was injected subcutaneously with 0.1 ml of 1% carrageenin suspension. The volume of the paw was measured plethysmographically 3 hours after the injection, and the difference in volume between the edematous foot and the normal foot was regarded as the degree of edema. Each percent inhibition was calculated in comparison with the control. The test compounds were administered orally 30 minutes before the injection of carrageenin. 
     The analgesic activity of the 2-aminomethyl-5-phenyloxazoles was compared with that of aminopyrine. 
     (A) Writhing syndrome induced by acetic acid 
     Six male mice of ddY strain, each weighing between 25 to 30 grams were used in the present experiment. The animals were injected intraperitoneally with 0.1 m/10 g of a 0.6% aqueous acetic acid solution 10 minutes after the test compound was injected subcutaneously. Thereafter, the total number of writhings of a group was recorded for 20 minutes, and percent inhibition was calculated in comparison with the control. ED 50  was calculated according to Litchfield-Wilcoxon&#39;s method. 
     (B) Electrical stimulation method 
     Five male mice of ddY strain, each weighing between 25 to 30 grams were used for each group. Bipolar electrode was placed on the tail root of mouse. The mouse was stimulated with the square wave (5 m sec, 1 Hz), and the minimum voltage of squeak response was measured at 5, 10, 15, 30, 45 and 60 minutes after intraperitoneal administration of the test compound. Positive analgesic response was determined in cases where increase in the minimum voltage was observed. ED 50  was calculated according to Weil&#39;s method. The actute toxicity values (LD 50 ) of the 2-aminoethyl-5-phenyloxazoles were determined in the following manner: 
     The animals were administered intraperitoneally with the test compounds, and mortality was observed for 168 hours. LD 50  was calculated according to Weil&#39;s method. The results are shown in Table I. 
     
                                           TABLE I__________________________________________________________________________                           Anti-inflammatory                           Activity                           (carageenin-                           induced rat paw                           inflammation)                                    Analgesic Activity                                    AcOH induced                               Percent                                    Writhing in                                            Electrical                           Oral                               Inhibition                                    Mice    Stimulation                           Dose                               of   ED.sub.50                                            ED.sub.50                                                   LD.sub.50 in                                                   MiceCompound                        mg/kg                               Swelling                                    (mg/kg. s.c.)                                            (mg/kg.                                                   (mg/kg.__________________________________________________________________________                                                   i.p.) ##STR10##                      25 50 100                                5 40 48                                    10.1    32     238 ##STR11##                      12.5 25 50 100                               16 43 65 60                                    1.9     35     283 ##STR12##                      100 7    78      77     336 ##STR13##                      25 50  100                                5 40 48                                    10.1    32     238 ##STR14##                      12.5 25 50 100                               16 43 65 60                                    1.9     35     283 ##STR15##                      100 7    78      77     336 ##STR16##                      100 17   22      46     141 ##STR17##                      25 50 100                               25 29 65                                    6       50     476 ##STR18##                       50 100                               23 47        21.4   141 ##STR19##                       50 100                               38 55               141 ##STR20##                      25 50 100                               28 58 42            283 ##STR21##                      100 21                  283 ##STR22##                      100 14                  141 ##STR23##                      100 14           54     141 ##STR24##                      100 22                  168 ##STR25##                      25 50 100                               27 56 68            141 ##STR26##                       50 100                               24 38        47     566 ##STR27##                       50 100                                4 32               283 ##STR28##                       50 100                               45 53        54     238 ##STR29##                       50 100                               24 44               238 ##STR30##                      100 14                  141 ##STR31##                      100 6                   283 ##STR32##                       50 100                                8 54               336 ##STR33##                      12.5 25 50 100                                6 27 57 50                                    16.0    30.8   283Aminopyrine                     12.5                               9    37      96     270                           25  23                           50  47                           100 65__________________________________________________________________________ 
    
     The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents. 
     Physicians will determine the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment. 
     When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally. The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 50-300 mg/kg orally per day. 
     Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified. 
    
