PL113772B1 - Process for preparing novel acetohydroxamic acids - Google Patents

Description

The subject of the invention is a method for preparing new acetoihydroxic acids of the general formula 1, in which R2 and R3 are the same or different and denote a hydrogen atom or an alkyl group with 1-6 carbon atoms, and Rx denotes an alkyl group with 1-6 carbon atoms. 6 carbon atoms, an N,N-disubstituted carbamyl group of the formula ZAN-CO-, in which Zx and Z2 are the same or different and denote a cycloalkyl group with 5-6 carbon atoms, a phenyl group optionally substituted, in particular by one or several halogen atoms or groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, methylenedioxy, NH2, NO2 or CF3, a 3-hydantoinyl group of the formula 2, in which Xx is a group phenyl optionally substituted, in particular by one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, an NH2, CF3 group or a halogen atom, X2 is a hydrogen atom and an alkyl group with 1-6 carbon atoms carbon mach, or a phenyl group optionally substituted with one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, methylenedioxy, NH2, NOa, CF8 or a halogen atom, a benzydrylcarbonamide group of the formula 3, in which each phenyl group may be substituted in particular by one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, NH2, NO2, CF, or halogen atoms, the group having the formula *o Z3CH2-S- in which Z3 is an aryl group, in particular an α-naphthyl, p-naphthyl or phenyl group, each of which may be substituted with one or more alkyl groups with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, NH0 NO2, CF3 or halogen atoms; a group of the formula Z4-A-, in which Z4 is a phenyl, α-naphthyl, or p-naphthyl group, in which each phenyl ring may be substituted in particular with one or more groups such as an alkyl group with 1-4 atoms carbon, alkoxy with 1-4 carbon atoms, methylenedioxy, halogen, NH2, NO2 or CF3 group or adamantyl group, and A stands for groups with the formulas -NHCO-, -N(alkyl C^CO-, -N (cycloalkyl C^JCO-, -CONH-, -CON(alkyl C1-4)-, -CON(cycloalkyl C5_6)-, -NHCONH-, -N(C6H5)CQNH-, group of formula 4, except that Z4 may be a benzhydryl group optionally substituted with one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, methylhydroxy groups, halogen atoms, NH2, NOa or CF3 groups in each of the two rings phenyl groups of this group, when A is different from CONH, a group of the formula Z4'NH-, in which Z'4 is a phenyl group preferably substituted with one or more halogen atoms, or Rx is a benzimidazolyl group of formula 5, in which Z$ denotes an aryl group, especially a phenyl group, wherein the aryl group and the ring (a) may optionally be based on one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms. carbon mach, methylenediboxy, NHa, NOa, CF, or a halogen atom or B.x means a tricyclic group (T) of the formula 6, in which Yx means a group -CH2CHa- or -S-, Y2 means a group -N-, Y, means the group -GH2-, or". -CO- and each phenyl ring may be substituted in particular by one or more alkyl groups with 1-4 carbon atoms, alkyl groups with 1-4 carbon atoms, methylenedioxy, NHj, NO2, CF3 or a halogen atom, optionally in the form of their salts with metals or, if the Rx substituent is basic, in the form of their acid addition salts. These compounds are used in medicine, especially as agents acting on the central nervous system. ¦ Among the metal salts of the compound of general formula 1, mention may be made especially of alkali metal salts, metal; and other alkali metals, zinc, magnesium and aluminum, for example salts corresponding to the general formula 7, in which M is Na, K, Vi <3a Vz Zw Vi Mg or i/, Al. The halogen atom means the fluorine atom .u, chlorine, bromine or sodium. Preferred halogen atoms from the pharmacological point of view are fluorine, chlorine and bromine atoms, and chlorine and bromine atoms from the point of view of synthesis reaction mechanisms. It is known that some of the known hydroximic acids turned out to be inactive in medicine, especially 4-a acid -naphthyioxy-3-hydroxy-butyrohydroxamic acid described in Comparative Example V of the US Pat. No. 3619,702. Others turned out to be interesting in relation to the central nervous system, especially Mphenylsulfinyl)butyrohydroxamic acids, 4-(ip-flvorophenylsulfinyl6)buityrohydroxamic acid, 3-hydroxamic acid and 4-(p-cVioiTophenylsulfinyl acid). )butyrohydroxamic acid described in examples XII-XV of the French patent description no. 228.5859, as well as (P-be-hydrylsulfiinyl)acetohyidikisamic, 3-(benzhydrylsulfinyl)proipionohydroxamic and 4-(enzhydrylsidfynyl)butynx)hydroxamic acids described a.d in examples I, VI and IX of British patent description No. 1,520,812. It has now been found that acetohydroxamic acids can be used in medicine as agents acting on the central nervous system (CNS), especially as psychotropic agents. For the preparation of hydroxamic acids and their metallic salts, classical reactions can be used. In the method of the invention, new acetobydrophyamic acids of the general formula 1, in which Rlf Rj and R3 have the meanings given above, are prepared by reacting the halide of the appropriate carboxylic acid or the carboxylate of a lower alkyl of 1-3 carbon atoms, represented by the formula 26 with hydroxylamine. The reactions are carried out in a solution or suspension in pyridine or in a lower alcohol with 1-3 carbon atoms, such as methanol, ethanol, propanol and isopropanol, and the course of the reaction is presented in scheme 1. The substituent Z in the formula 26 is a halogen atom. , preferably chlorine or bromine or a metal, ethoxy, propoxy or isopropoxy group. When Z is a halogen atom, the reaction of the acid halide with hydroxylamine dichloride is carried out in a solution in pyridine. When Z is a lower alkyl group with 1-3 carbon atoms, carboxylation reactions with hydroxylamine hydrochloride are carried out in solution or in suspension in an alkanol with 1-3 carbon atoms. The compounds produced according to the invention are used for the preparation of preparations. pharmaceuticals containing, in combination with a physiologically acceptable filler, at least one compound of formula I or one of its non-toxic metal salts. and Moreover, the compounds of the general formula 1, in which Rj is a group of the formula Z3 and have the above-mentioned meaning, constitute valuable raw materials for the preparation of the corresponding compounds containing a sulfinyl group instead of the merfcapto group. Compounds containing the Z3-CH2-SO group have the same properties as the compounds of formula 1 obtained by the method according to the invention. Some of the results of pharmacological tests of the products obtained according to the invention are summarized. These products were tested on mice and rats. They were administered in suspension (unless otherwise indicated) in a solution of gum Arabic by the intraperitoneal route in the amount of 20 ml/kg for mice and 5 ml/kg for rats. Trials with the preparation CRL 40373 (product from Example I). a. Toxicity: at doses of 64, 128, 256, 512 and 1024 mg/kg - no deaths were observed in isolated mice. b. Action on the central nervous system. 40 Interaction with apomorphine. A group of six rats received a subcutaneous injection of apomorphine (0.5 mg/kg). 30 minutes after administration of CRL 40373 it was observed that it had no effect on the stereotypical behavior of the rat caused by apomorphine. 45 Interaction with amphetamine. Thirty minutes after administration of CRL 40373, amphetamine was injected intraperitoneally at a dose of 2 mgflcg. CRL 40373 has been observed to have an inhibitory effect on the typical effects of amphetamine, with this effect. is proportional 50 to the doses. Cooperation with reserpine. Each of the six mice received CRL 40373 after intraperitoneal administration of the reserve (2.5 mg/(kg). There was no effect on post-reserpine hypothermia and ptosis. 55 Interaction with oxotremorine. 30 minutes after administration of CRL 40373, each of 12 mice received intraperitoneal injection of oxotremorine (0.5 mg/kg). In terms of temperature, CRL 40373 at doses of 128 and 512 mg/kg was found to induce a hypothermic effect and deepen the temperature drop caused by oxotremorine. In terms of CRL tremors 40373 has no significant effect on the effect of oxotremorine. With regard to peripheral cholinergic symptoms, CRL 40373 *5 in high doses (106 and 512 mg/kg) increases salivation and excessive tearing caused by oxotremorine. Action in a trial of four plates, pulling and electroshock. The test was performed on 10 sensitive EVIC CEBA mice 30 minutes after the administration of CRL 40373. It was observed that CRL 40373 did not increase the number of punishment passes, did not result in increased lack of motor coordination and did not modifies the effects of convulsive electroshock. Effects on motor function. Spontaneous mobility. Thirty minutes after receiving CRL 40373, the test mice (6 and 12 controls) were placed in an actimeter, where their mobility was recorded for 30 minutes. It has been observed that CRL 40373 at high doses (128 and 512 mg/kg) causes a decrease in the motor activity of mice. The reduced motor activity by habituation disappears (residual motility). Mice that stayed in the actimeter for 18 hours received CRL 40373. These mice were then placed in a cage and after half an hour their mobility was recorded for 30 minutes (6 experimental animals next to 12 control animals). It was found that CRL did not cause the resumption of exploratory activity in mice accustomed to their environment. Mobility reduced by hypoxic aggression. 30 minutes after administration of CRL 40373 (10 experimental mice, 20 controls) were subjected to hypobyric anoxia (pressure reduction to 800 hPa for 90 seconds, decompression for 45 seconds), and then placed in an actimeter where their mobility was examined for 10 minutes. It was observed that CRL 40373 did not increase motor recovery in mice whose mobility was reduced by hypobaric anoxia. Effect on intergroup aggressiveness. After three weeks of residence in each half of a cage separated by an opaque wall, mice were given CRL 40373 30 minutes before the partition was removed. The number of acts of aggression that occurred within 15 minutes was recorded. It was found that CRL 40373 significantly reduced the number of acts of aggression. These tests show that CRL 40373 is a sedative. Tests with the preparation CRL 40385 (product of Example III). a. Toxicity: No deaths were observed at the doses given above for CRL 40373. It was found that at high doses (1024 and 512 mg/kg), on the one hand, the separated mice were calmed down, combined with an increase in the feeling of fear, and on the other hand, the hair was straightened within 24 hours. At doses of 32-256 mg/kg, mice were found to be excited and hyperactive. LD50 values by the intraperitoneal route were as follows: LDM (separated mice): 1500 mg/kg LDW (grouped mice): 1050 mg/kg CRL 40385 was found to be significantly more toxic to grouped mice than to separated mice. The ratio of LD50 for separated mice: LDW for grouped mice is 1.43. Although there was an increase in toxicity for grouped mice, we cannot talk about group toxicity, b. Effect on the central nervous system. 5 . Synergy with apomorphine. A group of 6 rats received a subcutaneous injection of 0.5 mg/kg of amorphine 30 minutes after administration of CRL 40385. It was observed that CRL 40385 in high doses causes an increase in the duration of stereotypical behavior induced by apomorphine. Interaction with amphetamine. Within 30 minutes after administration of CRL 40385, rats received injections of 2 mg/kg of amphetamine intraperitoneally (6 animals). It was observed that at a dose of 256 mg/kg 15 CRL 49385 causes the duration of typical amphetamine effects to be prolonged. Interaction with reserpine. Four hours after the administration of reserpine (2.5 mgy/kg), mice received CRL 40385. It was found that at doses of 64, 128 and 256 mg/kg, CRL 40385 caused moderate antagonism in relation to post-reserpine oxaz hypothermia and did not modify the intensity of palpebral ptosis. caused by reserpine. Interaction with oxotremorine. 