SU657016A1 - 1,2-hydrosilamineketone derivatives possessing neutrotropistic activity - Google Patents

Description

Compounds of formula 1 can also be prepared by reacting 1,2-haloketones with anti-benzaloxime followed by hydrolysis of the intermediate H- (2-keto-substituted) -ict-phenylnitrons formed according to the scheme ° O CHj

R-C-C-CH HON - CHC H5-.R-c-c-N CHC, H. five

I CH; BEFORE

 R-C-C -NHOH-HC

i.H3

1,2-Haloketones are easily obtained by halogenating the corresponding ketones synthesized by the reaction of substituted benzenes with Chlorohydric iso-butyric acid according to Friedel-Crafts.

Example 1. N- (3-Oxo 2-methyl-3-p-methylphenylpropyl-2) -hydroxylamine hydrochloride {Ha}.

Chilled solutions 31 (0.45 mol) of hydroxylamine hydrochloride in 75 ml of water with a solution of 85 g (2.06 mol) of NaOH in 150 ml of water are poured. The resulting solution is diluted with 1 l of methanol, the precipitate of sodium chloride is filtered. The filtrate is stirred is added over a period of 1.5 hours (O, -6 mol) P methyl-cC-bromoisobutyrophenone in 200 ml of methanol, the mixture is boiled. 6 The reaction mass is evaporated, the precipitated oL-hydroxylaminoxime is filtered,

The crude C-hydroxylaminocox Pa is mixed with 60 ml of concentrated JCl and boiled for 30 minutes. The solution is cooled and the precipitated sab-hydroxylamino ketone 1a hydrochloride is filtered off. Yield 89%, mp 137-139 ° C (from acetonitrile), W spectrum H (KVG-): 1,675 cm () s PMR spectrum (fljO): 1.97 (6H, hem.-SJ 2.43 (ZN CHj aromatic ring), 7.55 (4H, complex signal of aromatic protons).

Found,%: C 57.52; I 7D1; N5.83j se 15.38,

with H gNOgce.

Calculated,%: C 57.30; H 7.02; N6.10; All D5,44.

Example 2. M- (3-Oxo-2 methyl-3-P-chlorophenylpropyl-2) -hydroxylamine hydrochloride (16).

Under the conditions of Example 1 p-chloro-dL-bromoisobutyrophenone, hydrochloride 172-hydroxylamino ketone 16 is obtained in 75% yield, m.p. 126127 C (from a mixture of ethanol and ether). IR spectrum (KBr) s 1680 (0-С). PMR spectrum () I 1.97 (6H, hem. CHi), 7.58 (4H, complex signal of aromatic protons).

Found,%: C 48.03; H 5.33,. N5.89; Se 28.08,

. Calculated,%: C 48.01; H 5.24 g, N 5.60 se 28.35.

Example 3. N- (2-Oxo-2-methyl-3-P-fluorophenylpropyl-2) hydroxylamine hydrochloride (1c).

Under the conditions of example i, from p-fluoro-oL-bromoisobutyrophenone with a total of 48%, hydrochloride 1,2-hydro5 of silaneketon 1c is obtained, m.p. 123-125 ° C (from a mixture of ethanol and benzene). IR spectrum (CVG): 1670 cm (). PMR spectrum (D20): 1.95 (6H, hem.-SNE), 7.48 (4H, complex signal of aromatic protons).

Found,%: C 51.12; H 5.72; 5.71; All 14.88; F8,60.

 13. f OgPce.

Calculated,%: C, 51.40; H 5.57; 5 N5,99; All 15.18; F98,10.

Example 4. N- (3-Oxo-2-methyl-3-p-methoxyphenylpropyl 2) -hydroxylamine hydrochloride (1g).

