20 . 9 g ( 75 . 0 mmol ) of n -[ 2 - hydroxy - 3 -( 1 - piperidinyl ) propoxy ]- 3 - pyridine - carboximidamide [ hung . pat . 177 . 578 ( 1976 )] was dissolved in 300 ml of benzene . to this solution 150 ml of 1 n sodium hydroxide solution was added , followed by dropwise addition of 19 . 5 ml ( 168 mmol ) of benzoylchloride . after stirring the mixture intensively for 2 hours , 7 . 1 g ( 67 mmol ) of sodium carbonate and a further portion of benzoylchloride ( 9 . 75 ml ; 84 mmol ) was added , and the stirring was continued overnight . the phases were then separated , the organic layer was extracted with 1n sodium hydroxide solution and water , dried and evaporated to dryness . the residue ( 41 g oil ) was dissolved in 150 ml of acetone , and 8 . 7 g ( 75 mmol ) maleic acid was added . the obtained precipitate was filtered off , washed with acetone , and dried . 14 . 7 g ( 52 . 8 mmol ) of n -[ 2 - hydroxy - 3 -( 1 - piperidinyl ) propoxy ]- 3 - pyridine - carboximidamide [ hung . pat . 177 . 578 ( 1976 )] was dissolved in 160 ml of chloroform . 7 . 7 ml ( 55 mmol ) of triethylamnine was added , followed by dropwise addition of a solution of palmitoylchloride ( 14 . 7 g ; 56 . 5 mmol ) in 85 ml of chloroform . the mixture was stirred overnight at room temperature . next day further amount of 3 . 8 ml of triethylamine and 7 . 4 g of palmitoylchloride was added , and the stig was continued for one more day . the solution was extracted then with water , 5 % acetic acid and water , successively , dried over anh . sodium sulphate , and evaporated to dryness . the residue ( 28 . 2 g oil ) was dissolved in ethyl - acetate , and the product was precipitated by addition of 30 ml of 1n hcl / ethyl acetate . the thick , white precipitate was filtered off , washed with ethyl acetate and dried . 50 g ( 0 . 245 mol ) of m - trifluoromethyl - benzamidoxime and 33 . 7 g ( 0 . 6 mol ) of potassium hydroxide was dissolved in a mixture of dimethyl sulphoxide and 170 ml of water , and the mixture was cooled to 0 ° c . 48 ml ( 0 . 6 mol ) of epichlorohydrin was added , and the reaction mixture was stirred at 0 ° c . for 5 hours , then kept in a refrigerator overnight . next day 250 ml of water was added , and the mixture was extracted with ethyl acetate ( 4 × 250 ml ). the combined organic phases were washed with water , dried , treated with charcoal and evaporated to dryness , to yield m - trifluoromethyl -- n -( 2 , 3 -- poxypropoxy )- benzanidine , as a colourless oil . to the obtained oil 400 ml of 18 % of hydrochloric acid solution and 60 ml of ether were added , and the mixture was cooled to - 5 ° c ., while stirring . 17 . 4 g ( 0 . 25 mol ) of sodium nitrite , dissolved in 60 ml of water was added slowly in 40 min ., and the reaction mixture was stirred for another 20 minutes . the mixture was extracted then with ether ( 2 × 160 ml ), and the combined organic phases were washed with water twice . to the ethereal solution 340 ml of 20 % of sodium hydroxide solution was added , and the two - phase system was refluxed for 1 hour , while stirring . the phases were then separated , the organic layer was washed with brine until neutral , dried and evaporated to dryness to give m - trifluoromethyl - n -( 2 , 3 - epoxypropoxy )- benzimidoyl chloride , as a colourless oil . a mixture of 1 . 19 g ( 4 . 2 mmol ) n -[( 2 , 3 - epoxy ) propoxy ]- 3 - trifluoromethylbenzenecarboximidoyl chloride and 0 . 89 ml ( 8 . 5 mrnol ) of tert - butylamine in 12 ml of isopropyl alcohol was refluxed for 2 hours . solvent was removed under reduced pressure . the residue was dissolved in ethyl acetate , and 0 . 98 ml of methanolic hydrogen chloride solution ( 4 . 3n ) was added and the mixture was concentrated to small volume under vacuum , then diluted with ether . the precipitate that formed was recovered , washed with cold ether and dried . ir ( kbr ): 3423 , 3233 , 2978 , 2880 , 2784 , 1620 , 1570 , 1479 , 1441 , 1400 , 1383 , 1340 , 1238 , 1167 , 1128 , 1101 , 1072 , 1038 , 982 , 930 , 897 , 804 , 787 , 714 , 694 cm - 1 5 . 0 g ( 15 . 6 mmol ) of n -[ 2 - hydroxy - 3 -( 1 - piperidinyl ) propoxy ]- 2 - thiophenecarboximidamide monohydrochloride was dissolved in 19 ml of water , then 6 . 1 ml of concentrated hydrochloric acid was added . the solution was cooled to - 5 ° c ., then a cold solution of 4 . 4 g ( 63 . 8 mmol ) of sodium nitrite in 2 . 4 ml of water was added dropwise . throughout the reaction the internal temperature was maintained at 0 ° c . when addition was completed the mixture was stirred for a further one hour . cold benzene ( 60 ml ) was added and the mixture was made alkaline with slow addition of a cold solution of 3 . 