30 minutes after administration of CRL 40385, mice (6 animals) received an intraperitoneal injection of 0.5 mg/kg oxofcremorine. It was observed that in terms of temperature, CRL 40385 at doses of 32 and - 128 mg/kg caused slight antagonism towards hypothermia 33 caused by oxotremorine. With regard to tremor, at a dose of 128 and especially 5il2 mg/kg CRL 40385 reduces the intensity of oxotremorine-induced tremor. With regard to cholinergic symptoms: peripheral CRL 35 does not modify the increase in salivation, tearing and defecation that occurred after oxotreniorin injection. Action in the four-plate, traction and electroshock test. Within 30 minutes after receiving CRL 4*, a group of 10 mice were tested. It was found that CRL 40385 did not cause an increase. number of passages punished, does not cause a deficit in motility and in large doses counteracts the convulsive effects of electroshock. Action on motility. Spontaneous mobility. Thirty minutes after receiving CRL 40385, mice were placed in an actimeter, where their motility was recorded over a 30-minute period. CRL 50 40385 at doses of 128 and 256 mg/kg was found to cause a moderate increase in spontaneous motor activity. At higher doses this effect disappears. Mobility limited by habituation to confinement. After 18 hours in the actimeter, the mice received CRL 40385. These mice were then placed in a cage and after 30 minutes the recording of motility began. The experiment lasted 30 minutes. It was found that starting with a dose of 32 mg/kg, ORL 40385 causes the resumption of activity in animals accustomed to being confined. Mobility limited by aggression with hypoxicine. Within 30 minutes after administration of ORL 40385 mice (10 experimental and 20 control ) were subjected to 6 hypobaric anoxia (lowering the pressure to 113,772,800 hPa within 90 seconds and decompressing it for 45 seconds), after which they were placed in an acftimeter, and their mobility was recorded for 10 minutes. It has been observed; that CRL 40585 resulted in an improvement of motor recovery in mice whose activity was limited by hitpoxic aggression. This effect appeared at a dose of 32 mg/kg and increased with increasing dose to 512 mg/kg. Effect on aggressiveness intergroup. After 18 hours of residence on both sides of the partition dividing the cage with groups of 3 mice, they received CRL 40386 and 30 minutes later the partition was removed. The number of acts of aggression that occurred within 15 minutes was recorded. It was found that CRL 40385 reduces the aggressiveness of the tested animals. Test of the anticataleptic effect. CRL 40385 or amantadine was administered intraperitoneally 4.5 hours after the injection of 12.5 mg/kg prochloreprazine. Catalepsy was assessed every 30 minutes in the cork test (9 ohm), four kxi tests, cross-legged test and cross-over test on the same side. It was found that CRL 40385 counteracts the cataleptogenic effect of prochlorperazine at a dose of 256 mg/kg. This effect, however, is less intense than that obtained with an S times lower dose of amantadine. Effect on the conditioned reflex of prolonged avoidance. Rats placed in a swing box were conditioned to avoid the electric shock by changing sides. The shock was preceded by a 3-second sound and light stimulus, which was interrupted when changing sides or after 8 seconds. The sequences were repeated every 20 seconds. Animals conditioned for several dozen minutes showed an avoidance level close to 100%. They continued to be stimulated every 30 seconds and gradually were no longer able to change sides during the 3 seconds during which no shock occurred. After 24 hours, the animals appeared to have lost their conditioned reflexes and were unable to avoid virtually any juice. CRL 40385 was then administered and any reoccurrence of avoidance was monitored until the effect disappeared. The product has been found to cause re-occurrence of avoidance in animals with loss of conditioned reflex as a result of prolonged experience. Such an effect can be approximately considered as the return of conditioned activity in a tired animal. The conducted tests show that CRL 40385 acts on the central nervous system. Some of these effects bring to mind antidepressant-type activity, while others bring to mind psychostimulant-type activity. The most important property, however, is the anti-fatigue effect of the product, which does not act as an amphetamine substance (no particular toxicity in grouped mice), but rather as a dopaminomimetic substance (such as piribedil, methylergonethrin, amantadine, apomorphine, dapa combined with cardopa). , although CRL 40385 but.'works; hypothermic like them). c. Effects on the heart and blood vessels. In the above-mentioned tests, CRL 40385 was administered suspended in a gum arabic solution at a volume of 2 ml/kg. HDpotentiary effect of a4anp in rats with spontaneously induced non-high blood pressure. 7 rats received orally 100 mg/kg CRL 40385, and then 2 hours later, a new dose of 100 mg/kg of this drug. After the first administration, it was found that blood pressure dropped on average by 10%, heart rate dropped by 8% (statistically significant result), from 364 to 334 beats/minute. After the second administration, it was observed that the blood pressure decreased gradually and reached its maximum 4 hours after the second administration, rising from 210 hPa to 190 hFa (that is, a statistically significant reduction of 13°). The heart rate does not change. .... !. The psychostimulant properties of CRL 40385 and its hypotensive effect at a dose of 100 mg/kg orally allow for its use in therapeutics, not only as an anti-fatigue agent. A test with the preparation CRL 40382 (product from Example II). CRL 40382 is characterized by an original psychopharmaceutical profile in that it antagonizes the stereotypical behavior induced by amtetamine without modifying the other effects of this substance (immobility, group toxicity). 'This antagonism appears to be specific to amphetamine stereotypies, as CRL 40382 does not counteract the effects of apomorphine and methylphenidate. In addition, CRL 40382 causes a moderate decrease in motility and, although it does not cause catalepsy itself, it enhances the cataleptogenic effects in borderline cases. dose of a neuroleptic. The mechanism of action of CRL 40382 appears to be different from that of other substances that counteract the stereotypical effects induced by amphetamine. It seems unlikely that CRL 40l3(8i2) acts as α-methyltyrosine to inhibit dopamine synthesis. A blockade of the dcpaminergic receptor comparable to that observed with classical neuroleptics (phenothiazines and butyrophenones) cannot be maintained in the absence of the antigonistic effects of oxotremorine. Exhaustion or inactivation of amphetamine-sensitive groups seems to be the most probable hypothesis. From this point of view, CRL 40382 differs from reserpine or tetrabenazine, which deplete other dopamine groups. However, the moderate sedative effect and the absence of catalepsy and motor failure indicate that CRL 40382 has an antipsychotic effect combined with a moderate sedative effect without the risk of causing secondary neurological effects. Tests with the preparation CRL 40400 (product from Example IV) a. Toxicity: At doses of 128, 256, 512 and 1024 mg/kg CRL 40400 does not cause any deaths in isolated mice. b. Action on the central nervous system. CRL 40400 does not modify stereotypies induced by apomorphine and amphetamine in rats and oxotremorine and reserpine in mice. However, it is observed that CRL 40400 affects the motility of mice*nsra: 9 10 Trials with the CRL 40258 preparation (product from Example VI. a. Toxicity. Doses of 1024 mg/kg and 512 mg/kg cause the death of mice within 35 minutes and 24 hours respectively. LD0 is higher than 256 mg/kg. b. Action on the central nervous system. Interaction with reserpine. In high doses, CRL 40258, which is a temperature-lowering agent, deepens the hypothermia induced by reserpine. At doses of 128 and 32 mg/kg, postreserpine ptosis is increased. Interaction with oxoiremorin In mice, CRL 40258 adds its effect to the temperature-lowering effects of oxotremorin, but does not modify the intensity or duration of oxotremorin-induced tremor. .Effects in the four-plate, stretching and electroshock test. At high doses (32 and 128 mg/kg) CRL 40258 is observed to cause severe motor inability in mice and an increase in the lethal effects of electroshock.Effect on motility in mice. Starting with doses of 8 mg/kg CRL 40258 causes a decrease in motor activity. However, residual mobility and motor recovery after hypoxia do not improve. Test with the preparation CRL 40438 (product from Example VII). a. Toxicity: LD0 of mice is higher than 1024 mg/kg. ib. Action on the central nervous system. A psychopharmacological study of CRL 40438 showed a number of excitatory-type effects: increased reactivity in mice; occurrence of stereotypic movements in large doses and intensification of stereotypy induced by apomorphine and amphetamine; a moderate increase in spontaneous motor activity, but the stimulating effect was very pronounced when motor activity was limited by habituation to confinement; anti-consumer effect in the prolonged avoidance test. In addition, CRL 40438 moderately combats hypothermia and post-reserpine ptosis, oxsoftremorine-induced shivering and, at high doses, reduces aggressive behavior in mice. The effects observed after administration of CRL 40438 are similar to those described for CRL 40385 and suggest antidepressant or psychostimulant activity. The procedures and results of the prolonged avoidance test described above are as follows: Rats placed in a shuttle box were ¬ were conditioned to avoid an electric shock within 5 seconds by changing sides. The shock was preceded by a 3-second sound and light stimulus that disappeared during the change of sides or after 8 seconds. The sequences were repeated every 20 seconds. The animals conditioned after about ten minutes showed /©. avoidance (changing sides during sound and light stimuli before the electric shock occurred) close to 100%. The rats continued to receive the stimulus every 20 seconds and gradually became unable to avoid the shock any longer. After 24 hours, the animals appeared to have lost all conditioned reflexes and had virtually no shock avoidance. CRL 40438 was then administered and any resumption of the drug was monitored until the effect disappeared. At doses of 64, 128 and 256 mg/kg, the intraperitoneal route of CRL 40438 causes the resumption of avoidance behavior in animals that have lost conditioned reflexes as a result of prolonged exposure. Trials with CRL 40439 (product of Example VIII). a. Toxicity. For mice, the LD0 is higher than 1024 mg/kg. At a dose of 1024 mg/kg, mice reach a phase of moderate arousal within 10 minutes, followed by calm and a decrease in muscle tension. At doses of 512 and 256 mg/kg only calming and reduction of muscle tension are observed. At a dose of 128 mg/kg, none of these symptoms are observed. b. Action on the central nervous system. CRL 40439 increases the temperature-lowering effect of reserpine and oxotremorine at a dose of 512 mg/kg. It does not affect post-reserpine ptosis and moderately reduces the intensity of oxotremorine-induced tremors. tJ mice CRL 404*39 causes at a dose of 512 mg/kg a very serious reduction in spontaneous motility, and at a dose of 128 mg/kg it causes the resumption of motor activity in an animal accustomed to its confinement and does not improve motor recovery in an animal whose mobility has been restricted. linked by hipojbaric anoxia. Finally, CRL 40439 moderately reduces intergroup aggressiveness in mice. Test with CRL 40446 (product of Example 9). a. Toxicity. At doses of 16, 32, 64, 128, 512 and 1024 mg/kg for mice, CRL 40446 did not cause any mortality. tb. Action on the central nervous system. At a dose of 512 mg/kg, CRL 40446 has a partial antagonistic effect on post-reserpine hypothermia, but does not affect post-reserpine ptosis. CRL 40446 reduced spontaneous motility in mice at doses of 128 and 512 mg/kg and did not cause any resumption of myotioric activity in mice (regardless of whether they were habituated to confinement or were subjected to hybaric ainoxia). CRL 40446 moderately reduces intergroup aggressiveness in mice. Trials with the CRL 4044T preparation (product from pf*T- clade X). a. Toxicity. In mice, the LD0 is higher than 1024 mg/kg. At a dose of 8 and 12 mg/kg (mice) and 64 mg/kg (rats), CRL 40447 causes sedation within 30-60 minutes* b. Action on the central nervous system. At a dose of mg/kg, CRL 40447 reduces spontaneous motility in mice. Trials with preparation 40450 (product from Example 11). a. Toxicity. In mice, LD0 is higher than 1024 mg/kg. b. Action on the central nervous system. In a high dose <512 mg/kg) CRL 40450 deepens hypo- 10 15 20 25 30 35 40 45 50 55 et11*772 lt lfc termie; induced by ¦-reserpine and oxotreniorine and reduces the intensity of tremors induced by oxotreniorine. Moreover, at a dose of 512 mg/kg, it reduces spontaneous mobility in mice. At doses of 512 and 2:56 mg/kg, it reduces intergroup aggressiveness in mice. Trials with the CRL 40464 preparation (product from Example XII). a. Toxicity. In mice, LDQ is higher than 1024mg^kg. 10 b. Action on the central nervous system. CRL 40464 at a dose of 256 mg/kg reduces the intensity of amphetamine stereotypies. It aggravates hypotarmia induced by oxotremorine and moderately reduces the intensity of tremors induced by this agent. 