    
     EXAMPLE 1 
     (A) N-(4-chlorophenacyl) chloroacetamide 
     To a well stirred suspension of 20.6 g of 4-chlorophenacylamine hydrochloride in 70 ml of benzene and 70 ml of water which was cooled to below 7° C were added simultaneously 110 ml of 2N NaOH solution and 12.4 g of chloroacetyl chloride dissolved in 30 ml of benzene. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. At the end of this period, the formed precipitate was filtered, and the benzene layer was separated. The aqueous layer was extracted twice with 50 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The residue together with the precipitate obtained above was combined and recrystallized from ethanol to give 14.1 g (57 percent) of N-(4-chlorophenacyl) chloroacetamide. 
     (B) 2-Chloromethyl-5-(4-chlorophenyl)oxazole 
     A suspension of 12.3 g of N-(chlorophenacyl) chloroacetamide and 19.2 g of phosphorous oxychloride in 100 ml of benzene was heated at reflux for 2.5 hours. At the end of this period, the excess phosphorous oxychloride was removed in vacuo. The residue was poured into 200 ml of water and extracted with 100 ml of chloroform. The aqueous layer was extracted twice with 40 ml of chloroform. 
     The combined chloroform layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 10.7 g (94%) of crude 2-chloromethyl-5-(4-chlorophenyl) oxazole. Recrystallization from aqueous ethanol gave pure 2-chloromethyl-5-(4-chlorophenyl) oxazole, M.P. 50°-60° C. 
     (C) 2-Ethylaminomethyl-5-(4-chlorophenyl) oxazole hydrochloride 
     To a solution of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole in 50 ml of ethanol was added 3.2 g of 70% ethylamine aqueous solution, and the resultant solution was allowed to stand at room temperature overnight. At the end of this time, the solvent and the excess ethylamine were distilled off under reduced pressure, and then 30 ml of water, 10 ml of 2N NaOH solution and 50 ml of chloroform were added. The chloroform layer was separated and the aqueous layer was extracted twice with 30 ml of chloroform. The combined chloroform layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 2.1 g of crude 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole. This was dissolved in 15 ml of ethanol, and 5 ml of ethanolic saturated hydrogen chloride solution was added. Evaporation of the solvent followed by recrystallization from ethanol afforded 2.0 g (73 percent) of 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole hydrochloride, M. P. 194°-6° C. 
     I.R. (KBr): 2,950, 2,740, 1,480, 1,450, 1,115 1,090 810 cm -1 . N.M.R. (CDCl 3 , free base): δ 1.13 (triplet, -NCH 2  CH 3 ), 1.77 (singlet, --NH--), 2.72 (quartet, --NCH 2  CH 3 ), 3.90 (singlet --CH 2  N--), 7.15 ##STR34## 7.34 ##STR35## p.p.m. Analysis - Calcd. for C 12  H 13  N 2  O 1  Cl 1 .HCl (percent): C, 52.76; H, 5.17; N, 10.26; Cl, 25.96. Found (percent): C, 52.73; H, 5.09; N, 10.25; Cl, 25.71. 
     Various other 2-aminomethyl-5-phenyloxazoles were synthesized in accordance with the procedure of Example 1, and the results are summarized in Table II. 
     