Under the conditions of example 1, 1,2-hydroxylamino ketone hydrochloride is obtained from P-methoxy-c6-bromoisobutyrophenone with a yield of 60%; mp. 136-138 ° C (from a mixture of ethanol and ether). IR spectrum (KBr): (). Spectrum PMR (DgO): 2.07 (6H, hem.-SND), 5 3.73 (3N, CHjO-), 7.68, (4N, complex signal of aromatic protons).

Found,%: C 53.74; I am 6.48; N5.66; All 14,15-.

With N-bmozse.

0Calculated,%: C 53.76; H 5.56;

N 5.70: ce 14.43. .

Example 5. N- (3-Oxo-2-methyl-3-p-hydroxyphenylpropyl-2) -hydroxylamine hydrochloride (1d).

5 under the conditions of example 1, from p-hydroxy-cl-bromoisobutyrophenone with a yield of 51%, 1 g of 2-hydroxylamino ketone schrochloride is obtained, m.p. 172174 ° C (from a mixture of ethanol and ether).

40 IR spectrum (KBh) | 1675 (). PMR spectrum (SDE) 2CO: 1.75 (6I, hem.-SND), 7.37 (4Y, aromatic protons).

Found,%: with 52.61; H 6.05; N5.68; every 14.99.

45 NOj

BFCI "isofOn% C 52.31, H 6.09; .N6.05; every 15.31.

EXAMPLE 6 - (3-Oxo-2-methyl-3-P-methylfenyl-propyl-2) -carbohydroxy-50 silamin-gin hydrochloride (1a),

Under the conditions of Example 1, p-methyl. -oC-bromoisobutyrophenone with a yield of 76% is obtained by 1,2-hydroxylaminoxime 1a, mp, 146-148 ° C (from ethanol). IR spectrum (KVg): 1620).

Spectrum-PMR () 1.23 (6H, hem.SNd), 2.38 (W3, CHj aromatic col | Ca), 7.16 (4H, complex signal of aromatic protons.

Found,%: C, 63.40; H 7.61; N 13.50.