15 CRL 40464 reduces spontaneous motility in mice and at a dose of 128 mg/kg causes the resumption of motor activity in an animal accustomed to its confinement. Test with preparation 40468 (product of Example 15). a. Toxicity. At a dose of 1024 mg/kg CRL 40468 causes sedation and heaviness, reduced reactivity to touch and respiratory inhibition; mice were found dead 24 hours after injection. At a dose of 512 mg/kg, symptoms are comparable, but no mortality is observed. At lower doses (256, 128, 64 and 32 mg/kg), the behavior of mice is similar to that of control animals. 30b; Action on the central nervous system. CRL 40458 affects intergroup aggressiveness in mice. In large doses, it reduces the number of acts of aggression. Trials with the preparation CRL 40471 (product from Example XVI). a. Toxicity. The LDQ for mice is higher than 1024 mg/kg. At the tested doses (1024; 512, 256, 128 and 64 mg/kg) a decrease in mobility was observed in mice. 40 b. Action on the central nervous system. In the rat CRL 4047.1, it does not modify stereotypical behavior under the influence of amphetamine and apomorphine. In mice it exerts moderate antagonism of post-reserpine hypothermia. 45 . At a high dose (512 mg/kg), CRL 40471 severely limits the spontaneous movement of mice. CRL 40471 does not cause resumption of motor activity in mice accustomed to confinement. Finally, CRL 40471 does not improve motor recovery in mice whose mobility has been reduced as a result of hypobaric anoxia. However, it should be noted that mice that received a high dose of CRL 40471 (5.12 mg/kg) have motor recovery similar to that of horse mice. - 55 effects, while this dose causes a very serious reduction in spontaneous imotor activity. In high doses, CRL 40471 reduces intergroup aggressiveness in mice. v In summary, it can be said that CRL 60 40471 has a calming effect. It should be noted, however, that on the one hand, the anti-aggressive effect seems to result from the lack of any restriction of mobility, and on the other hand, the effect of reducing mobility observed in high doses is not found when motor activity was reduced by hypoxic hypoxia. Trials with the preparation CRL 40490 (product from Example XX). a. Toxicity - LDQ for mice is above 1024mg/kg. "." from Example XXI). a. Toxicity. In mice, the LDQ is over 1024 mg/kg (no mortality 24 hours after administration). b. Action on the central nervous system. At a dose of 256 mg/kg, CRL 40491 reduces the ¬ amphetamine stereotypy activity. At a dose of 512 mg/kg it causes a decrease in spontaneous motility in mice. At a dose of 256 mg/kg, this preparation reduces intergroup aggressiveness of mice and increases the resumption of moderate activity in mice accustomed to confinement. Trials with the preparation CRL 40500 (product of Example XXII) a. Toxicity CRL 49500 is more toxic than the products tested above. At doses of 1024 and 512 mg/kg it causes a rapid onset of sedation with a decrease in muscle strength and tone and hypothermia, unsteady gait; death occurs on average after 2, 6 and 18 hours, respectively. At a dose of 256 mg/kg the symptoms were identical, but the mice survived. In weaker doses of 128, 64 and 32 mg/kg there was only a sedative effect. b. Action on the central nervous system. CRL 40500 does not modify apomorphine (rats and mice) and amphetamine (mice) stereotypies. It deepens the hypothermia induced by reserpine and oxotremorine at doses of 128 and 32 mg/kg, and increases the peripheral effects of oxotremorine. At doses of 3 (2 and 128 mg/kg) CRL 40500 moderately limits the spontaneous movement of mice. At a dose of 128 mg/kg it causes a moderate resumption of motor activity in mice accustomed to being confined. It does not cause a significant improvement in motor recovery. mice reduced by hypobairic anoxia. At all doses tested, CRL 40500 reduces intergroup aggressiveness in mice. However, this effect, occurring with high intensity from the lowest dose used (0.8 mg/kg), does not increase with increasing doses and even a reduced effect is observed at high doses (64, 128 mg/kg). In summary, the psychopharmacological profile of CRL 40500 includes a moderate sedative effect at high doses and a significant reduction in aggressiveness at low doses. Trials with CRL 40509 (product with ¬ clade XXIII). a. Toxicity. For mice, the LDQ is higher than 512 mg/kg but lower than 1024 mg/kg. b. Effects on the central nervous system. Psychopharmacologically, CRL 40509 cha-113772 13 14 30 is characterized by as follows: sedation at a high dose of 256 mg/kg; anti-anoxidant-type effect at lower doses (64 and 128 mg/kg); anti-aggressive effect in very low doses (8 and 16 mg/kg). 5 Trials with the preparation CRL 40510 (product from Example XXV). CRL 40510 suspended in a solution of gum Arabic or in a solution of distilled water (solubility limit 1.3fV) was administered intraperitoneally at a volume of 20 ml/kg in mice, 10 ml/kg in rats and 5 ml/kg in rats. a. Toxicity. The LD0 for mice is higher than 124 mgykg. b. Action on the central nervous system. A psychopharmacological study of ORL 40510 showed that this product has an anti-ageing effect (four-plate test) and an anticonvulsant type (these effects observed after intraperitoneal administration also appear after intragastric administration). CRL 40510 produces a moderate sedative effect in high doses. CRL 40510 is therefore similar to benzodiazepines in its anti-aging and anti-convulsive effects, but differs from it in that it does not cause motor impairment and is relatively resistant to sedation. Moreover, like benzodiazepines, CRL 40510 moderately antagonizes tremors caused by oxotremorine. Trials with the preparation CRL 40513 (product of Example XXVI). a. Toxicity. In mice, LD0 is higher than 1024 m2/kg. Sedation and hypothermia are reported at high doses. b. Action on the central nervous system. A psychopharmacological study of CRL 40513 showed an antidepressant effect and improved motor recovery in mice whose mobility was reduced by hypobaric annexation. All pharmacological and clinical trials showed that the products obtained according to the invention are substances acting on the price. the nervous system as psychotropic substances, especially as sedatives, antidepressants, psychostimulants or antidrug substances, the sedative activity being common to all products. Of particular interest are the products of Example I - CRL 40373, from example II - CRL 40382, from example III - CRL 40385, which is the most preferred product* from example XVI CRL 50 40471, from example XX - CRL 40490, from example XXI - CRL 404&1, from example XXIII - CRL 40500 , from example XXV CRL 40510 and from example XXVI - 40513. The product from example I (CRL 40373) has been used successfully in clinical trials as a sedative in the form of a tablet containing 100 mg of the active substance in an amount of 2-3 tablets per day. The product from Example II (CRL 40382) has been used clinically successfully as a sedative in the form of a tablet containing 250 mg of the active ingredient, in an amount of 2-3 tablets daily. The product of Example III (CRL 40385) has been used clinically successfully for the treatment of fatigue. , In the form of a tablet and a gelatin capsule, each containing 100 mg of the active ingredient, in an amount of 2-3 tablets or capsules/day. The product from Example XVI (CRL 40471) has shown good clinical results as a sedative in the form of a tablet containing 0.250 mg active ingredient in the amount of 2 tablets per day. The product from Example XXV (CRL 40510) has been used with good results in humans as a sedative, antiaging agent, in the form of a gelatin capsule containing 20 mg of the active ingredient, in an amount of 3-4 capsules per day. Analogous results were obtained for preparations obtained by oxidizing the compound according to Example V to the sodium group. After oxidation, the product from Example V showed properties similar to the product from Example II (CRL 40382). The translations illustrate the method of the invention. Example I. Tributylacetohydroxamic acid. (CH3CH2CH2CH2)3C-C(0)NHOH code number: CRL 40373.( Solution of 4.56 g (0.02 mol) of tributylacetic acid, melting point 34-3G°C and boiling point 126-127°C (6.05 Pa) in 7.5 ml (0.1 mol) of thionyl chloride was stirred for 30 minutes. Then the whole was heated for an hour in aqueous water and then evaporated to dryness under reduced pressure. The acid chloride thus obtained was added dropwise to a solution of 3.5 g (0.05 mol) of hydroxylamine hydrochloride in 25 ml of pyridine, stirred for 1 hour at 2°C, evaporated to dryness under reduced pressure, 2N HCl was added, strained, washed with water, dried, washed with pentane and recrystallized from diisopropyl ether. CRL 40373 was obtained with a yield of 48fV», melting point 133-134°C. Example 4 II. 3^(5,5-diphenylhydantomyl)acetohydroxamic acid. A compound of formula 1 in which Rx is a group of formula 8 and R2 and R3 represent hydrogen atoms, CRL code no. 40382. a. Preparation of S-^^diphenylhydantoine)-ethyl acetate. To a stirred solution of 12.6 g (0.05 mole) of 5,5-diphenylhydroxymethylene and 6.1 ml (0.055 mole) of ethyl bromoacetate in 100 ml of absolute ethanol was added dropwise over the course of 3 hours to the stirred solution heated at reflux temperature. sodium ethanate prepared from 145 g <0.05 grams of sodium and 100 ml of ethanol. The mixture was heated for another hour, the sodium bromide was filtered off while hot, cooled and filtered. 16.2 g (96% yield) of ester were obtained, melting point 184-185°C. b. Preparation of CRL 40382. 13.6 g (0.04 mole) of ethyl 3-(5,5-diphenylhydantDkyo)acetate were mixed with a hydroxylamine solution prepared from 4.2 g (0.06 mole) of hydroxylamine hydrochloride and 2, 3 g of sodium in 200 ml of methanol. After standing overnight at 20°C, the mixture was evaporated to dryness under reduced pressure, 100 ml of water were added, filtered and the filtrate was precipitated with 6N H2O. It was centrifuged, washed with water, dried and recrystallized from methanol. CRL 40382 was obtained with a yield of 87°C/t. This product had a double melting point; 132-434°C and then 214r-2160C,113TT2 15 16 " Example III. Tf-i(N,N-dw:uphenylcarbamyl)acetDhydroxamic acid. C6H5)2N-CO-€H2C(0)- - NHOH, code number CRL 40385. a. Preparation of ethyl N,N-diphenylcarbamylacetate. 7.5 g (7.5 g (0.1 mol) of diphenyl©-5 amine in 150 ml of anhydrous benzene were added dropwise while stirring) 0.3 mol) of ethyl malonate chloride and left overnight. The precipitate of diphenylamine hydrochloride was filtered off. The filtrate was washed with 1 N MCl and then with an acidic carbonate solution and water. The filtrate was dried, evaporated to dryness under reduced pressure, petroleum ether was added and strained. 12 g (85% yield) of the ester were obtained, melting point: 75°-76° C. b. Preparation of CRL 403B5: A solution of hydroxylamine was prepared with 7 g (0.1 mol) of the hydrochloride, hydroxylamine and 3.95 g (0.17 moles) of sodium in 250 ml of methanol. The sodium chloride was filtered off, 19.8 g (0.07 moles) of N,N-diphenylcarbamyl-ethyl acetate were added and left overnight. It was evaporated to dryness under reduced pressure, taken up with water, filtered, the filtrate acidified and filtered. The precipitate was washed with water and diisopropyl ether, dried and recrystallized from ethanol. 