SU910114A3 - Process for producing n-acyl-2-hydroxy1,3-diaminopropanes - Google Patents

Abstract

Acylated diaminopropane derivs. of formula (I) and their acid addition salts are new: In (I) R1 is 1-20C alkyl, 2-7C alkenyl, 1,3-pentadien-1-yl, 3-7C cycloalkyl or 4-8C cycloalkylmethyl (both opt. substd. by CH3), 5-7C cycloalkenyl or 6-8C cycloalkenylmethyl (both opt. substd. by CH3), adamantyl, adamantylmethyl, benzyl or phenethyl (both opt. 3,4-dimethoxy substd.), phenyl substd. by 2 CH3O's, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-ethylenedioxy, 2-F, 4-F, or by 2-CF3, or R1 is 2-, 3- or 4-pyridyl, or furyl. R2=H, 1-3C alkyl or methoxyethyl. R3 and R4 = H, halo, 1-3C alkyl or alkoxy. The following cpds. are excluded: (a) R1=3,4-dimethoxy 2-F-, or 2-CF3-phenyl or 2-furyl; R2=CH3; R3=H and R4=4-Cl; (b) R1=3,4-dimethoxyphenyl; R2=CH3 and R3+R4 = 3,4-dimethoxy). The cpd. are made e.g. by reacting the corresp. unacylated diamine with a reactive deriv. of R1COOH. (I) are useful for treating ulcers and have no effects on gastric secretion or the CNS. The usual adult dose is 150-450 mg (orally) per day. The cpd. N-acetyl-N2-methyl-N2-(4-chlorophenyl)-2-hydroxy-1,3-diaminopropa- ne has 7-day oral LD50 in mice of 2.26g/kg.

Description

() METHOD OF OBTAINING Y-ACYL-2-OXI-1, 3-DIAMINOPROPANES

The invention relates to a process for the preparation of new M-acyl-2-hydroxy-1,3-diamknopropanes which have biological activity and can be used in medicine.

A known method for the preparation of N-acyl-2-hydroxy-1, 3 diaminopropanes by the interaction of the corresponding epichloroRi-CONH-CHj is, in which R is a linear or branched alkyl radical containing from 1 to 20 carbon atoms, a linear or branched alkenyl residue containing from 2 to 7 carbon atoms, a 1,3-pentadiene-1-yl residue, a cycloalkyl or cycloalkylmethylene residue C, and these residues contain in some cases methyl, cycloalken-or cycloalkenmehydrins with substituted aniline 1 as a substituent.

The purpose of the invention is to obtain new compounds with valuable effect in the treatment of ul.

This goal is achieved by the fact that in the method of producing K-acyl-2. -oxy-1,3 diaminopropane General formula