WITH

Calculated,% C 63,50; H 7.69 Nl 3.50 °

Hydrolysis of 1,2-hydroxyl 1ooxy 65 ma 1a. Mix 2 g of 1,2-hydroxy laminoxime Pa with 20 ml of concentrated HSE and boil for 30 minutes. After cooling, the precipitate is filtered off. According to the melting point, spectral characteristics and elemental analysis data, the obtained compound is identical to 1,2-hydroxylamino ketone hydrochloride 1a Example 7. N- (3-Oxo-2-methyl-3-p-chlorophenylpropyl-2) -hydroxylamine hydrochloride (16), B the conditions of example 1, from p-chloro-a1-bromoisobutyrophenone get 1,2-hydroxylaminoxime PB with a yield of 69%, so pl. 146-148 ° C (from ethyl acetate). IR spectrum (KBG): 1610 cm (). PMR spectrum (): 1.28 (bH, hem-Sa, 7.22 (4H, complex signal of aromatic protons). Hydrolysis of 1,2-hydroxylaminoxy P 6 in The conditions of Example 6 yield, with a yield of 96%, the product, according to melting point, spectral characteristics and elemental analysis data, identical to 1,2-hydroxylamine ketone hydrochloride 1 B. Example 8. N- / 3-OKCo-2-Methyl-3-p fluorophenylpropyl-2 ) -hydroxylamine hydrochloride (1c). B. The conditions of example 1 from p-fluoro o (gbromizobutyrophenone with a yield of 70% get 1,2-hydroxylaminoxime C in, so pl..142-144 ° C (from ethyl acetate), IR spectrum (KBV): 1605 cm (C-H). Spectrum of PNR (): 1.25 (6H. Hem. -CHj), 7.22 (4H, complex signal of aromatic protons). Found,%: C 57.14; H 6.24-; N13.34; F8.95 C-io CH2 2 Calculated,%: C 56.78; H 6.14; N13.21; F8.96. Hydrolysis of 1, 2-hydroxylaminoxy Eve under the conditions of Example 6 gives you With a course of 98%, the product is identical to hydrochloride of 1,2-hydroxylamino ketone 1 Example 9. N- (3-Oxo-2-methyl-3-P-methylphenylpropyl-2) -hydroxy silminemine hydrochloride (1a). To a cooled solution of ethylate n Atri from 1.15 g (0.05 mol) of sodium in 100 ml of anhydrous alcohol, 6.05 g (0.05 mol) of antibenzaldoxime are added and stirred until complete dissolution. To the resulting solution, 12.9 g are added over 30 min. (0.05 mol) P-methyl-ob-bromoisobutyrophenone. The mixture is stirred for 3 hours; at room temperature, the NaBf precipitate is separated and the filtrate is completely evaporated. -Phenylnitron is obtained (Pa as crystallizable oil. To 2 g of crude oL-phenylnitron 1a, add 2 ml of concentrated HC6. Upon withdrawal, a precipitate is formed from the solution, which is filtered off, dried, dissolved in anhydrous alcohol and boiled for 2-3 minutes. The solution is filtered if necessary and dried after cooling. Dissolve the dry ether containing the drug. The 2-hydroxylamino ketone 1a is filtered off. Product weight 0.85 g. (52%) m.p. 137-1 (from acetonyl). IR spectrum (KB): 1675 (O-C). PMR spectrum (fljO) s 1.97 (6H, hem.-SY,), 2.43, (3N, -CH, aromatic rings), 7.55 (4H, complex signal of aromatic protons). Found,%: C 57.52; H 7.11; N5.83; her 15.83. S.N H.S. Calculated:,%: C 57.50; H 7.02; N6.10; every 15.44. Example 10. N- (3-OKCo-2-Methyl-3-P-chlorophenylpropyl-2) -hydroxylamine hydrochloride (16). Under the conditions of Example 1, p-chlorobromo-isobutyrophenone hydrochloride, 1,2-hydroxylamino ketone If, is obtained in 54% yield, m.p. 126-127s (from a mixture of ethanol and ether). IR spectrum (KVg): 1680 (0-C). PMR spectrum (DgO): 1.97 (6H, hem.-SIS), 7G58 (4H, complex signal of aromatic protons). Found,%: C 48.03; H 5.33; N5.89; Cg 28.08. Xu H ,,, N02Ce. Calculated,%: C 48.01; H 5.24; M5,60; Se 28.35. Example 11. N- (3-Oco-2-methyl-3-P-fluorophenylpropyl-2) -hydroxylamine hydrochloride (1c). Under the conditions of Example 1, 1,2-hydroxylamino ketone hydrochloride, 1c, is obtained from p-fluoro-ct-bromoisobutyrophenbane. Yield 49%, mp. 123-125 ° C (from a mixture of ethanol and benzene). IR spectrum (KVg): 1670cm (). Spectrum. PMR (D2O): 1.95, (6H, hem.CH-,), 7.48 (4H, complex signal of an aromatic proton). Found,%: C 51.12; H 5.72; Ы 5,71; Cg 14.88; F 8.60. H ,, N02CE F. Calculated,%: C 51.40; H 5.57; N 5.99; All 15.18; F 8.10. Example 12. N- (3-Oco-2-methyl-3-p-methoxiphenylpropyl-2) -hydroxylamine hydrochloride (1 g). Under the conditions of example 1, from p-methoxy-L. -Bromoisobutyrophenone, hydrochloride of 1, 2-g-udroxylamino ketone (1 g) is obtained. Yield 60%, mp. 136-138 ° C (from a mixture of ethanol and ether). IR spectrum (KBt-): 1680 cm (О С). PMR spectrum (DgO): 2.07 (6H, hem.