25 CRL 40385 was obtained with a yield of 58% and a melting point of 150-151°C. Example IV. α-(benzhydrylcarbonamido)acetohydroxamic acid. (C6H5)2CH-CO^NH-CH2- -C(0}NHOH, code no. CRL 40400, 30 ¦ a. Preparation of diphenylacetic acid chloride... 21.2 g ... (0.1 mol) of diphenylacetic acid was mixed cold with 75 ml (approximately 1 mole) of thionyl chloride. The reaction mixture was kept at reflux for 3 hours, cooled, and the excess thionyl chloride was evaporated to obtain the acid chloride which solidified at a temperature below 50°C. In this way, 22.9 ~g of acid chloride was obtained with a yield of approx. 99%. 40 b. Preparation of a-!(benzhydryl cariboinamido)-oetarau ethyl. A methanolic solution of 0.2 mole of glycine ethyl ester (base) was prepared by neutralizing a 10% methanolic solution containing 28 g (0.2 mole) of the appropriate hydrochloride with a solution of sodium methanols (5 g of Na in 50 ml of methanol, i.e. approximately 0.218 mol with methanols). The sodium chloride was filtered off, the methanol was evaporated, the amino ester was diluted with anhydrous benzene and the acid chloride in anhydrous benzene solution was added at room temperature (15-25°C). The temperature was observed to rise to about 35°C. Then the whole was heated at reflux for 2 hours, cooled, the precipitate formed was filtered off, benzene was evaporated, and the oil was collected and crystallized from a mixture of ethyl ether and isopropyl ether (50:50). The precipitate was filtered off and dried to obtain 19 g of α-(benzhydrylcarbonamide)acetic acid ethyl ester, which evaporated immediately at a temperature of 106-108°C, with a yield of 64%. c; Preparation of CRL 40400. 0.064 mol of 1-9 g) of the ester obtained above was dissolved in methanol and a methanolic solution of 0.10 mol of hydroxylamine (base) was prepared in the presence of an excess of 65 sodium methanols (0.065 mol) by adding 0.165 mol of sodium methoxide to t), 10 moles of hydroxylamine hydrochloride in a solution in methanol and filtering off the sodium chloride. Both methanol solutions were mixed and the reaction mixture was left at room temperature for 15°C; The methanol was then evaporated, water was added and the mixture was acidified by adding 3N HCl to precipitate 16.6 g of CRL 40400. The precipitate was dried and recrystallized from ethyl acetate. 13.0 g of CRL 40400 were obtained, melting immediately at 156°C, with a total yield of 46%. Example V. (p-Chloirobenzylmeric acid)acetohydroixamic acid. p-ClC6H4CH2-S-CH2-C(0)- -NHJ&H. a. Preparation of methyl (p-chlorobenzylmerkapito)acetate. Cold, 100 ml of anhydrous acetone, 21 g of potassium carbonate, 19.5 ml of p-chlorobenzyl mercaptan, 13.2 ml of methyl chloroacetate and 0.1 g of potassium iodide were mixed. The mixture thus obtained was stirred and kept at reflux temperature for 7 hours, then cooled and the K2CO3 precipitate filtered off. Acetone was evaporated from the mixture and ether was added. The ether solution was washed with 4M NaOH and then with water until the water rinses were neutral. It was dried over MgSO4 and the ether was evaporated. 34.5 g (yield 100%) of methyl (p-chlorobenzy-Iomercapto)acetate remained in the form of a chromatographically pure oil. b. Preparation of (p-chiorobenzylmeircapto)acetohydroxamic acid. A solution of 0.15 mole of methyl (p-Mobenzylmercapto)acetate in 50 ml of methanol was mixed with a solution of 0.225 mole of hydroxylamine (base) and 0.15 mole of sodium methanols in 150 ml of methanol. The resulting mixture was kept overnight at room temperature (15-25°C), then the methanol was evaporated, water was added and acidified with 3N HCl to precipitate (p--cVoroberisylmercapto)acetohydroxamic acid. 31.7 g of this acid were obtained, i.e. with a yield of 91%. Melting point about 130°C. Example VI. Sodium 0-{ia-phenothiazinyl)propiohydroxaminate (in the formula Rx means the group of formula 9, code no. CRL 40258). a. Preparation of methyl p^(1-phenothiazinyl)propionate. 25 g of 0410-phenothiazinyl) propionitrile in a solution in 200 ml of methanol with 25 g of sodium hydroxide pellets in a solution of 75 ml of water were heated under reflux for 20 hours. The alcohol was evaporated under reduced pressure, filtered over carbon, the precipitate was obtained with concentrated HCl, filtered, recrystallized from methanol and dried. 20 g of acid were obtained with a temperature of 161-162°C. The obtained acid was heated for 4 hours; at boiling point, under reflux in a solution in 40 ml of dichloroethylene, 10 ml of methanol and 0.5 ml of concentrated sulfuric acid. It was washed with water and dilute acid carbonate, dried, filtered over carbon, evaporated under reduced pressure and recrystallized from methanol. 19 g of methyl ester with a melting point of 64-66°C were obtained, with a yield of 7.2%. /-.,-: .113 J72 17 18 b. Preparation of CRL 40253. A solution of hydroxylamine was prepared from 10.5 g (0.15 mol) of hydroxylamine hydrochloride and 10.4 g (0.2 mol) of me. sodium tanols in 150 ml of methanol. The sodium chloride was filtered off and 22.3 g (0.08 mole) of methyl-P-10-phenothiazinyl)propionate were added to the filtrate. After 48 hours at room temperature, the reaction mixture was evaporated to dryness under reduced pressure. 100 ml of water and 10 ml of concentrated sodium hydroxide were added. It was strained cold, washed with 20 ml of ice water and recrystallized from 100 ml of water. CRL 40258 was obtained with a yield of 56%. Melting point 155-160°C (with decomposition). Example VII. 2-(N,N-diphenylcarbamyl)piohydroxamic acid. (C6H^2vN-CO-CH(CH3)- -C(d)NHOH, CRL code no. 40438. a. Preparation of ethyl 2-(N,N-diphenylcarbamyl)--propioate. To the prepared solution of sodium ethoxide from 1.15 g (0.05 grams of sodium) In 25 ml of ethanol, 14.15 g (0.05 mol) of ethyl (N,N-direnylcarbamylOmethylacetate) were added, and then 7.8 g (0.055 moles) of methyl iodide. At the end of the addition, the mixture began to reflux. The mixture was kept in this state for 15 minutes, then evaporated under reduced pressure, ether was added, washed with diluted HG1, diluted acidic carbonate and then water, and then dried , evaporated under reduced pressure and crystallized from petroleum ether. The given ester was obtained with a yield of 68%. Melting point: 39-40° C. b. Preparation of CRL 40438. 4.9 g (0.125 gram atoms) of sodium were added to 50 ml of anhydrous ethanol. in small pieces. A solution of 5.25 g (0.075 mol) of hydroxylamine hydrochloride in 50 ml of anhydrous methanol was neutralized with 2/3 of the sodium ethaphiolate solution thus obtained. Then 15 g (0.05 mol) of ethyl 2-(N,;N-diphenylcarbamyl) propriorate were added and then the remaining part of sodium ethoxide was added cold. The mixture was kept overnight at 5°C, evaporated to dryness under reduced pressure, ether was added and the sodium salt was filtered off. This salt was dissolved in water and the solution was acidified with concentrated HCl. After pressing, drying and crystallizing from acetonitrile, CRL 40438 was obtained with a yield of 68%. Melting point 171-172°C. Example VIII. 2-(N,N-diphenylcarbamyl)tuityrohydroxamic acid. (C6H5)2N-CO-CH- r(CaH5)-C(Ó)NHOH, code no. CRL 40439. a, Preparation of ethyl 2-{N,N-diphenylcarbamyl)-butyrate. Method A. To the solution 25.5 g (0.15 mole) of diphenylamine in 150 ml of benzene A solution of 14.3 g (0.075 mole) of (a-ethoxycarbonyl)butyryl chloride in 75 ml of benzene was added dropwise while stirring at 20°C. After overnight, the diphenylamine hydrochloride was filtered off. The filtrate was washed with dilute HCl, dilute sodium bicarbonate and water. It was then dried, evaporated under reduced pressure and recrystallized from diisopropyl ether to obtain the desired amidoester with a yield of 90µl/o. Melting point 64-65°C. Method B. A solution of sodium ethoxide was prepared from 0.46 g (0.02 gram atoms) of sodium in 15 ml of ethanol, 5.66 g (0.02 mol) (N,N) was added -difexiylcarb:myl)ethyl acetate, and then 4 g (0.025 mol) of ethyl iodide were added dropwise. It was heated for about 2 hours at reflux temperature until the pH was about 7, evaporated to dryness under reduced pressure, diluted with 100 ml of ether and continued processing as in method A. The same compound was obtained with a yield of 88°/ about. b. Preparation of CRL 40439. A solution of hydroxylamine hydrochloride (7 g, 0.1 mol) in 50 ml of methanol was basified with a solution of sodium ethoxide: [3.7 g (0.16 gram atoms of sodium) in 50 ml of anhydrous ethanol], after it was filtered and 18.6 g (0.06 mol) of ethyl 2^N:N-diphenyacarbamyl)butyrate were added to the filtrate. The mixture was left overnight, the alcohol was evaporated under reduced pressure, ether was added and the sodium salt was filtered off. The salt was dissolved in water, acidified with 3N H2O, the precipitate was filtered off and washed with water. After recrystallization from acetone, CRL 40439 was obtained with a yield of 64°C, melting point of 159-160°C. Example 9. (N,N-dW'Ucyclohexyl)-carbamylacetohydroxamic acid, (CflH11)2N-00-CH2- -C(0)NHOH, code no. CRL 40446. a. Preparation of N,N-dicyclohexylcarbamyl-ethyl acetate. To a stirred solution of 36 g (0.02 mol) of dicyclohexylamine in 200 ml of anhydrous benzene, 15 g (0.1 mol) of ethyl malonate chloride in a solution in 100 ml of anhydrous benzene were added dropwise, followed by 35 left overnight and then filtered, the filtrate washed with dilute HCl, dilute sodium bicarbonate and water. It is dried, evaporated under reduced pressure, 100 ml of petroleum ether are added and the mixture is filtered. 40-29 g of amide ester were obtained. Yield 99°/o, melting point 30-35°C. b. Receiving CRL 40446. A solution of 5.75 g ( 0.25 gram atom) of sodium in 100 ml of methanol. After 18 hours of contact, it was evaporated to dryness under reduced pressure, diluted with water and acidified with 3N HCl. 50 After filtering, drying and recrystallizing from ethanol, CRL 40446 was obtained with a yield of 68%. Melting point 198-200°C (with decomposition). Example . a. Preparation of ethyl 2-[3H(i5,5-diphenylhydaintoinyl)]propionate. A solution of 12.6 g (0.05 mol) of 5,5-diphenylhydantoin and 10 g (0.55 mol) of ethyl 2-bnomopropionate in 100 ml of ethanol was heated to reflux. A solution of 1.15 g (0.05 gram atom) of sodium in 100 ml of ethanol was added dropwise over 2 hours while stirring. The mixture was kept under reflux for 1 hour, the ethanol was removed under reduced pressure, 250 ml of ether was added, and the mixture was washed with a dilute NaOH solution and water. It was dried, evaporated and recrystallized from isopropyl ether. 14.6 g of ester with a melting point of 94-95°C were obtained with a yield of 83%. - ' - b. ; Prepared CRL 40447. A solution of 5.25 g (0.075 mol) of hydroxylamine hydrochloride in 150 ml of anhydrous methanol was cold-stirred with a solution of 2.88 g (0.125 gram atom) of sodium in 75 ml of methanol. The sodium chloride was filtered off and 17.6 g (0.05 mol) of ethyl 2-[3-(5',5-dw1UphenylGhydantoinyl)]i)iropionate was added to the filtrate. After contacting overnight, it was evaporated to dryness under reduced pressure, 200 ml of water were added, the mixture was acidified with 3N HCl, 50 ml of ether were added and the mixture was filtered off. The precipitate was washed with water and ether. After crystallization from methanol, CRL 40447 was obtained with a double melting point of 128-130°C and then: 205-2G6°C, with a yield of 60%. Example XI. 3-(5-ethyl-5-phenylhydantoinyl)acetohydroxamic acid, (compound of formula 1, where Ej is a group of formula 10 and R2 and R3 are hydrogen, code no. GRL 40450). a. Preparation of 5-ctylb-5-phenylhydantoin. A solution of 26.8 g (0.2 mol) of propioienone, 80 g (0.8 mol) of amcnium carbonate dissolved in 300 ml of water and 28 g (0.4 mol) ) potassium cyanide in 300 ml of ethanol was heated at reflux for 8 hours with stirring. This solution was cooled in a cooling mixture (ice and salt), as a result of which hydantoin was precipitated. The obtained precipitate was strained and washed with water. 27.1 g (yield 66%) of 5-ethyl-5-phenylhydantoin with temperature: melting 202°C. b. Preparation of 3-<5-ethyl-5-phenylhydantoin-:1)ethyl acetate. While stirring, a solution of 20.4 g (0.1 mol) of 5-ethyl-5-phenylhydantoin and 12.2 ml of ethyl bromoacetate in 200 ml of anhydrous ethanol was heated at reflux temperature, and a solution of sodium ethoxide prepared therefrom was added dropwise over the course of 3 hours. with 2.3 g (0.1 gram atom) of sodium and 200 ml of anhydrous ethanol. The whole was heated for another hour and then the alcohol was evaporated. The obtained precipitate was filtered off and then washed with water. 