Kz he

15 tyleno residue, which, if necessary, may be replaced by a methyl residue, an adamantyl or adamantylmethylene residue, a phenylmethylene residue, a phenylethyl 20 residue 3-dimethoxyphenylmethylene residue 3 | dimethoxy- nylethylene residue 3,4 methylenedioxyphenyl residue, Z. Ethylenedioxyphenyl residue, α-fluorophenyl, 2-fluorophenyl, 2-trifluoromethyl39 phenyl residue, dimethoxyphenyl residue, 2-pyridyl, 3 pyridyl, -pyridyl residue, 2-furyl; R is hydrogen, linear or branched C / (is an alkyl residue, a methoxyethyl residue; R, and R. are the same or different and mean hydrogen, halogen, C., alkyl or Cj-alkoxy, except for the fact that R means 3 Aimethoxyphenyl , 2-fluorophenyl 2-trifluoromethylphenyl, and Rn means hydrogen, methyl or ethyl, one of R Il Rj means -chloro, A-bromo, 4-fluoro, -methyl, -methoxy-residue or R and R means 3 -dimethoxy- the residue or R is 2-furyl, H2-methyl, and one of RO, and a chlorine residue, is a compound of the general formula R -CO-NH-CH2-Z II where R has the above values of f means -CH (OH) Cfi2 - halo gene or - CH - CH NO / Introduced into interaction with aniline of the general formula /: HN- (I K where R, 2, R о and R, have the above values, in the presence of a solvent at a temperature of from 15 to of the desired product in free form or as a salt. In the case when Z is CH (OH), the process is carried out in the presence of an acid-binding agent, namely potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, P and meper 1o To a solution of 39.5: g of 2-phenyl-5-chloromethyloxazolidine in 150 ml of chloroform and 16 ml of pyridine is added When stirring was added dropwise 15.7 g of acetyl chloride at -40 solution was allowed to warm to room temperature. After H h, 100 ml of concentrated hydrochloric acid is added to the mixture. After vigorous stirring, the separated aqueous phase is diluted with water to double volume and saturated with sodium chloride. After extraction with methylene chloride, after purification and removal of the solvent, 19.7 g of M-acetyl-2-hydroxy-3-chloro-1-aminopropane is obtained in the form of an oil, which can be further processed with IS g H-acetyl-2- hydroxy-3-chloro-1-aminopropane is added to 6.1 g of powdered potassium hydroxide in 200 ml of dioxane. After the addition of 7 g of 4-chloroaniline, the solution is stirred at room temperature for 1 hour, then filtered and the solvent is evaporated in vacuo. The oily residue is dissolved in a small amount of ethanol. After the addition of ether, 8 g of C-acetyl-N2- (A-chlorophenyl) -2-hydroxy-1,3-diaminopropane, Topl crystallizes. 123-124 C. Example2. In Example 1, 1.7 g of N-acetyl-2-hydroxy-3-chloro-1-aminopropane, 0 g of 4-chloroaniline are dissolved in 50 ml of isopropanol and stirred with 10 ml of a 30% aqueous solution of sodium hydroxide at room temperature. temperature for k h. The reaction mixture is diluted with toluene, the organic phase is separated, washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent in vacuo, an oily residue is obtained. This residue is treated with ether to separate unreacted 4-chloroaniline. From ethanol / ether mixture, crystallizes as described in Example 1, 3.0 g of M-acetyl | -N - (it-chlorophenyl) -2-hydroxy-1,3 diaminopropane, m.p. 123-12 0. Freeze. 6.8 g of M-acetyl-M - (4-chlorophenyl) -2 hydroxy-1,3-diaminopropane prepared according to Example 1 is heated in 5 ml of formic acid with 27 ml of a 36% aqueous solution of formalin for 3 hours in water bathhouse Pour over ice for processing. Brought to alkaline with dilute sodium hydroxide solution, the solution is extracted with chloroform. The organic phase is separated, washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent in vacuo, an oily residue is obtained, which crystallizes from ethyl acetate / ether. Get +, 8 g of N-acetyl-M2-methyl-M2- (-chlorophenyl) -2-hydroxy 1, 3 diaminopropane, so pl. 85-86C, Example. 