2 g ( 80 mmol ) of sodium hydroxide in 45 ml of water . the organic phase was separated and washed successively with 20 ml portions of water until the ph & lt ; 9 ( 3 - 5 times ). the organic solution was dried over anhydrous sodium sulphate , treated with charcoal , filtered and evaporated in vacuum ( t & lt ; 45 ° c .) to give 2 . 6 g of oil . this residue was dissolved in 5 ml of isopropyl alcohol and acidified ( ph 2 ) with isopropyl alcohol containing dry hydrochloric acid . the product was crystallised from n - hexane to give off - white material . following the process described in the previous example the following compounds were prepared : starting material : n -[ 2 - hydroxy - 3 -( 1 - piperidinyl ) propoxy ]- 4 - pyridinecarboximidamide in this case the final product was isolated at the end of the work - up procedure by dissolving the crude base in acetone , and adding an equivalent amount of maleic acid . 1 . 3 ml ( 15 . 2 mmol ) of epichlorohydrin was added to a solution of 1 . 6 ml ( 15 . 2 mmol ) of tert - butylamine in 8 ml of ethanol during 10 minutes with stirring , keeping the temperature below 20 ° c ., and allow to stand for 3 days . separately , 0 . 8 g ( 14 . 3 mmol ) of potassium hydroxide was dissolved in a mixture of 20 ml of ethanol and 3 ml of water and into this solution 3 . 42 g ( 15 . 2 mmol ) of n - hydroxy - 3 -( trifluoromethyl )- benzamide potassium salt and the formerly prepared solution of epichlorohydrin and tert - butylamine were added . the reaction mixture was stirred and boiled for 10 hours , then the solvent was evaporated . the residue was triturated with 20 ml of dichloromethane and 10 ml of water , the organic phase was separated , washed with 5 ml of water and 5 ml of saturated sodium chloride solution , dried over sodium sulphate , filtered and evaporated . the oily residue was crystallised in a mixture of acetone - hexane to yield white powder as title compound . ir ( kbr ): 2976 , 2858 , 1612 , 1556 , 1379 , 1352 , 1313 , 1273 , 1165 , 1130 , 1072 , 694 cm - 1 to the solution of 8 . 0 g ( 45 . 9 nmol ) of 1 - aminooxy - 2 - hydroxy - 3 -( 1 - piperidinyl )- propane dissolved in 60 ml of chloroform 4 . 9 ml ( 45 . 9 mmol ) of hexylisocyanate was added and the reaction mixture was stirred for 20 hours at room temperature . after addition of a further 1 . 6 ml ( 15 mmol ) of hexylisocyanate , the stirring was continued for two more hours , when the solvent was evaporated in vacuum . white crystalline product was obtained by triturating with petroleum ether . ir ( kbr ): 3310 , 2932 , 2858 , 2804 , 1666 , 1551 , 1454 , 1377 , 1306 , 1092 , 1040 , 995 , 791 , 725 , 604 cm - 1 following the process described in the previous example the following compounds were prepared : ir ( kbr ): 3354 , 2932 , 2856 , 2810 , 2777 , 1666 , 1543 , 1486 , 1377 , 1308 , 1155 , 1134 , 1076 cm - 1 17 . 5 g ( 0 . 05 mole ) of n -[ 2 - hydroxy - 3 -( 1 - piperidinyl ) propoxy ]- 3 - pyridinecarbox - imidamide dihydrochloride was dissolved in 50 ml of thionyl chloride , boiled for one hour , then the mixture was evaporated to dryness . the residue was dissolved in 300 ml of methanol , treated with charcoal and after filtration the solvent was evaporated in reduced pressure . the residue was dissolved in the minimum amount of ethanol and refrigerated to yield crystalline n -[ 2 - chloro - 3 -( 1 - piperidinyl ) propoxy ]- 3 - pyridinecarboximidamide dihydrochloride as intermediate compound . 13 . 2 g ( 35 . 7 mrnmole ) of n -[ 2 - chloro - 3 -( 1 - piperidinyl ) propoxy ]- 3 - pyridinecarbox - imidamide dihydrochloride was added to a solution of 16 . 5 g ( 143 . 5 mmole ) of potassium tert - butoxide dissolved in 150 ml of tert - butanol . the mixture was boiled for 6 hours , then evaporated in vacuum . 100 ml of 5 % sodium hydroxide solution was added and the mixture was extracted three times with 300 ml portions of ethyl acetate . the organic layer was dried over sodium sulphate , filtered and evaporated to dryness . the residue was triturated with diethyl ether to yield the title compound as white crystals . for the production of 200 mg tablets containing 50 mg of effective substance use : for each 2 ml injection vial containing 2 mg of effective substance use :
the invention relates to a method of treating or preventing illnesses resulting from damaged endothelial cells , wherein the method comprises administering to a patient a product comprising hydroxylamine derivatives of the general formulae ## str1 ## with the proviso that in the compounds of general formula when x comprises a -- nr 3 r 4 group and y comprises a hydroxyl group , the x group is condensed with the y substituent to form an intramolecular ring represented by general formula ## str2 ##