27.2 g of ester with a melting point of 120-1.2.1°G was obtained, yield 93%. c. Preparation of CRL 40450 11.6 g (0.04 mole) of the product obtained above were mixed with a hydroxylamine solution prepared from 4.2 g (0.06 mole) of hydroxylamine hydrochloride in 100 ml of methanol and 2.3 g (0.1 gram atom) sodium in 100 ml of methanol. After standing overnight at room temperature, the mixture was evaporated to dryness under reduced pressure, 100 ml of water were added and filtered. The solution was acidified. 3N HCl, the organic phase was extracted with ethyl acetate and then evaporated. An oil was obtained, which was dissolved in the smallest possible amount of ethyl acetate and heated slightly, then cooled, the precipitate was centrifuged and washed with ethyl acetate. After pressing off and recrystallizing from ethanol, CRL was obtained with a yield of 43%. Melting point 201-202°C. Example XII. N-(4-chlorophenyl)carbamylacetohydroxamic acid. Cl-C6H4NH-CO-CH2C- -<0NHOH, CRL code no. 40464. a. Preparation of N-(4-chlorophenyl)car1bamyl-5 ethyl acetate. To a solution of I&.7 g (0.1 mol) of 4-chloroaniline and 100 ml of anhydrous benzene, a solution of 7.5 g (0.05 mol) of ethyl gin chloride in 25 ml of anhydrous benzene was added dropwise while stirring! The mixture was stirred for another 2 hours at room temperature, and then the precipitate of 4-chloroaniline hydrochloride was squeezed out. The filtrate was evaporated to dryness under reduced light: to isopropyl ether and the precipitate were added to the residue and filtered. 11.5 g were obtained (yield 95% of the given product. Melting point .32°C., "' b. Preparation of CRL 40464. A solution containing 3.5 g (0.005 mol) of hydroxylamine hydrochloride, 0, 1 mole of sodium methoxide and 1.2.1 g (0.05 mole) of ethyl N-(4-chlorophenyl)carbamylacetate were left for 4 hours at 20°C and then evaporated to dryness under reduced pressure, 100 ml of water were added, filtered and acidified with 3N HCl. The precipitate was filtered off, washed with water and dried. After recrystallization from 95% ethanol, CRL 40464 was obtained with a yield of 82%; melting point 212-<2 µC (with decomposition). Example XIII . (3,4-dichlorobenzylthio)a.cetohyric acid (a compound of formula 1, in which Rx is a group of formula 11 and R2;R3=H). 30 a. Preparation of 3,4-acid dichlorobenzylthioacetic acid. A mixture of 19.5 g (0.1 mole) of 3,4-dichlorobenzyl chloride and 7.6 g (0.1 mole) of thiourea in 50 ml of water was heated with stirring for 30 minutes at reflux temperature under reflux condenser 35 and then a solution of 16 g (0.4 mol) of NaOH in 25 ml of water was added dropwise at a temperature of 60-70°C. The whole was heated for 15 minutes at reflux temperature and then at a temperature of 60-70 °C, a solution of 15 g (0.15 40 mol) of chloroacetic acid, 7 g of sodium carbonate and 50 ml of water was added dropwise and the mixture was kept under reflux for 1 hour. Cold acidified with concentrated CHI, extracted with ether, washed with water, dried and evaporated. Petroleum ether was added to the residue and the precipitate was filtered off. 21 g (yield 83%) of the title compound were obtained, melting point 63-84°C. b. Preparation of (3,4-dichlorp,beinsyl-50)acetoihydroxamic acid. 20.2 g (0.08 mol) of (3,4-dichlorobenzylthio)acetic acid was esterified with 10 ml of methanol in the presence of 0.6 ml of H2SO4 and 100 ml of dichloroethane. The mixture was heated to reflux for 4 hours, washed with water, then with dilute acidic carbonate and dried. It was evaporated under reduced pressure. The oily residue was treated in methanol with a solution of hydroxylamine (0.1 mol) in the presence of 0.18 mol of sodium methoxide; After 60 hours, it was evaporated to dryness under reduced pressure, water was added, filtered over carbon, acidified with 3N HCl, extracted with ether, dried, evaporated and recrystallized from isopropyl ether. 15 g of the title product *5 were obtained, melting point 75-76°C. Yield 7i%i.21 and ii? 772 22 Example )- tNHOH. ,.. ¦ a. Preparation of ethyl 2-(p-;ChlorQbenzyl1;ia)i)'ropanoate. Mixture of 19.5 ml (0.15 mol) of 4-chlorobenzyl mercaptan, 27.1 g (0.15 mol) of ethyl α-formopropionate, 21 g of potassium carbonate and 0.1 g of potassium iodide in 100 ml of anhydrous acetone were kept at reflux temperature for 6 hours. The precipitate was filtered off, washed with acetone and the filtrate was evaporated under reduced pressure. 200 ml of ether were added to the residue, washed with dilute NaOH, dilute KCl and water. Dried and evaporated under reduced pressure. b. Preparation of 2-(p-chlorobenzylthio)-propiohydroxamic acid. 105 g (0.15 mol) of hydroxylamine hydrochloride was mixed with a solution of sodium methoxide prepared from 5.75 g (0.25 gram atom) of sodium in 200 ml of methanol. The sodium chloride was filtered off, and 25.85 g (0.1 mol) ethyl 2-(p-chlorobenzylthio)pyropionate. After overnight, it was evaporated under reduced pressure, 200 ml of water were added to the residue, filtered and precipitated with 3N HCl. The precipitate was drained, washed with water and dried to give 20.2 g (yield 82%D of the title compound, melting point 104-105°C. EXAMPLE 15 Proceeding essentially as described in Example 2, but replacing 5,5-diphenylhydantoin 5,5-Di(p-chlorophenyl)hydantoine (compound of formula 12) with a melting point of 319-320°C, 3-[5,5-idiwu(p-chlO'rophenyyl)hydantoinyl]acetate was obtained. ethyl acid with a melting point of 145°C and 3-(5,5-divalve-(pHchlorophenyl^ydantoinyllacetohydroxamic acid) with a melting point of 139^141°C (code no. CRL 40468). Example XVI. 5-(10.l-dihydrogen acid) - dibenzoCb^lazepineJcarbonylacetohydroxamic (a compound of formula 1, in which Rx is a group of formula 13, 1^ and R3 are hydrogen atoms, code number CRL 40471). Stirring was carried out in a stream of nitrogen and at a temperature of 20°C for 16 hours9, 8 g (0.05 mole) of iminodibenzyl and 7.5 g (0.05 mole) of ethylmalonyl chloride in 100 ml of benzene. The mixtures were washed with dilute acidic carbonate and water, then dried and filtered over carbon. It was evaporated under reduced pressure. Ethyl 5-(10.1-di;hydro-dibenzo{ib,f]azepine)carbonylacetate was obtained as an oil as a residue and was mixed with a hydroxylamine solution prepared from 3.5 g ( 0.05 mol) of hydroxylamine hydrochloride, 2.3 g of sodium and 200 ml of methanol. The next day, the methanol was evaporated under reduced pressure, 150 ml of water were added, filtered over carbon, the acid was precipitated with 3N HCl, the precipitate was filtered off and dried. After recrystallization from methanol, CRL 40471 was obtained in the form of a salmon-colored powder with a yield of 76%. Melting point 201-202°C (with decomposition). Example XVII. 4-aminophenylcarbamylacetoihydroxaminic acid hydrochloride. NH2C6H4- -NH-CO-CH2C(0NHOH HC1, code number CRL 40472. a Preparation of ethyl 4-nitrophenylcarbamylacetate. To a solution of 27.6 g (0.2 mol) of p-nitroaniline ~ in 200 ml of methylene chloride kept at at the boiling point under a salty reflux condenser, a solution of 15 g (0.1 mol) of ethyl malohate chloride in 50 ml of methylene chloride was added dropwise. The next day, the precipitate of p-nitroaniline hydrochloride was filtered off, the filtrate was evaporated under reduced pressure, and ether was added to the residue isopropyl alcohol, the precipitate was filtered off and crystallized with ethyl acetate. 22 g (87% yield) of the title compound were obtained. Melting point 102-103°C. ... b. Preparation of ethyl 4-aminophenylcarbamylootate. 25.5 g (0.1 mol) of the above product in 250 ml of ethanol was reduced with hydrogen in the presence of 2 g of palladium on carbon as a catalyst. The catalyst was filtered off, the residue was evaporated under reduced pressure, isopropyl ether was added and the precipitate was filtered off to obtain 21, 5 g of the title amino ester, melting point 58-59°C. Efficiency 97%! c. Preparation of CRL 40472. A mixture of 17.8 g (0.08 mole) of ethyl 4-aminophenylacetate, 7 g (0.1 mole) of hydroxylamine hydrochloride and 4.6 g (0.2 atoms) of sodium in 250 ml of anhydrous methanol was kept at 20°C for 2 hours. The methanol was evaporated under reduced pressure, 100 ml of water were added, the mixture was acidified with 6N HCl and the precipitate was filtered off. After recrystallization from 80 ml of water, CRL 40472 was obtained with a yield of 64%. Melting point 164-165°C (decomposition). Example XVIII. 4-Aminobenzamidoacetohydroxaimic acid hydrochloride. NH2C6H4CO- -NH-CH2C<0)NHO[N Ha, code no. CRL 40473 a. Preparation of ethyl 4-aminobenzamidoacetate. Hydrogenated 17.6 g (0.07 mol) of ethyl 4-nitrobenzamidoacetate in a solution in 250 ml of ethanol in the presence of 2 g of palladium on carbon as a catalyst. The catalyst was filtered off, the residue was evaporated to dryness under reduced pressure, 100 ml of isopropyl ether were added and the precipitate was filtered off. 15 g (yield 87% of the title compound with a melting point of 93-94°C) were obtained. b. Preparation of CRL 40473. Small pieces of sodium were added to 150 ml of anhydrous methanol (5.75 g , 0.25 gram atom). The obtained cold sodium methoxide solution was poured into a solution of 10.5 g (0.15 mol) of hydroxylamine hydrochloride in 100 ml of anhydrous methanol. The cold stirred for half an hour, the sodium chloride precipitate was filtered off and added 22.2 g (0.1 μl) of ethyl 4-aminobenzamidoacetate were added to the filtrate. The next day it was evaporated to dryness under reduced pressure, 100 ml of water was added to the residue and the hydrochloride was precipitated by adding 6N H2O to pH 1. The precipitate was drained and washed with 10 ml of white water. After recrystallization from a mixture of methanol-water 60 (4:1 by volume), dfeL 40473 was obtained with a yield of 7-2V, melting point 182-185°C (with decomposition). Example XIX, Ka-naphthylmethylene)-thio]acetohydroxamic acid (compound of formula 1, in which Rx is a group of formula 14, RjjiR3=H),ifWTO 23 U a. Preparation of (a-naphthylmethylene)thio acid - vinegar. In a three-necked flask with a capacity of 1 liter, equipped with a magnetic stirrer, a reflux condenser and an addition funnel, a solution of 15.2 g (0.2 mol) of thiourea in 100 ml of water was placed and added at a time at a temperature of 50-60°C. 35.3 g (0.2 mol) a-chloromythylnaphthalene. Heated to boiling point and kept at boiling for 15 minutes. Thiurotti salt was precipitated. Then it was cooled to 60°C and at this temperature a solution of 32 g of NaOH (3.8 mol) in 50 ml of water was added dropwise. The resulting mixture was kept at boiling point until the solution became transparent, cooled and a solution of about 0.28 mol of sodium chloroacetate obtained by neutralizing 26.36 g of chloroacetic acid in 200 ml of water with 23, was added dropwise at a temperature of 60-70° C. 52 g of sodium carbonate. The whole was then kept at boiling point for half an hour, then cooled, acidified in the cold by adding 3N HCl and (α-ina-methylmethylene)thioacetic acid was precipitated and strained. 44.5 g of product were obtained (yield 95%), melt immediately at a temperature of 102-103°C. b. Preparation of ethyl (a-naitylmethylene)thioacetate. 19.7.2 g (0.085 mol) of the above product were dissolved in 160 ml of 1,2-dichloroethane, 16 ml of anhydrous ethanol and 1.6 ml of concentrated sulfuric acid were added. The whole was kept at reflux temperature for at least 2 hours, cooled, the organic layer was decanted and the formed water was removed, then washed with a dilute sodium hydroxide solution and then with water. Dry over MgSO4 and the solvent was evaporated. 