3.0 g of N-acetyl-M - (Achlorophenyl) -2-hydroxy-1,3-diaminopropane prepared according to Example 1 is stirred in 45 ml of dioxane with 3.7 g of sodium bicarbonate in 7.5 ml of water and if, ml of dimethyl sulfate for 30 min at Mix with 10 ml of 5 10% sodium hydroxide solution and maintain the temperature for a further 10 minutes. The solvent is then removed in vacuo and the material is treated with chloroform. After treatment, 2.0 g of H-acetyl-M-methyl-H - (-chlorophenyl) -2-hydroxy-1,3-diaminopropane are obtained, m.p. 85-86 s. EXAMPLE 5. If 19I8 g of 2-phenyl-5-chloromethyloxazolidine are introduced, with measure 1 s T, g of cyclohexylcarbonyl chloride in 8 ml of pipyridine and 100 ml of chloroform, then they are obtained after crystallization from ether / petroleum ether, Qg cyclohexylcarbonyl-2-hydroxy-3-chloro-1-aminopropane, TopPl.90 91 C. 4.4 g of the amide thus obtained are reacted according to the example of 2.2 g of aniline in 50 ml of dioxane with the addition 1.3 g of potassium hydroxide. 3.0 g of M-cyclohexylcarbonyl-M -pheNIL-2-OXY-1, 3-diaminopropane are obtained. m.p. I S-ISO G crystallized from ethanol. Example 6. 1g of N-methylaniline is heated with 2.0 g of N-cyclohexylcarbonyl-2-hydroxy-3-chloro-1-aminopropane for 2 hours at, then cooled, dissolved in chloroform and washed with dilute aqueous sodium hydroxide solution. After treatment as indicated in Example 1, an unrefined oil is obtained, which is purified by chromatography on an alumina column at the activity lie stage using toluene-methylene chloride. From this acetate, l, i g of N-cyclohexylcarbonyl-N2 -methyl-N2-phenyl-2-oxy-1,3-diaminopropane are obtained, m.p. 83-85 G. Example. 2.2 g of N-cyclohexyl carbonyl-2-hydroxy-3-chloro-1-aminoprop7 on and 1, 3-N-methylaniline were added, in accordance with Example 5, with 0.7 g of potassium hydroxide in 50 ml. di ocean. 2.3 g of N -cyclohexylcarbonyl-H2-methyl-M2-phenyl-2-hydroxy-1, 3 diaminopropane are obtained from the benzene / petroleum ether mixture, mp. C. EXAMPLE 8. If N-cyclohexylcarbonyl-2-hydroxy-3-chloro-1-aminopropane is introduced in conjunction with Example 1 with 3-chloro-2-methylaniline, then Nyf-cyclohexyloxycarbonyl- N2- (3-chloro-) 2-methylphenyl) -2-hydroxy-1,3 Diaminopropane, m.p. 123С. 146 EXAMPLE 9 6.0 g of N-cyclohexylcarbonyl-2-hydroxy-3-chloro-1-aminopropane are stirred in 80 ml of ether with 1.8 powdered potassium hydroxide for 18 hours at room temperature. After adding sodium sulfate, the solution is filtered and concentrated in vacuo. When cooled, precipitated as crystals, 5 g of M-cyclohexylcarbonyl-2,3-epoxy-1-aminopropane, m.p. US-BO C. 2.5 g of the epoxide thus obtained are heated with 1.5 g of N-methylaniline and 0.8 g of glacial acetic acid for 5 hours at. Then the reaction mixture was dissolved in chloroform, washed with an aqueous solution of sodium hydroxide. From ethyl acetate, 2.6 g of N-cyclohexylcarbonyl-M -methyl-L, -phenyl-2-hydroxy-1, 3-diaminopropane are obtained in the form of crystals, mp.8385 C. In contrast to Example 9, 1.8 g of M-cyclohexylcarbonyl-2, 3-epoxy-1-aminopropane and 1.1 g of N-methylaniline are heated under reflux in 50 ml of isopropanol for 6 hours. After removing the solvent in vacuo, example 1 is obtained 6 g of N-cyclohexylcarbonyl-N2-methyl-N2-phenyl-2-oxo-1, 3-diaminoprphene crystallized from ethyl acetate, m.p. 83-85C. Example 11. According to example 1, prepared from 2-phenyl-5-chloromethyloxazoline c 3, dimethoxyphenyl-. N- (3,4-dimethoxyphenylacetyl) -3-chloro-2-hydroxy-1-aminopropane acetyl chloride, m.p. 128-130C. According to Example 9, from the Negro, N- (3, -dimethoxyphenylacetylene-acetyl) -2,3-epoxy-1-aminopropane idrofuran is obtained in benzenetetrag, t, pl. . 