                                           TABLE II__________________________________________________________________________    ##STR36##                          Elemental analysis Upper:                                      Calculated  (percent) Lower:                                      Found(percent) No.    R.sub.1         ##STR37##  Addition moiety                           M. P. (° C)                                  Yield (%)                                       C    H    N    Cl__________________________________________________________________________    ##STR38##        NHCH.sub.3 HCl    186-188                                 79   58.80 58.72                                           5.83 5.90                                                12.47 12.26                                                     15.78 15.692    ##STR39##        NHCH.sub.2 CH.sub.3                   HCl    166-168                                 76   60.37 60.19                                           6.33 11.74 11.68                                                     14.85 14.753    ##STR40##        NHCH.sub.2 CH.sub.2 CH.sub.3                   HCl    194-196                                 82   61.77 61.74                                           6.78 6.87                                                11.09 11.18                                                     14.03 13.814    ##STR41##         ##STR42## HCl    197-198                                 85   53.99 54.05                                           6.27 6.24                                                9.69 9.74                                                     24.52 24.365    ##STR43##        NH(CH.sub.2).sub.3 CH.sub.3                   HCl    150-152                                 75   63.03 63.08                                           7.17 7.23                                                10.50 10.49                                                     13.29 13.216    ##STR44##         ##STR45## HCl    179-181                                 88   60.37 60.30                                           6.33 6.41                                                11.74 11.56                                                     14.85 14.837    ##STR46##        NHCH.sub.3 2HCl   159-162                                 77   44.70 45.00                                           4.43 4.38                                                9.48 9.64                                                     35.98 35.588    ##STR47##         ##STR48## 2HCl   215-217                                 83   54.36 54.31                                           5.62 5.62                                                9.76 9.79                                                     24.69 24.379    ##STR49##         ##STR50## HCl    180-182                                 90   52.76 52.41                                           5.17 5.11                                                10.25 10.34                                                     25.96 25.9010    ##STR51##        NHCH.sub.3 HCl    160-161                                 78   47.32 47.20                                           4.69 4.64                                                10.03 9.99                                                     25.40 24.9011    ##STR52##        NHCH.sub.2 CH.sub.3                   HCl    165-166                                 80   56.14 56.20                                           5.50 5.44                                                10.92 10.6812    ##STR53##        NHCH.sub.3 HCl    188-193                                 83   50.98 50.74                                           4.67 4.73                                                10.81 10.71                                                     27.36 27.1613    ##STR54##        NHCH.sub.3 HCl    201-203                                 85   50.98 50.80                                           4.67 4.60                                                10.81                                                     27.36 27.2014    ##STR55##        NHC.sub.2 H.sub.5 193-196                                 78   52.76 52.96                                           5.17 5.07                                                10.26 10.20                                                     25.96 25.90 15    ##STR56##        NHC.sub.2 H.sub.5                   HCl    206-209                                 75   45.38 45.20                                           4.44 4.40                                                8.82  8.8016    ##STR57##        NHC.sub.2 H.sub.5                   HCl    195-199                                 85   46.86 46.88                                           4.26 4.26                                                9.11 9.05                                                     34.58 34.4417    ##STR58##        NHCH.sub.2 CH.sub.2 CH.sub.3                   HCl    235-240                                 84   54.37 54.11                                           5.62 5.45                                                9.75 9.53                                                     24.69 24.5818    ##STR59##        NHCH.sub.2 CH.sub.2 CH.sub.3                   HCl    199-201                                 78   54.37 54.20                                           5.62 5.50                                                9.75 9.70                                                     24.69 24.6019    ##STR60##        NHCH.sub.2 CH.sub.2 CH.sub.3                   HCl    183-185                                 80   57.67 57.60                                           5.96 5.94                                                10.35 10.1820    ##STR61##         ##STR62## HCl . 1/2 H.sub.2 O                          124-126                                 75   54.20 54.47                                           6.17 6.05                                                9.03 8.98                                                     22.85 23.0321    ##STR63##        NHCH.sub.2 CH.sub.3                   HCl    219-221                                 70   52.76 52.96                                           5.17 10.26 10.20__________________________________________________________________________Compound ##STR64##                                  Elemental analysis Upper:                                      Calculated (%) Lower: Found(%)                                      1                         M. P.  YieldNo. R.sub.1       Addition moiety                         (° C)                                (%)   C    H    N    Cl__________________________________________________________________________21##STR65##    2HCl        190-195                                69    53.34 53.28                                           6.43 6.36                                                11.66 11.65                                                     19.68 19.6322##STR66##    2HCl        196-202                                71    50.80 50.58                                           5.86 5.87                                                11.11 11.06                                                     18.74 18.8223##STR67##    2HCl        195-198                                73    48.68 48.59                                           5.62 5.55                                                10.65 10.6524##STR68##    2HCl        185-190                                68    48.68  48.38                                           5.62 5.60                                                10.65 10.62                                                     26.95 26.7325##STR69##    2HCl        195-200                                72    43.76 43.94                                           5.05 4.93                                                9.57 9.6126##STR70##    2HCl        218-223                                74    44.78 44.68                                           4.93 5.01                                                9.79 9.61                                                     33.04 32.93__________________________________________________________________________ 
    