19.8 g of (a-na-phthylmethylene)t:ooctamethylene (total yield 89%) were obtained in the form of a clear orange oil. c. Preparation of [(a-naphthylmethylene)thio]-acetohydroxamic acid. Obtained above ester (0.076 mol) diluted with 50 ml of methanol was added to a solution of hydroxylamine prepared from 7.92 g (0.114 mol) of hydroxylamine hydrochloride in 190 ml of methanol and 4.37 g (0.19 gram atoms) of sodium in 190 ml of anhydrous methanol. overnight, during which the whole was kept at a temperature of 20°C, the methanol was evaporated, water was added to the residue (alkaline medium), it was filtered over carbon, acidified by the addition of 3N HCl, and the acid [(a-naphthylmethylmethylene thioiacetohydroxanes, were filtered off, washed with water and then with ether and dried. After recrystallization with ethyl acetate, 11.2 g (0.0403 mol) of the product were obtained, melting immediately at T219-130°C. Total yield: 59%. Example XX 2-(1-phenylbenzimidazolyl)acetohydroxamic acid (compound of . formula 1, where Rx is a group of formula 15, R2 and R3 are hydrogen, code no. 40490). a. Preparation of 2-(1-phenylbenzimidazolyl)ethyl acetate. At 20°C, a solution of 11.75 g (0.064 mol) of o-aminodiphenylamine in 90 ml of ethanol was mixed and 12.5 g (5.064 mol) of ethyl acetate hydrochloride was added. After 1 hour of contact, the ammonium chloride formed was filtered off and the filtrate was evaporated under reduced pressure. Ether was added to the residue, washed with water, dried, the ether was evaporated, the remaining petroleum ether was recrystallized, the precipitate was filtered off and recrystallized from isopropyl ether. 16 g of the title ester were obtained, melting point 84°C. Efficiency 89%. ! bV Preparation of CRL 40490. A solution of hydroxylamine was prepared from 3.5 g (0.05 mol) of hydroxyamine hydrochloride in 50 ml of anhydrous methanol and 2.3" (0.1 gram atom) of sodium in 50 ml of anhydrous methanol. aqueous methanol. The sodium chloride formed was filtered off and 14 g (0.05 mol) of ethyl 2-(1-1-enylbenzimidazolyl)acetate were added to the filtrate and left overnight. Evaporated to dryness under reduced pressure, water was added, 31H2O was neutralized, the precipitate was filtered off, washed with water and dried. After crystallization from methanol, CRL 41490 was obtained with a yield of 68%. Melting point 212-215°C (with decomposition). Example XXI. 3,4-acid dichloroenylcarbamylacetohydroxamic (a compound of formula 1, in which Rx is a group of formula 16, R2 and R3 are hydrogen, CRL code no. 40491). 25 a. Preparation of 3,4-diChlorophenylcarbamyl-ethyl acetate. A solution of 15 g (0.1 mol) of ethyl malonate chloride in 100 ml of methylene chloride was added dropwise to a solution of 32-4 g (0.2 mol) of 3,4-dichloroaniline and 200 ml of methylene chloride, while stirring at 20°C. The mixture was stirred for another 2 hours and the precipitate was strained. After separation of the 3,4-dichloroaniine hydrochloride, the filtrate was evaporated to dryness under reduced pressure, and the residue was recrystallized from isopropyl ether. 24.5 g of the title product were obtained, melting point 74-75°C. Efficiency 89%. b. Preparation of CRL 40491. A solution of sodium methoxide was prepared from 3.7 g (0.16 grams) of sodium and 100 ml of anhydrous methanol, and this solution was added cold to the solution of 5*6 g (0.08 mol) of the hydrochloride. hydroxylamine and 100 ml of anhydrous methanol. The formed sodium chloride was filtered off and 22 g (0.078 mol) of ethyl 3,4-di-di-chlorophenylcarbaylacetate were added to the filtrate. It was left overnight, evaporated to dryness under reduced pressure, water was added, acidified with 3N HCl* and dried. After crystallization from ethanol, CRL 40491 was obtained with a yield of 62%. Melting point 201-22°C. Example wherein Rj is a group of formula 17. R2 and R3 are Hydrogen, code no. 40500. 55 a; Preparation of -3,4-dichloroanllinoacetic acid. Solution 32.4 g (0.2 mol) 3,4-dichloroaniline, 28 g (0.2 ml) of sodium acetate, 200 ml of acetic acid and 40 ml of water were stirred at reflux temperature. Over the course of 53 half an hour, a solution of 28.5 g ( 0.3 mol) of chloroacetic acid and 15.9 g (0.15 mol) of sodium carbonate in 100 ml of water. The mixture was kept at reflux temperature for 3 hours, 30 ml of concentrated hydrochloric acid were added and the the acetic acid was evaporated under reduced pressure. The residue was diluted with ether, washed with water, the acid was extracted with dilute sodium bicarbonate, precipitated again with 3N HCl, the precipitate was filtered off and dried. 27.2 g of acid with a melting point of 128-130°C were obtained. b. Preparation of ethyl (3,4-dichloroanilino)acetate, solution of 27.5 g (0.11 (25 mol) of a,4-dichloroanilinodic acid, 190 ml of divisuioroephthane, 15 ml (0.2 mol) of ethanol and 1 .5 ml of concentrated H2SO4 was heated under reflux for 4 hours. Washed with water and dilute sodium bicarbonate, dried and evaporated to dryness under reduced pressure. Recrystallization of the residue in ethanol gave the ester. with a melting point of 103-104°C with a yield of 78P/o. 07 mol) of hydroxylamine hydrochloride in 100 ml of methanol. Sodium chloride was filtered off and 16.1 g (0.065 mol) of ethyl 3,4-dichloroanilinoacetate were added to the filtrate. It was left overnight, evaporated to dryness under reduced pressure, water was added, was filtered over carbon, precipitated with 3N HCl and the precipitate was filtered off. After recrystallization from ethyl acetate, CRL 40500 was obtained with a yield of 36°/«a. Melting point 138-140°C (with decomposition). Example XXIII. 3,4,5-trimethoxyphenylcarbamylacetohydroxamic acid (compound of formula 1, where Rj is a group of formula 18, R2 and R3 are hydrogen, code no. 40509). a. Preparation of ethyl 3,4,5-trimethoxyphenyl caramylacetate. To a solution of 18.3 g (0.1 mol) of 3,4,5-trimethoxyaniline in 150 ml of anhydrous benzene, a solution of 7.5 g of ethyl malonide chloride in 50 ml of anhydrous benzene was added dropwise at reflux temperature. After heating under reflux for 1 hour, the reaction mixture was cooled, the precipitate was filtered off and washed twice with 50 ml of ether. The filtrate was washed with dilute H2O and the water was dried and evaporated. The residue was recrystallized from a mixture of ethyl acetate and isopropyl ether (1:1 by volume). 12 title compounds were obtained with a melting point of 93°C. Yield 80%. b. Preparation of CDL 40509. 4.15 g (0.18 gram atoms) of sodium were added in small pieces to 100 ml of anhydrous methanol. This solution was poured cold into a solution of 7 g (0.0 mol) of hydroxylamine hydrochloride in 100 ml of methanol, the sodium chloride was filtered off and 23.8 g (0.08 mol) of ethyl 3,4,5-trimethoxyphenylcarbamylacetate were added to the filtrate. It was left overnight, evaporated to dryness under reduced pressure, diluted with water, acidified with 3N HCl, the precipitate was filtered off and washed with cold water and isopropyl ether. After recrystallization from methanol, CRL 40509 was obtained, melting point 195-196° C. (with decomposition). Efficiency 49°/a.Example XXIV. (3-Trifluoromethyl-phenyl)carbamylacetohydroxamic acid, m-CF3C6H4-NH-CO-eH8C(0)iNHOH, CRL code no. 40512. 3172 26 Proceeding essentially as in Example XXIII, but substituting 3,4, 5-trimethoxyaniline 3-trifluoromethylaniiline obtained (3-tri- fluorornethylphenyl)kar! ethyl bamylacetate, melting point 67°C, and then ORL 40512, melting point 206-207°C (with decomposition), which was recrystallized from ethanol. Example XXV. 2,6-dichlorophenylcarbamylacetohydroxamic acid, (compound of formula io 1, where Rx is a group of formula 19, R2 and R3 are hydrogen, code no. 40510). Proceeding essentially as described in Example XXIII, but replacing 3,4,5-trimethoxyaniline with 2,6-dichloroaniline, ethyl 2,6-dichlorophenylcarbamylacetate was obtained, melting point 115-110°C, and then CRL 40510 with a melting point of 175-176°C (with decomposition), for which the solvent for crystallization was a mixture of ethanol and isopropyl ether. 20 Example XXVI. N-phenylourieidoaicetylhydroxamic acid, C6H5-NH-COHNH-CH2-0(0NHOH, code no. 40513. a. Preparation of ethyl N-phenylureidoacetate. To a stirred solution 17.6 g (0.17 mol) of amino-25 acetate ethyl in 200 ml of anhydrous benzene, 21 g (19 ml, 0.175 mol) of phenyl isocyanate were added dropwise, maintaining the temperature at 40°C. The mixture was stirred for another 2 hours at 20° C. and left overnight. The precipitate was filtered off, washed with isopropyl ether and dried. and 2|6.6 g (yield .71*/o) of the title compound with a melting point of 110-111°C were obtained. :. b. Preparation of ORL 401513. 22.2 g (0;1 mol) of the above obtained product was added with a solution 35 hydroxylamine prepared from 7.7 g (0.1 mol) of hydroxylamine hydrochloride, 5.07 g of sodium and 200 ml of methanol. After contacting for 3 hours, the solution was evaporated to dryness under reduced pressure, 300 ml of water were added and the mixture was cold acidified with 3N HCl. The precipitate was filtered off, washed with water and isopropyl ether and dried. After recrystallization from ethanol, CRL 40313 was obtained with a yield of 57%/vol. Melting point 165-166°C. Example XXVII. (p-fluorobenzene)-acetohydroxamic acid. (p-PICgH^Hg-S-CH^CJÓ)- JNHOH.. a. Preparation of p-fluorobenzylthioacetic acid. In a three-necked flask with a capacity of 1 liter, equipped with a magnetic stirrer, a reflux condenser and an addition funnel, a solution of 15.2 g (0.2 mol) of thiourea in 100 ml of water was placed and 28.9 g (28.9 g) ( 0.2 mol) p-fluorobenzyl chloride. It was heated to reflux temperature and held at this temperature under reflux for approximately 15 minutes until the solution became clear. It was then cooled to 60°C and a solution of 32 g (0.8 mol) of NaOH in water was added dropwise at this temperature. The whole was kept at boiling point for 30 minutes, cooled and a 60-70°C solution of approximately 0.28 mol of sodium chloroacetate obtained by neutralizing 26.46 g of chloroacetic acid in 200 ml of water with 23, 52 g of sodium carbonate. The whole was heated at reflux temperature for 30 minutes, cooled, acidified with 3h HCl, the oil obtained was diluted with methylene chloride, washed with a dilute solution of acidic sodium carbonate, filtered over carbon, acidified again with 3N HCl to precipitate the p acid. -fluorobenzylthioacetic acid, which was squeezed off. After recrystallization from cyclohexane, 33.4 g of this acid were obtained, melting immediately at a temperature of 63°C. (5 moles) of the acid obtained above were dissolved in 160 ml of 1,2-dichloroethane, 1-6 ml of anhydrous ethanol and 1.6 ml of concentrated sulfuric acid were added. The whole was kept at reflux temperature for approximately 6 hours, cooled, the organic phase was decanted, the water formed was removed, washed with a dilute solution of sodium acid carbonate and then with water. The solution * was dried over Na2SO4 and the solvent was evaporated. 17.4 g of p-fluoro- ethyl benzylthioacetate in the form of yellow oil. Total yield 893/o. c. Preparation of (p-fluorobenzylthio)acetohydroxamic acid. The previously obtained ester (0.0763 mol) was added to a solution of hydroxylamine prepared from 7.92 g (0.114 mol) of hydroxylamine hydrochloride in 190 ml of methanol and 4.37 g of sodium in 190 ml of anhydrous methanol. After overnight at room temperature, the methanol was evaporated, water was added, filtered over carbon, acidified with 3N HCl and (p-fluoroibenzylthio)aceitohydroxamic acid was precipitated, which was strained and washed with water. 11.2 g of acid was obtained, melting immediately at 115-°C. 116°C. Efficiency 68*/p. Example XXVIII. (p-methoxybenzylthio)acetohydroxamic acid. CH/-C6H4-OH2-! S-CH2C- -(O)NHOH. a. Preparation of p-methoxybenzyothioacetic acid. In a three-necked flask with a capacity of 1 liter, equipped with a magnetic stirrer and a reflux condenser, there was placed a solution of 18.24 g (0.24 mol) of thiourea in 104 ml of hydrobromic acid with a concentration of 48°C and 20 ml of water. The mixture was heated to 60°C and 27.6 g (0.2 mol) of p-methoxybenzyl alcohol were introduced into it. The temperature was raised to 95°C and allowed to cool. Crystals of thiuronium salt appeared, it was filtered off and strained. The precipitate was introduced into a 500 ml three-necked flask containing 60 ml of NaOH. The mixture was heated to 70°C and a solution of 16.6 g (0.164 mol) of chloroacetic acid dissolved in 30 ml of water was added dropwise. The whole was then kept at reflux temperature for 30 minutes, then cooled, acidified with 3N HCl, methylene chloride was added to the obtained oil, washed with a dilute solution of acidic sodium carbonate, filtered over carbon, acidified again with 3N HCl to precipitate the acid. p-methoxybenzylthioacetic acid. 25.7 g of this acid were obtained. Melting point 60°C, yield 60%. this. Preparation of ethyl p-methoxybenzylthioacetate. 