5.2 g of the epoxy compound described above are heated with 1, 2. g of acetic acid and 2.3 g of M-methyl-4-chloroaniline c. for 5 m at 60 ° C. After treatment as indicated in Example 9, an oil is obtained which, after reacting with p-toluenesulfonic acid and after digesting with petroleum ether, crystallizes as a salt of p-toluenesulfonic acid from acetone. Teach 6.0 g of p-toluenesulfonate - (1,3-DImethoxyphenylacetyl) -M / -megopo- (A-chlorophenyl) -2-hydroxy- | 1.3 Diminopropane, m.p. 170-172 S. 9 Example 12: According to Example 1 of 9.1 g of M-furoyl-2-hydroxy-3 chloro-1-aminopropane (mp. 73 C) with 2.6 g of potassium hydroxide in 130 ml of tetrahydrofuran 7.0 N-fupoyl-2,3-epoxy-1-aminopropane is obtained, which is then reacted with k, () g 3 fluoroaniline and 2.7 g of acetic acid without purification as an oil. After the treatment, 6 g of N, α-furoyl-MD- (3-fluoroaniline) -2-hydroxy-1,3 diaminopropane are obtained in the form of an oil. Example 13. N-furoyl N-2 - (3-fluoroaniline) -2-hydroxy-1, 3-diaminopropane or Example 3 is heated in 31 ml of formic acid with 15.5 ml of Zb-aqueous formalin solution for 3 m in a water bath and process. Get 2.2 g M / FUROIL-M-methyl-M - (3-fluorophenyl) -2-OXI-1, 3-diaminopropane, t, pl. 8688 C, in the form of crystals from a mixture of isopropanol / ether. Example 1. To a solution of 15.0 g of 2-phenyl-5-chloromethyloxazolidine in 200 ml of chloroform and 6 ml of pyridine at C and 15.2 g of dropping, with stirring, 3, -dimethoxybenzoyl chloride in 0 ml of chloroform. The solution is heated to room temperature. After the It expires, 20 ml of concentrated hydrochloric acid is added, the phases are mixed well for 10 minutes and separated. The separated aqueous phase is diluted twice with water and saturated with common salt. After extraction with chloroform, after drying and removing the solvent, 15.0 g of H- (3, -Dimethoxybenzoyl) -3-chloro-2-hydroxy-1-aminopropane are obtained in the form of an oil, which can be reacted further without further purification. Crystallized from ethanol with toluene, the substance melts at. To 1.8 g of finely powdered potassium hydroxide in 160 ml of dioxane was added 8.2 g of the obtained substance. va and 4.0 g of 2-chloraniline. After stirring for 14 hours at room temperature and filtering, the solution was evacuated, the remaining residue was treated with chloroform and washed with water. After drying and removing the solvent, 5.1 g of (3,4-dimethoxybenzoyl) -N, - (2-chlorophenyl) -2-hydroxy-1, 3 diaminopropane 0 is obtained as an oily residue, which crystallizes from acetone, m.p. 1141164. P p and /. ep 15. 3.5 g of M- (3,4-dimethoxybenzoyl) -2-hydroxy-3-chloro-1-propylamine in 250 ml of benzene is mixed with 0.8 g of finely ground potassium hydroxide for 16 hours at room temperature . The solution is filtered and evacuated. After crystallization from toluene, 2.5 g of (3,4-dimethoxybenzoyl) -2,3-epoxy-1-aminopropane are obtained, m.p. 108-111 ° C. 4-Bromo-n-propylaniline, then dissolved in chloroform, is added. The reaction mixture is washed with water, dried over sodium sulfate, and filtered. After removal of the solvent, 2.6 g of oily NJ- (3,4-dimethoxybenzoyl) -N2-propyl-N- (4-bromophenyl) -2-OXY-1, 3-diaminopropane, crystallized from a mixture of acetone and petroleum ether, are obtained. m.p. 12b-128c. PRI me R 1-6. 4.2 g of M- (3-chloro-2-oxipropyl) -3,4-dimethoxybenzamide in 75 ml of dioxane are stirred for 6 hours at 30-40 ° C with 3.0 g of 2-bromo aniline and 1.0 g powdered potassium hydroxide. The filtered solution was evacuated and the remaining crude oil was filtered through alumina of activity II with a mixture of chloroform and ethyl acetate. 2.7 g of (3,4-dimethoxybenzoyl) -2 -2-bromophenyl-2-hydroxy-1,3 diaminopropane crystallizes from a mixture of acetone and petroleum ether, mp.114Pb C. Approx. 17o 4.1 g (3,4-dimethoxybenzoyl) -M-phenyl-2-hydroxy-1, 3-diaminopropane in 19 ml of formic acid and 10 mm of Zb-aqueous formalin solution is heated for 3 hours in water Mixed with ice, the reaction solution was basified with a dilute sodium hydroxide solution and the substance was isolated from chloroform. 3.3 g of (3,4-dimethoxybenzoyl) -N -methyl-N-phenyl-2-hydroxy-1, 3-diaminopropane crystallizes from etr1H acetate, mp 141142 ° C. Example 18: 3.4 g of N., - (3,4-dimethoxybenzoyl) -M2-phenyl-2-hydroxy-1, 3 diaminopropane is dissolved in 60 ml of dioxane, mixed with 2.5 g of bicarbonate. sodium in 5 ml of water and after adding 2.7 ml of dimethylsul99