     The following compounds are prepared in a similar manner. 
     2-butylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-sec-butylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-isobutylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-octylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-ethylaminomethyl-5-(3-chlorophenyl) oxazole 
     2-propylaminomethyl-5-(2-chlorophenyl) oxazole 
     2-methylaminomethyl-5-(4-bromophenyl) oxazole 
     2-methylaminomethyl-5-(3-bromophenyl) oxazole 
     2-methylaminomethyl-5-(2-bromophenyl) oxazole 
     2-ethylaminomethyl-5-(3-bromophenyl) oxazole 
     2-ethylaminomethyl-5-(2-bromophenyl) oxazole 
     2-propylaminomethyl-5-(4-bromophenyl) oxazole 
     2-propylaminomethyl-5-(3-bromophenyl) oxazole 
     2-propylaminomethyl-5-(2-bromophenyl) oxazole 
     2-methylaminomethyl-5-(4-fluorophenyl) oxazole 
     2-methylaminomethyl-5-(3-fluorophenyl) oxazole 
     2-methylaminomethyl-5-(2-fluorophenyl) oxazole 
     2-ethylaminomethyl-5-(4-fluorophenyl) oxazole 
     2-ethylaminomethyl-5-(3-fluorophenyl) oxazole 
     2-ethylaminomethyl-5-(2-fluorophenyl) oxazole 
     2-propylaminomethyl-5-(3-fluorophenyl) oxazole 
     2-propylaminomethyl-5-(2-fluorophenyl) oxazole 2-diethylaminomethyl-5-(4-chlorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(2-fluorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(3-fluorophenyl) oxazole 
     2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(2-bromophenyl) oxazole 
     2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(3-bromophenyl) oxazole 
     2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(4-iodophenyl) oxazole 
     EXAMPLE 2 
     (A) N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide 
     A suspension of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole and 1.94 g of potassium phthalimide in 15 ml of dimethylformamide was stirred at room temperature for one hour. The reaction mixture was poured into 300 ml of water, and the resultant precipitate was filtered and recrystallized from ethanol to give 2.4 g (71 percent) of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide. 
     (B) 2-aminomethyl-5-(4-chlorophenyl) oxazole hydrochloride 
     A solution of 3.4 g of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide and 0.55 g of 100% hydrazine hydrate in 50 ml of ethanol was heated at reflux for one hour. At the end of this period, the formed precipitate was filtered off, and the filtrate was evaporated to dryness in vacuo. The residue was shaken with 2N HCl - chloroform and the 2N HCl - layer was evaporated to dryness under vacuo. The residue was recrystallized from ethanol to give 1.9 g (78 percent) of 2-aminomethyl-5-(4-chlorophenyl) oxazole hydrochloride, M.P. 200° C (decomposition). 
     I.R. (KBr, free base): 3,340 1,550 1,480 1,100 940 820 cm -1 . N.M.R. (CDCl 3 , free base): δ 4.50 ##STR71## 7.70 ##STR72## 7.73 (double doublet, ##STR73## 
     Analysis - Calcd. for C 10  H 10  ON 2 .HCl (percent): C, 49.00; H, 4.11; N, 11.43; Cl, 28.93. Found (percent): C, 48.79; H, 4.20; N, 11.18; Cl, 29.06. 
     Various other 2-aminomethyl-5-phenyloxazoles were synthesized in accordance with the procedure of Example 2, and the results are summarized in Table III. 
     
                                           TABLE III__________________________________________________________________________Compound ##STR74##           M.P.                     Yield                         Elemental Analysis Upper: Calculated                        (percent) Lower: Found(percent)No.   R.sub.1  Addition moiety               (° C)                    (%) C  H   N  Cl__________________________________________________________________________    ##STR75##       HCl     232-236                    81  57.01 56.69                           5.26 5.26                               13.30 13.28                                  16.83 17.182    ##STR76##       HCl     233-237                    78  52.52 52.38                           4.41 4.41                               12.25 12.053    ##STR77##       HCl     194-199                    79  49.00 49.10                           4.11 4.11                               11.43 11.40                                  28.93 28.83__________________________________________________________________________ 
    
     The following compounds are prepared in a similar manner. 
     2-aminomethyl-5-(3-chlorophenyl) oxazole 
     2-aminomethyl-5-(4-bromophenyl) oxazole 
     2-aminomethyl-5-(3-bromophenyl) oxazole 
     2-aminomethyl-5-(2-bromophenyl) oxazole 
     2-aminomethyl-5-(4-fluorophenyl) oxazole 
     2-aminomethyl-5-(3-fluorophenyl) oxazole 
     2-aminomethyl-5-(2-fluorophenyl) oxazole 
     EXAMPLE 3 
     Tablets suitable for oral administration 
     Tablets containing the ingredients indicated below may be prepared by conventional techniques. 
     
         ______________________________________                Amount perIngredient           tablet (mg)______________________________________5-(4-chlorophenyl)-2-ethylaminomethyloxazolehydrochloride        125Lactose              30Corn starch          20Crystalline cellulose                75Silica               2Magnesium stearate   2Total                254       mg______________________________________ 
    
     EXAMPLE 4 
     Capsules for oral administration 
     Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture. 
     
         ______________________________________                Amount perIngredient           capsule (mg)______________________________________5-(4-chlorophenyl)-2-ethylaminomethyloxazolehydrochloride        250Magnesium stearate   2Lactose              48Total                300       mg______________________________________ 
    
     EXAMPLE 5 
     Sterile solution for infusion 
     A 0.25 g portion of 5-(4-chlorophenyl)-2-ethylaminomethyloxazole hydrochloride is dissolved in saline to give a total volume of 500 ml and the resulting solution is then sterilized.