24 g (0.112 mol) of the acid obtained above were dissolved in 210 ml of 1,2-dichloroethane, 22 ml of anhydrous ethanol and 2.2 ml of concentrated 4-sulfuric acid were added. The mixture was kept at boiling point for about 6 hours, cooled, the organic layer was decanted and the resulting water was removed. Washed with dilute acidic carbonate solution and then with water. The solution was dried over NaSO4 and the solvent was evaporated. 26.5 g of ethyl p-methoxybenzylthiootate were obtained in the form of a clear yellow oil with a yield of 96%. c. Preparation of (p-methoxybenzylthio)-acetohydroxamic acid. The above product (0.110 mol) diluted with 50 ml of methanol was added to a solution of hydroxylamine prepared from 11.63 g (0.165 mol) of hydroxylamine hydrochloride in 275 ml of methanol and from 6.32 g of sodium in 275 ml of anhydrous methanol. After keeping overnight at room temperature, the methanol was evaporated, water was added, filtered over carbon and acidified with 3N HCl to precipitate Cp-methoxybenzylthio)acetohydroxamic acid. After straining and washing with water, 1.91.1 g of this acid were obtained, melting immediately at 107°C. Yield: 77%. Example XXIX.-(2,4-dichlorobenzylthio)acetohydroxamic acid (compound of formula 1, where Rx is a group of formula 20, R2 and E3=H). a. Preparation of 2,4-diochlorobenzylthioacetic acid. In a three-necked flask with a capacity of 1 liter there were placed 115.2 g (0.2 mol) of thiomone: disappears in 100 ml of water. The mixture was heated to 50-60°C and 39.1 g (0.2 mol) of 2,4-dichlorobenzyl chloride was added in one go. The mixture was heated to reflux temperature and kept at reflux for 15 minutes. During this time the solution became transparent. Then it was cooled and a solution of 32 g (0.8 mol) of NaOH in 50 ml of water was added dropwise at a temperature of 60°C. It was heated again at reflux temperature for 30 minutes, cooled and a solution of approximately 28 moles of sodium chloroacetate obtained by neutralizing 26.46 g of chloroacetic acid in 200 ml of water with 23.52 g of NaHCO3. The whole was heated at reflux temperature for 30 minutes, cooled, filtered and acidified with 3N HOL. The obtained precipitate was drained, re-dissolved cold in a dilute acid carbonate solution, washed with methylene chloride, filtered and acidified again. 41.7 g of product were obtained, melting immediately in temperature 72-73°C. Efficiency 8a%. b. Preparation of ethyl 2,4-dichlorobenzylthioacetate. 37.65 g (0.15 mol) of the acid obtained above were dissolved in 283 ml of ly2-dichloroacetate, 28.5 ml of anhydrous ethanol and 2.9 ml of concentrated sulfuric acid were added. The whole was kept at reflux temperature for about 6 hours, cooled, the organic phase was decanted, the water formed was removed, and washed with a dilute solution of acidic carbonate and water. The solution was then dried over Na2SO4 and the solvent was evaporated. 43.6 g of a yellow oil consisting of ethyl 2,4-dichloro:benzylthioacetate were obtained. Total efficiency 90%. c. Preparation of (2,4-dichlorobenzylthio)acetohydroxamic acid. The ester obtained above 10 15 29 25 30 35 40 4? 50 55 6929 lmmn £0 (0.156 moles) add) to; hydroxylamine solution prepared from 16.38 g (0.235 molal of hydroxylamine hydrochloride in 300 ml of methanol and 9 g (0.391 gram atom) of sodium in 300 ml of anhydrous methanol. After contacting overnight at room temperature, the methanol was evaporated, water was added and filtered over carbon. , acidified with 3N HCl to precipitate (2,4-dichlorobenzylthio)acetoihydroxamic acid, which was strained and washed with water. 28 g of acid were obtained, melting immediately at 116° C. Yield 67%. Example XXX Acid (2, 6-dichlorobenzylthio)acetohydroxamic, (a compound of formula 1 in which Rx is a group of formula 21, R2 and R3=H). Proceeding as described in Example XXIX, but replacing 2,4-Cl2C6H3CH2Cl with 1-e-CljCgHgCHgCl, 2,6-dichlorobenzylthioacetic acid was obtained (yield 83%, melting point 81-8(20C) and then 2,6-dichlorobenzylthioacetic acid - ethyl chlorobenzylthioacetate (yield 89%) in the form of a yellow oil and (2,6-dichlorobenzylthio)acetohydroxamic acid (yield 71%, melting point 124°C). Example 31. (4-nitrobenzylthio)- -acetohydroxamic, p-N02C6H4CH2-S-CH2-CtO)- -NHOH. a. Preparation of ethyl 4-nitrobenzylthioacetate. 43.2 g (0.2 mol) of p-nitrobenzyl bromide, 200 ml of acetone, 0.2 g of potassium iodide, 24 ml of thioglycolate were introduced into a three-necked flask with a capacity of 1 liter. ethyl, i.e. a slight excess and 27.6 g (0.2 mol) of potassium carbonate. The mixture was kept at reflux temperature for approximately 4 hours until the bromide derivative was completely reacted. Acetone was evaporated, ether and water were added to the obtained oil, the ether phase was washed with a dilute NaOH solution to remove excess thiol, then with a dilute HCl solution and dried to obtain 49 g of the title compound in the form of an orange oil. Efficiency 95%. b. Preparation of (4-nitrobenzylthio)acetohydroxamic acid. The above-obtained ester (0.156 mol) diluted with 50 ml of methanol was added to a solution of hydroxylamine prepared from 16.38 g (0.235 mol) of hydroxylamine hydrochloride in 300 ml of methanol and 9 g (0.301 gram atom) of sodium in 300 ml of anhydrous methanol. The whole was left overnight at room temperature, the sodium chloride formed was filtered off, the reaction mixture was acidified directly, the solvent was evaporated, the obtained precipitate was dissolved in water and squeezed. After recrystallization from isopropyl alcohol, 27 g of (p-nitrobenzylthio)acetohydroxamic acid were obtained, melting immediately at a temperature of 118-419°C. Efficiency 72%. Example XXXII. [<3,4-Methylenedioxybenzyl)thio]acetohydrokisamic acid, (a compound of formula 1, where Rj is a group of formula 22, R2 and R3*H. a. Preparation of 3,4-methylenedioxyphoensylthioacetic acid. A solution of 18.24 g (0.24 mol) of thiourea in 104 ml of 48% hydrobromic acid and 20 ml of water was placed in a three-necked flask with a capacity of 1 liter, equipped with a magnetic stirrer and a reflux condenser. The mixture was heated to 60°C and 30.4 g (0.2 mol) of piperonyl alcohol were introduced into it. The temperature was raised to 95°C and the mixture was left to cool. Crystals of thiuronium salt appeared. It was filtered and the salt was centrifuged. The precipitate thus obtained was poured into a three-necked flask with a capacity of 500 ml along with 60 ml of sodium hydroxide solution. The mixture was heated to 70°C and 15.6 g (0.164 mol) of chloroacetic acid in 30 ml of water was added dropwise The whole was then kept at reflux temperature for 30 minutes and then cooled. The resulting precipitate was acidified with 3N HCl, dissolved in a dilute solution of acidic sodium carbonate, washed with methylene chloride, filtered over coal and acidified again with 3N HCl in to precipitate the 3,4-methylenedioxybenzylithioacetic acid which was separated. After recrystallization from a mixture of isopropyl ether-petroleum ether (1:1 by volume) 16-2 g of this acid were obtained (yield 40%). Melting point 87°C (melts immediately). b. Preparation of 3,4-methylenedioxybenzylthioethyl acetate. 18.08 g (0.08 mol) of the acid obtained above were dissolved in 160 ml of 1,2-dichloroacetate, 16 ml of anhydrous ethanol and 1.6 ml of concentrated H4SO4 were added. The batch was heated at reflux temperature for about 30 6 hours, cooled, the organic phase was decanted and the water formed was removed, washed with a dilute acid carbonate solution and then with water. The solution was then dried over Na2SO4 and the solvent was evaporated. 21 g of ethyl 3,4-methylenedioxybenzylthioacetate were obtained in the form of an orange oil. Efficiency 96%. c. Preparation of (3,4-methylenedioxyibenzylthio)acetohydroxamic acid. The product obtained above (0.085 mol) was added to a solution of hydroxylamine prepared from 8.76 g (0.126 mol) of hydroxylamine hydrochloride in 210 ml of methanol and 4.83 g (0.21 gram atom) of sodium in 210 ml of anhydrous methanol. The mixture was left overnight at room temperature, the methanol was evaporated, water was added, it was filtered over carbon, acidified with 3N H2O, the precipitate was filtered off and washed with water. 14.5 g of (3,4-methylenedioxybenzylthio)-acetohydroxamic acid were obtained, melting immediately at a temperature of 127-128°C. Efficiency 70%. so Example XXXIII, Dianethoxybenzylthio)acetohydrokisamic acid, a compound of formula 1, in which Rx is a group of formula 23, R2 and R3=H). a. Preparation of 3,4-dimethoxybenzylthioacetic acid. In a three-necked flask with a capacity of 55 liters, equipped with a magnetic stirrer and a reflux condenser, 13.07 g (0.1712 mol) of thiourea and 86 ml of water were placed. The whole was heated to a temperature of 50-60° C. and 32 g (0.1712 mol) of 3,4-dimethoxy-M benzyl chloride were introduced at one time. Heated to boiling and kept under these conditions for 15 minutes, the solution then became clear. Then it was cooled to 60°C and a solution of 27^52 g (0.688 mol) of NaOH in 43 ml of water was melted. W was heated again at reflux temperature for 30 minutes at 31 lfs m 3? The mixture was cooled and a solution of sodium chloroethane obtained by neutralizing 22.76 g of chloroacetic acid in 172 ml of water with 20.23 g of NaHCO3 was added dropwise at a temperature of 60-70°C. The mixture was heated at reflux for 30 minutes, cooled, filtered and acidified with 3N HCl. After recrystallization from toluene, 28.7 g of 3,4-dimethoxybenzylthioacetic acid were obtained. Efficiency 69%. Melting point 9-4°C (instant melting). b. Preparation of methyl 3,4-dimethoxybenzylthioacetate. 24.2 g (0.1 mol) of the above-obtained acid were dissolved in 200 ml of anhydrous methanol and 4 ml of concentrated sulfuric acid were added. The whole was refluxed for about 3 hours, the methanol was evaporated and the residue was diluted with ether. , the organic layer was washed with a dilute solution of sodium acid carbonate, then with water, dried over Na2SO4 and the solvent was evaporated. 24.2 g (94% yield) of the title compound were obtained in the form of an orange oil. c. Preparation of (3,4-diniethoxybenzylthio)aceitohytdroxamic acid. The ester obtained above (0.0945 mol) was added to a solution of hydroxylamine prepared from 9.95 g (0.143 mol) of hydroxylamine hydrochloride in 200 ml of methanol and 5.45 g (0.237 gram atoms) of sodium in 200 ml of anhydrous methanol. The mixture was left overnight at room temperature, the precipitate was filtered off, the methanol was evaporated, water was added, it was filtered over coal, acidified with 3N HCl, methylene chloride was added to the oil obtained, dried over Na2SO4, evaporated and taken up with ethyl acetate. After filtration and washing with ether, 16.9 g (70% yield) of the title compound were obtained, melting immediately at 78° C. Example XXXIV. [N-(p-chlorophenyl)-ureido]acetóhydroxamic acid, p-Cl C6H4NH-COUNH-CH2-C Proceeding essentially as described in Example XXVI, but replacing the phenyl isocyanate with p-chlorophenyl isocyanate, the following was obtained: N- Ethyl (p-chlorophenyl)ureidoacetate (yield 62%, melting point 160-461°C) and CRL 40517 after crystallization from a mixture of dimethylformamide-ethanol (1: 1 by volume). Yield 58%, melting point 220-222°C (with decomposition). Example XXXV. α-naphthylcarbamyl-α-ethohydroxamic acid (a compound of formula 1, in which Rx is a group of formula 24, R2 and R3 are hydrogen, code no. CRL 40518). a. Preparation of ethyl a-naphtha and naphtha. While stirring, a solution of 28.6 g (0.2 mol) of α-naphthylamine in 200 ml of anhydrous benzene was refluxed and a solution of 15 g (0.1 mol) of ethylmalonyl chloride in 50 ml of anhydrous benzene was added dropwise. The mixture was heated under reflux for another hour, the precipitate of α-naphthylamine hydrochloride was strained and washed with ether. The filtrate was washed with dilute HCl and water. It was dried, evaporated to dryness under reduced pressure, isopropyl ether was added, filtered and recrystallized from ethyl acetate-petroleum ether (1:1 by volume). 