the veil is heated for 60 hours at 60-70 ° C. The solution is then mixed with 60 ml of a 15% aqueous sodium hydroxide solution, the solvent is removed in a vacuum and the substance is isolated from chloroform. Obtain 2.0 g of (3, -dimethoxybenzoyl) -M2-methyl-MD-phenyl-2-OXI-1, 3 diaminopropane, so pl. .

PRI me R 19. According to Example I, 5.6 g of M- (3-chloro-2-hydroxypropyl). dimethoxybenzamide is reacted with 1.2 g of potassium hydroxide and 2 g of aniline in 350 ml of benzene. 3.1 g of isolated (3, -dimethoxybenzoyl) -N-phenyl-2-hydroxy-1, 3-diaminopropane as a crude oil according to example 15 in 30 ml of dioxane are reacted with 1 ml of diethyl sulfate and 2.7 g sodium bicarbonate in 5.6 ml of water. 1.3 g of NJ- (3, -dimethoxibenzoyl) -N-ethyl-N 2Phenyl-2-hydroxy-1, 3 diaminopropane are obtained, which crystallize from ethyl acetate, m.p. .

Example 20. 2, And g M- (2,3-epoxypropyl) - 31-dimethoxybenzamide. and 1.2 g of N-methylaniline in 30 ml of toluene is refluxed for 5 hours. The reaction solution is then concentrated in vacuo to dryness and the remaining residue is filtered through alumina of activity II with a mixture of chloroform and toluene. Get 2.2 g (3, Dimethoxybenzoyl) -M2-methyl-Ml-phenyl-2-hydroxy-1, 3 diaminopropane, crystallized from a mixture of acetone and petroleum ether, so pl,

PRI me R 21. According to Example 15, 1 +, 5 g of N- (3, -methylenedioxybenzoyl) -2-hydroxy-3-chloro-1-aminopropane, m.p. 128-130 ° C are introduced into the reaction with 3.5 g of potassium hydroxide in 600 ml of benzene. The reaction solution is then dried over sodium sulfate, filtered and concentrated in vacuo.

10.5 g of M- (3, -methylenedioxybenzoyl) -2,3-epoxy-1-aminopropane are obtained from the concentrated solution, m.p. 117-119C. 2.2 g of the obtained epoxide, together with 1.5 g of chloro-M-methylaniline and 1 ml of glacial acetic acid, are heated for 6 hours at. After treatment according to Example 15, 2.0 g, α-methylenedioxybenzoyl) -Y methyl-MS C-chlorine is obtained.

phenyl) -2-hydroxy-1,3 diaminopropane, m.p. 1tO-1 3C, crystallized from a mixture of methylene chloride and ether

EXAMPLE 22. According to Example 15, 3, + - methylenedioxybenzoyl (-chlorophenyl) -2-oxy-1, 3-diaminoprphenol, t are obtained from N- (2.3 epoxypropyl} -A-methylenedioxybenzamide and 4-chloroaniline) mp 158-1 boc

PRI me R 23. According to Example 17, 9.8 g, (3, -methylenedioxybenzoyl) (4-chlorophenyl) -2-hydroxy-1,3-diaminopropane is converted into 5 ml of formic acid and 27 ml of B; formalin. The isolated substance crystallizes from a mixture of methylene chloride and ether. Obtain 1 g of (3, -methylenedioxybenzoyl) -M, 2-methyl- {-chlorophenyl) -2-hydroxy-1,3 Diaminopropane m.p. l40-lit3C.

PRI me R 2s. According to examples 14-23 from M-dimethoxybenzoyl- (3it-methylenedioxybenzoyl) or (3,4-ethylenedioxybenzoyl) -3-chloro-2-hydroxy-1-aminopropanes, the corresponding M-acyl-2-hydroxy-M2-phenyl- 1, 3-diaminopropanes or -acyl-2-hydroxy-Ml-alkyl-M-phenyldiaminopropanes, and under certain conditions, the first acyl compounds mentioned can be alkylated.