-Cid), 3.73 (3H, -OCHJ, 7.68 (4H, complex signal of aromatic protons). Found,%: 53.74; H 6 , 43; N5.66; Ce 14.15. C H gNOgCE. Calculated,%: C 53.76; H 6.56; N5.70; Ce 14.43. Example 13 M - ( 3-Oxo-2-methyl-3-P-hydroxyphenylpropyl-2) -riuipoxylamine hydrochloride (1d) Under the conditions of Example 1, 1,2-hydroxylamino ketone hydrochloride 1e is obtained from p-hydroxy-CC-bromoisobutyrophenone. mp 172-174 ° C) (from a mixture of ethanol and ether). IR spectrum (KBt-): 1675 (). NMR spectrum (Cfl,) j, CO: 1.75 (bN, hem.-Ciy, 7.37 (4H complex signal of aromatic protons). Found: C 52.61; H 6.05 N5.68; ce 14.99. C oH NOjCe. Calculated: C 52.31; H 6.09; N 6.05; se 15.31. Example 14. N- (3-Oxo-2-methyl g-3- -thienylpropyl-2- (hydroxylamine hydrochloride (1g)., Example 1 from c-thienyl-cJL-bromoisobutyloketone receive 1,2-hydroxylamino ketone hydrochloride 1g. Yield 48%, mp. 142-144C ( ethanol and ether mixtures.) IR spectrum (KVg): 1660 (O-C), PMR spectrum (): 1.77 (6H, hem.-CH), 7.40 (ZN, complex signal of the tienitelus residue). Found ,%: C 43.21; C 5.37; N 6.12; Ce 16.01; S 14.43. NOaCeS. Calculated,%; C 43.34; H 5.49; N6.32; All 15.99; 514.43. Example: p-15. M- (3-Oxo-2-methyl-3- (3, 4-dimethoxyphenyl) -propyl-2) -cytsroxylamine hydrochloride (1e). of example 1, from (, 4-dimethoxy-cX - bromoisobutyrophenone p, N- (1-keto-1- (3, 4-dimethoxy phenyl) -2-methylpropyl-2) -oC-phenylnitron Ron Pe is obtained. Yield 49%, mp 153-155 ° C (ethanol) Found:% C 69.59; H 6.31; N4.16. “2-1. . Calculated,%: C, 69.70; H 6.47; N 4, 28. Hydrolysis of β-phenylnitron Pa. Inject 1 g of cc-phenylnitron with 5 ml of concentrated nse and 10 ml of ethyl ether for 5 minutes. 15 ml of water are added to the mixture. The ether layer is separated, the acid layer is extracted once more. The acidic layer is neutralized with soda to pH 7-8. The precipitate formed is dissolved in 15 ml of dry ether, and dry hydrogen chloride is passed into the resulting solution. The precipitated hydrochloride of 1,2-hydroxylamino ketone 1E is filtered off. Output 98%, mp. 151-153 ° C (from ethanol). Found,%: C 52.54; H 6.86; N5.06; every 13.05. C (2nd se. Calculated,%; C 52.30; H 6.57; KB, 07; se 12.85. The results of biological tests indicate that newly synthesized compounds have pronounced stimulating neurotropic activity. These compounds cause a pronounced excitement of animals, increase motor orientation activity, increase the intensity, the rate of performance of the workload, followed by a period of depletion and relatively rapid restoration of working capacity. The toxicity of the proposed compounds is given in Table 1. Table 2 Table 1 All of the synthesized substances have psychostimulant properties. Already in small doses (0.5-2 mg / kg) they cause animals to become agitated, their physical activity increases, and reactions to stimuli increase with doses up to 10-50 mg. / kg signs of stimulation of the central nervous system are increased, steriotypy, hyperhidrosis, salivation, exophthalmos, and increased respiration are added. At doses above 100 mg / kg, convulsive twitching is sometimes noted. With the introduction of toxic doses of animals death occurs when the phenomena of a sharp excitation of the central nervous system and convulsions. Substances 1, 1c, 1d, 1g, 1g have the most pronounced psychostimulating properties. . The duration of the stimulating effect depends on the dose of the preparation. Small doses (0.5-2 mg / kg) cause a noticeable arousal in animals for 30-40 minutes, with an increase in doses, the excitatory effect lasts 1.5-3 hours. Compared with phenamine, the stimulating effect of hydroxylamino ketones develops faster and is less long. BJ and none on the indicative motor activity. Investigate the effect of all synthesized substances on the motor orientation activity. The measurements are carried out twice: 20 and 60 minutes after the administration of the substance. Mice for 10 min is placed in the registrar of motor activity DAER-20. Investigated substances