23.5 g (yield 91%) of the title compound were obtained, melting point 80-81°C. c. Preparation of CRL 40518. 19.3 g (0.075 mol) of ethyl 5α-naphytylltcarbamylacetate was treated with a hydroxylamine solution prepared from 5.6 g (0.08 mol) of hydroxylamine hydrochloride and 3.68 g of sodium in 250 ml of methanol. After 5 hours of contact, it was evaporated to dryness under reduced pressure, 400 ml of cold water were added, filtered on carbon, cold precipitated with 3N HCl, filtered and washed with water. After recrystallization from ethanol, CRL 40318 was obtained with a yield of 62%. Melting point 184-186°C (decomposition). 15 Example XXXVI. 1-<4-ibenzihydrylpiperazino)acetohydroxamic acid hydrochloride (compound of formula 1, in which Rx is a group of formula R2 and R3 are hydrogen, code no. 40536). 20 a. Preparation of 1-(4-benzhydrylpiperazino)-ethyl ethane. While stirring, a mixture of 17.5 g (0.07 mole) of benzylpiperazine, 12.76 g (0.07-5 mole) of ethyl bromoacetate, 9.8 g of ethyl bromoacetate was heated under reflux for 4 hours. (0.07 mol) potassium carbonate and 0.1 g potassium iodide in 180 ml ethanol. After overnight, it was evaporated to dryness under reduced pressure, 250 ml of ether were added, washed three times with water, extracted with 3N HCl, Na2CO3 was precipitated, filtered off, washed with water and dried. 21.5 g of the title compound were obtained, melting point 54-56°C. Efficiency 91%. b. Preparation of CRL 40536. A solution of hydroxylamine was prepared from 4.2 g (0.06 mol) of hydroxylamine hydrochloride and 2.5 g (0.11 gram atom) of sodium in 250 ml of methanol. The precipitate was filtered off and 16.9 g (0.05 mol) of the above product was added to the filtrate. The next day it was evaporated under reduced pressure, water, isoneutralized 3N HCl were added, extracted with methylene chloride, the extract was washed with water, dried, evaporated under reduced pressure, an ethanol solution of hydrogen chloride was added to the residue, the precipitate was filtered off and recrystallized from ethanol. . CRL 45-40536 was obtained with a yield of 421%, melting point 206--Ej08oC (with decomposition). Example XXXVII. N,N-diphenylureidoacetohydroxamic acid. (C6H5)2N-00-NH-CH2C(0)-NHOH code no. 40537. 50 a. Preparation of ethyl N,N-diphenylfureidoacetate. A sodium methanol solution was prepared from 4.6 g (0.2 gram atom) of sodium in 100 ml of anhydrous methanol. This solution was poured cold into a solution of 28 g (0.2 mol) of aminoacetate hydrochloride:5* ethyl in 150 ml of methanol. The sodium chloride formed was filtered off, the filtrate was evaporated to dryness under reduced pressure and 200 ml of benzene were added to the residue, dried over sodium sulfate, filtered and evaporated. 100 ml of benzene was added to the oily residue ff and a solution of 21 g (0.09 mol) of diphenylcarbamyl chloride in 50 ml of benzene was added dropwise at a temperature of 25-30°C. Stirred for another 4 hours at 30°C, washed with water, dried, evaporated to dryness under reduced pressure and recrystallized from ethanol.33 Nana-34 to obtain 20.8 g of the title product, melting point 106°C. Efficiency 78%. b. Preparation of CRL 40537. 18 g (0.06 mol) of the product obtained above were added to 250 ml of a methanolic solution of hydroxylamine prepared from 5.6 g (0.08 mol) of hydroxylamine hydrochloride and 3.45 g of sodium. After 24 hours of contact, it was evaporated to dryness under reduced pressure, water was added, precipitated with 3N HCl, washed with water, dried and recrystallized from diethylformamide to obtain CRL 40537 with a yield of 65%. Melting point 228-230°C (with decomposition). Example XXXVIII. (1-Athiamantyl)-carbamylacetohydroxamic acid (formula 27, code no. 40499). a. Preparation of ethyl acid. At a temperature of 20°C, stirring was carried out until 30.4 g (0.2 mol) of 1-adamaintinine was dissolved in 200 ml of anhydrous benzene, and then a solution of 15 g (04 mol) of ethyl malonate chloride in 30 ml of benzene. After standing overnight, the adamantamine hydrochloride was filtered off, washed with benzene, the filtrate was evaporated to dryness under reduced pressure, isopropyl ether was added and the precipitate was filtered off. The desired product was obtained with the yield 70*/o. Melting point 97-96° C. b. Preparation of CRL 40499. 15.1 g (0.057 mol) of the product obtained above was added to a methanol solution of hydroxylamine prepared from 4.2 g of hydroxylamine hydrochloride and 2.75 g of sodium in 150 ml of anhydrous methanol. Stirred for 4 hours at 25°C, evaporated, methanol under reduced pressure, 300 ml of water added, acidified with 3N HCl, the precipitate was filtered off, washed with water, dried and recrystallized from ethanol. CRL was obtained. 40499 with a yield of 57*/*, melting point 215-216°C (with decomposition). *0 Patent claim A method of preparing new acetohydroxamic acids of the general formula 1, in which R2 and R3 are the same or different and denote a hydrogen atom or an alkyl group with 1-6 carbon atoms, and Rj denotes an alkyl group with 1-6 carbon atoms. 6 carbon atoms, an N,N-disubstituted carbamyl group of the formula ZAN-CO-, in which Zx and Z2^a are the same or different and denote a cycloalkyl group 50 with 5r-6 carbon atoms, a phenyl group optionally substituted, in particular by one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, methylenedioxy, a halogen atom, an NHg, NO2 or CF3 group, a 3-hydantoinyl group of formula 2, in which Xj is a phenyl group optionally substituted, especially with one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, an NH2 or CF3 group or * halogen atom, Xj is a hydrogen atom, an alkyl group with 1-6 carbon atoms a or a phenyl group optionally substituted with one or more groups such as an alkyl group with 1-R4 carbon atoms, an alkoxy group with 1-4 carbon atoms, methylenedioxy, halogen atom, NHg group, NO| or CF3 a benzhydrylcanbonamide group of formula 3, in which each phenyl group may be substituted in particular by one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, halogen atoms, NHg groups, NO2 or CF3, a group of the formula ZjCHj-S-, in which Z3 is an aryl group, especially an α-naphthyl, 0-naphthyl or phenyl group, each of which may be substituted with one or more alkyl groups having 1-4 carbon atoms and alkoxy with 1-4 carbon atoms, a halogen atom, NH2, NOa or CF3 groups, a group with the formula Z4-A-, in which Z4 is a phenyl group, an a-naphthyl group, an 0-naphthyl group, in which each phenyl ring , may be substituted in particular by one or more groups such as an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, methylenedioxy, a halogen atom, an NHr NOa or CF3 group or an adrantyl group, and A means groups with the formulas -NHCO-, -N(alkyl C1-4)CO-, -N(cyclo-alkyl X! 5^)CO-, rCONH-, -CON(alkyl C1-4)-, -OON- -(cyclopalkII t^)-, -NHCONH-, -N^^COiNH-, group of formula 4, except that Z4 may be a benzhydryl group optionally substituted with one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, methylenedioxy groups, halogen atoms, NH2, NO2 or CF3 groups in each of the two phenyl rings of this group, when A is different from -CONH-, a group of the formula Z'4-NH-, in which Z'4- is a phenyl group preferably substituted with one or more halogen atoms, or R1 is a benzimidazolyl group of the formula 5, in which Z5 is an aryl group, especially phenyl, and the aryl group and ring (a) may be optionally substituted with one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, methylenedioxy, halogen atom, NHj, NO2 or CF3 groups or Rx means a tricyclic group (T) of the formula 6, in which Yx means a -OH^CH2-, or -S- group, Y2 means a -N- moiety, Y3 means -CH2- or -CO- group, and each phenyl ring may be substituted in particular by one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, methylenedioxy, halogen groups, NH^NO2 or CF3, optionally in the form of their metallic salts or their acid addition salts when Rx is a residue of a basic nature, characterized in that an acetic acid derivative of the formula 26, in which R1, R2 and R3 have the above-mentioned meanings ¬ no and Z is a halogen atom or an alkoxy group with 1-3 carbon atoms is reacted with. hydroxylamine.113 772 KrV~ NHO R3 Formula 1 X, N :0 0 Formula 2 Formula 4 // \s CH-CO -NH- Formula 3 vjy2-Y3- C6H, C6H3 6H5' ar o c I Ri-C-Cx -.0 NHO-M Formula 7 Formula 9 Cl-fCH2-S Cl Formula 11 N-CO- CHZCHS CJH,4—fO II o Formula 10 p-ClC6H< p-ClCfcl-^-j- K NHJI ii O Formula 12 ,*0 \x ^CH2-S - Cl ci' CU0-NH- Cl -NH-CO- Formula 16 CHA CHP-f VNH-CO- CH,0 Style 18113 772 Q-NH-CO- Style 19 Q"CHrS" xi Style 21 CH3Q- PL PL

Claims (1)

1. Patent claim A method of preparing new acetohydroxamic acids of the general formula 1, in which R2 and R3 are the same or different and denote a hydrogen atom or an alkyl group with 1-6 carbon atoms, and Rj denotes an alkyl group with 1-6 carbon atoms. 6 carbon atoms, an N,N-disubstituted carbamyl group of the formula ZAN-CO-, in which Zx and Z2^a are the same or different and denote a cycloalkyl group 50 with 5r-6 carbon atoms, a phenyl group optionally substituted, in particular by one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, methylenedioxy, a halogen atom, an NHg, NO2 or CF3 group, a 3-hydantoinyl group of formula 2, in which Xj is a phenyl group optionally substituted, in particular by one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, an NH2, or CF3 group or a halogen atom, Xj is a hydrogen atom, an alkyl group with 1-6 carbon atoms A or a phenyl group optionally substituted with one or more groups such as an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon atoms, methylenedioxy, a halogen atom, an NHg group, NO | or CF3 a benzhydrylcanbonamide group of formula 3, in which each phenyl group may be substituted in particular by one or more alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms, halogen atoms, NHg groups, NO2 or CF3, a group of the formula ZjCHj-S-, in which Z3 is an aryl group, especially an α-naphthyl, 0-naphthyl or phenyl group, each of which may be substituted with one or more alkyl groups having 1-4 carbon atoms and alkoxy with 1-4 carbon atoms, a halogen atom, NH2, NOa or CF3 groups, a group with the formula Z4-A-, in which Z4 is a phenyl group, an a-naphthyl group, an 0-naphthyl group, in which each phenyl ring , may be substituted in particular by one or more groups such as an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, methylenedioxy, a halogen atom, an NHr NOa or CF3 group or an adrantyl group, and A means groups with the formulas -NHCO-, -N(alkyl C1-4)CO-, -N(cyclo-alkyl X1-5^)CO-, rCONH-, -CON(alkyl C1-4)-, -OON - -(cyclpalkll t^)-, -NHCONH-, -N^^COiNH-, a group of formula 4, except that Z4 may be a benzhydryl group optionally substituted with one or more alkyl groups with 1^4 carbon atoms, alkoxy groups with 1-4 carbon atoms, methylenedioxy groups, halogen atoms, NH2, NO2 or CF3 groups in each of the two phenyl rings of this group, when A is different from -CONH-, a group with the formula Z'4-NH- , in which Z'4- is a phenyl group preferably substituted with one or more halogen atoms, or R1 is a benzimidazolyl group of the formula 5, in which Z5 is an aryl group, especially phenyl, wherein the aryl group and the ring (a) may be optionally substituted with one or more alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, methylenedioxy, a halogen atom, NHj, NO2 or CF3 groups or Rx denotes a tricyclic group (T) of the formula 6, in which Yx is a group -OH^CH2-, or -S-, Y2 is a moiety -N-, Y3 is a group -CH2-, or -CO-, and each phenyl ring may be substituted in particular by one or several alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, methylenedioxy, a halogen atom, NH^NO2 or CF3 groups, optionally in the form of their metallic salts or their acid addition salts when Rx is a residue of a basic nature, characterized in that the acetic acid derivative of formula 26, in which R1, R2 and R3 have the meanings given above and Z is a halogen atom or an alkoxy group with 1-3 carbon atoms, is reacted z. hydroxylamine.113 772 KrV~ NHO R3 Formula 1 -.0 NHO-M Formula 7 Formula 9 Cl-fCH2-S Cl Formula 11 N-CO- CHZCHS CJH,4—fO II o Formula 10 p-ClC6H< p-ClCfcl-^-j- K NHJI ii O Formula 12 ,*0 \x ^CH2-S - Cl ci' CU0-NH- Cl -NH-CO- Formula 16 CHA CHP-f VNH-CO- CH,0 Formula 18113 772 Q-NH-CO- Formula 19 Q"CHrS " xi Model 21 CH3Q- PL PL