EXAMPLE 25 If 2-chloromethyl-5-phenyloxazolidine according to an example is reacted with 2-fluorobenzoyl chloride, then M- (3-chloro-2-hydroxypropyl) -2-fluorobenzamide, m.p. 77 78С „3.9 g of the obtained substance according to example 14 is introduced into interaction with 2.0 g of N-propylaniline and 1.0 g of potassium hydroxide in 50 ml of dioxane and treated. 1.9 g of N. - (2-phterobenzoyl) -N2 propyl-N, - phenyl-2-hydroxy-1,3-diaminopropane, ToPL are obtained. 9b-97 C, crystallized from a mixture of isopropanol with cyclohexane.

Example 26. According to Example 15, 2.3 g of N- (3-chloro-2-hydroxypropyl) -2-fluorobenzamide is reacted with potassium hydroxide to produce N- (2,3-epoxypropyl) -2-fluorobenzamide. The oil obtained without purification, together with 1.1 g of N-propylaniline in 50 ml of toluene, is refluxed for 6 hours. After removing the solvent from isopropanol with cyclohexane, 1.6 g of (2-fluorobenzoyl) -M1-poopyl M crystallizes. .2.feM91 nile-2-hydroxy-3-hydroxy-1, Zdiaminopropane t pl. 9b-97s. Example 27. According to Example 25, reacting M- (3-chloro-2-oxypropyl) -2-fluorobenzamyl with aniline to give (2-fluorobenzoyl) -N2-phenyl-2-hydroxy-1, 3 diaminopropane as an oil. Example 28. 2.9 g (2-fluorobenzoyl) -M2.phenyl-2-hydroxy-1.3 diamino propane in 15 ml of dioxane with 3.0 g of sodium bicarbonate in 6 ml of water and C, m diethyl sulfate is heated for 30 minutes at. After treatment according to Example 19, 1.5 g of NJ - {2-fluorobenzoyl) -M2-ethyl-M2-phenyl-2-OXI-1, 3 diaminopropane are obtained, m.p. C, crystallized from a mixture of isopropanol with cyclohexane. EXAMPLE 29. According to examples, from the corresponding Ny- (2-fluorobenzoyl) (-fluorobenzoyl) or (2-trifluoromethylbenzoyl) -3-x op-2-hydroxy-1, 3-diaminopropanes, the corresponding N-acylN 2 -phenyl-2-hydroxy-1,3 diaminopropanes or M (α-acyl-M2-alkyl-M2-phenyl-2-hydroxy-1, 3-diaminopropanes, the first being alkylated under certain conditions. EXAMPLE 30. If 2-chloromethylphenyloxazolidine according to Example H is reacted with 2-furancarboxylic acid chloride, then M-furoyl-3 chloro-2-hydroxy-1-aminopropane is obtained, mp C. According to Example 15 of 20, t g described but The above compound in 300 ml of tetrahydrofuran with 6.0 g of potassium hydroxide gives 10 g of the amide of M- (2,3-epoxypropyl) -furan-2-carboxylic acid as an oil. 8.2 g of the obtained substance is reacted with 3 , 2 ml of glacial acetic acid and 8.2 g of 4-bromoaniline and treated according to Example 15. 6.0 g of N -pyroyl-N2- (-bromophenyl) -2-hydroxy-1 crystallized from the crude oil upon trituration with ether, 3 diaminopropane from a mixture of ethyl acetate and petroleum ether, t „pl. 132-133C. Example 31., 8g of N-furoyl-S - (4-bromophenyl) -2-oxy-1,3-diaminopropanol in 27.0 mL of formic acid and 13.5 ml of Zb solution of formalin are heated for 3.5 hours in a water bath. The reaction mixture poured on ice is treated according to Example 17. 3.3 g of N-furoylmethyl-N - {-bromophenyl) -2-hydroxy-1,3-diaminopropane crystallized from isopropanol are obtained, m.p. 10b-107 C. Pr and mr 32. According to examples 30 and 31, the corresponding N is obtained from H-furoyl-3-chloro-2-hydroxy-1, 3 diaminopropanes; -Fypoyl-N 2 -alkyl-M 2 -phenyl-2-hydroxy-1,3-diaminopropanes or N-phyroyl-N / -phenyl-2-oxy-1,3-diaminopropanes, the former being alkylated under known conditions. The melting points of the obtained new compounds are given in Tables 1-3. The novel compounds have a pronounced, directly suppressive ulcer activity with a good therapeutic spectrum without affecting gastric secretion. Their use restores the physiological balance in the mucous membrane damaged by the disease. Description of pharmacological research methods. Acute toxicity. The acute seven-day toxicity is determined after a single oral administration of an NMPI white mouse orally on an empty stomach. The LD 5-0 values are calculated via EDV by Probtt aH analysis (Cavalli-Sforra L., Fischer Gustav-Verlag. Stuttgart, 1964, S.I 53). Test on induced indometating star in rats. The test was carried out modified according to U.Jahn and R.W.Adrian (Arzheim Forsh Drug-Res ,,, 1969, 19, S 36). The test substance was administered to at least 6 male rats weighing 170,200 g in a volume of 0.5 ml of suspension medium (100 g animal weight / oral) The control animals receive a corresponding volume of suspension medium. One hour after administration, 20 mg / kg indomethacin is administered orally to the rats 0.5 ml of suspension medium (10 g of animal weight) in order to cause ulceration. Animals are killed 2k h after administration of indomacin. Evaluation is carried out modified by O. Munchow (Arzheim Forseh trug-Res. 195, S. ). Calculate the mean and standard the deviation of the number of stars and they will determine the inhibitory effect of the subject and