the motor orientation is stimulated, but after 1 h after administration, their stimulating activity decreases markedly (Table 2). Table 2

Influence on body temperature. All substances keep the body temperature of the mice at l-3s. The most pronounced hyperthermic effect was observed in compounds 1, la, IB; however, after 1 h after administration of the substance, it decreases (Table 3).

55

Table3

The effect on the conditionally-rapid Compare the amount of positive reaction. in rats. The studied responses in the group on the conditions. At low doses (0.5–2.6 mg / kg), a ny irritant (150 combinations per

facilitate the production of conditional-turnover-day). The results show that body reflex. The drug is administered to rats (10 in a group) for 15 min.

before the start of the experiment, the control stomachs are on. 4th day of training, and

, they get the equivalent volume isotonic - in the control group - on the 8th

solution of sodium chloride. (Table 4).

- In rats who received the drug, a steady conditioned reflex was produced T a b l and c a

KfftJcaM with a conditioned-defensive reflex was injected, test substances were administered and after 30 minutes the duration of the latent period of the reaction was determined. Substances lead to a percussion effect on the amount of food consumed. Use substances 1, 1a, 1b, phenamine. All drugs significantly reduce the amount of consumed my food. In this case, the male rats ({7 days) are trained to use sweetened milk from a graded vessel. Then set the mode: daily from 12 to 16 chaFen1min

Control

mating of the latent period in small doses; high doses make it difficult to perform a conditional reaction due to pronounced excitement, motor anxiety, stereotypy (Table 5).

Table 5 0.04 ows for 4 hours the usual manger is replaced by a graduated vessel of milk. The amount of consumed milk is noted daily for 4 days. On Day 5, 20 minutes prior to replacing the shell, the test groups receive the test substance, and the control group receives physiological saline. The amount of milk consumed in ml / kg is determined (Table 6X) (Table 6-15 Effect on running speed and swimming depletion of mice.) have a significant impact on the performance, fatigue of laboratory animals. For them the following effects are characteristic: an increase in the intensity and speed of the workload; fast

0.1 2.4 ± 0.06 99 + 1.7 118 ± 6.4 154 ± 1.2 2.0 1.2 ± 0.008 31.6 + 4.6 122 ± 9.8 168 + 4.8

0.12.9 + 0.06 89 + 1.6124 ± 5.6117 + 1.6

2.01.8 + 0.08 49 ± 2.8118 ± 5.2124 ± 1.2

0.11.9 + 0.07 94 + 2.7129 + 2.5186 + 11.4

2,01.4 + 0.09 38 ± 2.6120 ± 2.6174 ± 8.4

0.12.5 + 0.08105 + 2.4119 + 1.6198 ± 7.1

2.01.3 + 0.06154 + 1.6116 + 5.4169 ± 5.4

ABOUT

amine

0.13.4 ± 0.06108 ± 9.465 + 5.452 ± 1.7

2.02.6 + 0.04218 ± 18.669 ± 5.261 + 2.7

Control

4.2 + 0.09 55 + 9.2 98.2 + 9.3 154 ± 3.6 As can be seen from the table, small doses increase the duration of swimming of mice, and large ones shorten it. This is due to a sharp excitation, high intensity motor activity. However, later on, on the 2nd day after the substance was injected, the duration of swimming increased in the experimental groups as compared to the control group, after administration of phenamine, a more pronounced depleting effect was observed.