1391

Standard substances as a percentage of the ratio to the control.

Effect on gastric secretion of rats administered under anesthesia pH measurement)

To study the effect of a substance on gastric secretion, a modified M, N test method is used. Chosh and HOShild.CBrlt.J.Phermacol, 1958, 13 5). The study was conducted on anesthetized male rats weighing 200-230 g. For this, the stomachs of rats through the cardinal and pyloric catheter perfusion 1 ml / min. N. + Ltd. sodium hydroxide solution. The pH of the perfusate, which exits the stomach through the pyloric catheter, is measured using single-rod measuring chains and continuously recorded. To determine the control value after the expiration of the preliminary 20 minutes, intraperitoneal injection of 10 mg / kg acetylcholine is carried out. The reference value is set to 100. After reaching the baseline again, the test substance is administered intraduodenally. For evaluation using the Simpson's rule, the numerical value of intergall surfaces is determined.

Compound

N - (2,3 Dimethoxybenzoyl) -M-methyl-H2 - (-chlorophenyl) -2-hydroxy-1,3 diaminopropane

N - {2, -dimethoxybenzoyl} -M2-methyl-S, - (-chlorophenyl) -2-hydroxy-1,3 diaminopropane

N - (3,5-Dimethoxybenzoyl) -M -methyl-M - (4-chlorophenyl) -2-hydroxy-1,3 diaminopropane

N - (3, -dimethoxybenzoyl) -M -methyl-S - (4-isopropylphenyl) -2-hydroxy-1,3-Diaminopro

N - (3, t-dimethoxybenzoyl) -N2 -methyl-N2- (3, -dichlorophenyl) -2-hydroxy-1,3 Aiaminoprop

Nyf - (3, "-dimethoxybenzoigg) -NY-isopropylphenyl-2-hydroxy-1, 3-diaminopropane

 (3, -ethylene-dioxibenoyl) -H-methyl- (4-chlorophenyl) -2-hydroxy-1,3 diaminopropane

(2,6-dimethoxybenzoyl) -M2 methyl- (4-chloro-phenyl) -2-hydroxy-1,3, diaminopropane

Flachen-lntegral. The suppression of secretion is determined from the differences between the surfaces before and after the administration of the substance. For example, the following new compounds are being investigated according to the methods described: 1) (3,4-dimethoxy6-benzoyl) (2-chlorophenyl-2-hydroxy-1, 3 diamino, propane;

10 2) (3, -Dimethoxibenzoyl-N "-methyl H - (3, -Dichlorophenyl) -2-OXI-1, 3-diaminopropane; H) (3, -Dimethoxybenzoyl) -M, -propyl-L2 .- { -chlorophenyl) -2-hydroxy-1,315 diaminopropane;

(k) K - (2-fluorobenzoyl) -M, -methyl-Ni- (3, -Dichlorophenyl) -2-hydroxy-1,3-Diaminopropane;

5) H-furoyl-M -methyl-M -C-isopro-2-pilphenyl) -2-hydroxy-1,3-diaminoprop en, As standard substances,

6) Atropinsulfate;

7) Sucus lignirital.

5 The research results are summarized in table, k,

From the obtained data it follows that the substances obtained by the proposed method with the absence of suppression of the scientific research institute of gastric secretion have a good antiulcer effect. Table 1

M.p.

96-97 132-13 128-130 107-108 138-1А2 103-10 186-187 140-J2

15910116 (3, Dimethoxybenzoyl) -Y2 (2-methylphenyl) -2-hydroxy-1,3 diaminopropane (3, -Dimethoxybenzoyl) -M2- (3 methylphenyl) -2-hydroxy-1,3-diaminopropane N. (- ( 3, Dinotoxibenzoyl) -N2 .- (3 chloro-2-methylphenyl) -2-hydroxy 1,3-diaminopropane hydrochloride (3,4-dimethoxybenzoyl) -M2- (2,6-dimethylphenyl) -2-hydroxy-1,3- Diaminopropane (3, -Dimethoxybenzoyl) -M, -methyl-I2- (3phenyl) -2-hydroxy-1,3-diaminopropane

Connection.1T.pl., C

.. tab. 12

Table 2 122-125 96-100 158-163 99-101 155-159

17

Compound

N.f -pypoyl N- (4-chlorophenyl) -2-hydroxy-1, 3 diaminopropane

M-furoyl-N2 - (- methoxyphenyl) -2-hydroxy-1, 3 diaminopropane

Mh | FUROIL-S-methyl-H2 (-fluorophenyl) -2-OXI-1, 3-diaminopropane

M-furoyl-M2-methyl- 42- (-methylphenyl)

18 Table 3

M.p. WITH

1 5-127 113-116 Oil

150

10,000

Table

peritoneal

Claims (2)

300 19 Claim 1. Investigation of M-acyl-2-hydroxy-1, 3-diaminopropanes of the general formula Rl-CONIt-CIli-CK-CHz N- / II and h. it is RJ V in which R is a linear or branched alkyl radical containing from 1 to 20 carbon atoms, a linear or branched alkenyl residue containing from 2 to 7 carbon atoms, 1.3 pentadiene-1-yl residue, cycloalkyl or cycloalkylmethylene residue , in which these residues contain in some cases methyl cycloalkene or cycloalkenmett as a substituent, an ilen residue C, which, if necessary, can be replaced by a methyl residue, an adamantyl or adamantylmethylene residue, a phenylmethylene residue k, phenylethylene residue, 3, α-dimethoxyphenylmethylene residue, 3, α-dimethoxyphenylethyne residue, 3 methylene dihydroxymethyl residue, 3, "ethylenedioxyphenyl residue, α-fluorophenyl, 2-fluoro-phenyl, 2-trifluoromethylphenyl residue, -phenyl, 2-fluoro-phenyl, 2-trifluoromethylphenyl residue, -phenoryl, 2-fluoro-phenyl, 2-trifluoromethylphenyl residue, -phenoryl, 2-fluoro-phenyl, 2-trifluoromethylenphenyl, , 3 pyridyl-, 4-pyridyl residue, 2-furyl; R2 is hydrogen, linear or branched alkyl residue, methoxyethyl residue; Ro, and R4 are the same or different and are hydrogen, halogen, C., alkyl or C / t--, alkoxy, except that R osHachchaet 3, -dimethoxyphenyl, 2-fluorophenyl 91 20 2-trifluoromethylphenyl, and Rj is hydrogen, methyl, or ethyl, one of R3 and R4 is -chloro, -bromo, -fluoro, -methyl, -methoxy, or R and R are 3, -dimethoxy, or R. is 2-furyl, R -methyl, and one of the R- and R 4-chloro residue characterized in that the compound of the general formula 11 CO -NH-CH -Z, where R has the above values, Z-CH (OH) or CH-CH9 is introduced in the interaction with aniline of General formula III </ BR> where R2, R and R are as defined above, in the presence of a solvent at a temperature of from 15 to, followed by isolation of the desired product in free form or as a salt, 2. The method according to 1, about 1 t h and (a) 0 ° and the fact that, in the case when Z has the value t: CH (OH), the process is carried out in the presence of an acid-binding agent, namely potassium carbonate , sodium carbonate, hydroxides, sodium hydroxides.Sources of information taken into account in examination 1, laid out in the application of the Federal Republic of Germany 2221558, CL 12 р 10,01, 1973.