oh oh

oh oh

10,100

10 40.4 ± 0.8 18 ± 1.4 3.2 ± 0.06 + 1.0 ± 0.04

1a

100 55.6 + 6.6 19 ± 1.61.9 ± 0.6 + 1.4 ± 0.05

2.2 + 0.3

+ 1.6 ± D, 06 + 1.7 ± 0.02 1.5 ± 0.3 6 depletion; relatively fast recovery. Two experiments were conducted on male mice: determining the run time through a pipe 70 cm long, 3 cm in diameter, and the duration of the voyage to the exhausted hatch, up to 5 seconds under water (Table 7). Table 7 Effect on hypnotic and reaerpine effects. Substances 1, 16, 1d noticeably weaken, shorten the effect of sleeping pills; 1a, 1b, 1g in a large dose, even somewhat prolong it. This brings the last three substances together with a group of antidepressants. The effect of hydroxylamino ketones on the effects of hypnotics and reserpine is given in Table. 8 "Table 8

1035 ± 7.5 11 ± G, 8

IB

10060, 5 ± 1, 2 16 ±. , b

1041.5 + 6.4 15 + 42.6 + 0.09-0.9-1 + 0.12

Ir

10061.5i-i2.4 19 + 2.61.6 + 0.07–0.35 + 0.06

1031 + 6.4 12 + 1.51.9 + 0.12

1D

10020.1 + 2.801.6 + 0.09

1019.4 + 1.7 6 + 0.41.4 + 0 / 07-0.9 + 0.12

1G

100-001.0 + 0.07 + 0.8 + 0.04

Phenamine

iU

40.7 + 2.9 1, .7 ± 2, 5

Control Substances 1, la, 16, Ir, 1G reinforce the effect of apomorphic, arecoline - stimulators dopamine of the linergic structures of the brain. peripheral receptacle CHCTefviKi are studied in rats anesthetized with urethane (50 MF / KG). Blood pressure is measured over 2.5 h. At doses up to 2 mg / kg of substance, non-permanent changes in blood pressure and heart rate are reduced. I. Nevertheless, there is a tendency for a two-phase effect; first the depressor response (at 8–15 no. 1 Hg), then blood pressure to the initial level and more, high numbers (at 10–15 rt. A dose of 5 mg / kg leads to a clear two-phase effect +3.8 seconds, the npeccopHoli responds with a response of 394 ± 24 seconds, after which the blood pressure returns to normal. 1a, 1v, 1d, 1

2.0 ± 0.06

+ 1.4 ± 0f02

-0.9 ± 0.06 -0.4x0.04

1.2 + 0.07

Claims (2)

-1.9 + 0.2 The effect on the contraction of isolated organs (uterus and vas 4e fug15) 7 substances 1 and IB has been studied. When combined with TPAunH 10, they inhibit the spontaneous activity of myometrium by 30% f reduce the response of myometrium to acetylcholino. Both effects quickly disappear after washing. Thus, the proposed hydroxylamino ketone El are biologically active substances, possessing NIGI. 1, and a pronounced neurotropic psychotropic activity. DETAILED DESCRIPTION OF THE INVENTION Derivatives of 1,2-hydroxylamino ketones of general formula 1 O. “1 i R — C — C —HHOH HCt, i-cio), ce, where R; SNAR. A /. jLan HO- / O -n v, cH,, s V y СНО О -bladakdie neurotropic activity. 19 Sources of information taken into account in the examination 1. USSR author's certificate 333159, cl. C 07 S 49/00, 1972, 65701620 2. M.V. Rubtsov, L, G. Baychikov. Sikteticheskoe pharmaceutical preparations, 1971, N., p., 38. 3, L, B, Volodarsky, etc. ZORH, 2,114 (1966).