SU1218924A3 - Method of producing derivative of 4-aminobutyric acid - Google Patents

Description

The invention relates to organic synthesis; specifically to a method for the preparation of a 4-amino-butyric acid derivative exhibiting biological activity.

The purpose of the invention is to develop a method for producing an A-aminobutyric acid derivative that exhibits an increased biological activity, which consists in improving cerebral metabolism of the brain in the breakdown of its functions.

Example 1-. 1. Benzyl ester (2,4-dioxy-3,3-DImethyl-n-butyryl) amino-butyric acid (5 g) was dissolved in tetrahydrofuran (50 ml) and pyridine (3) was added to it. d). A solution of isobutyryl chloride (1.8 g) in tetrahydro-Luran (5 ml) was added dropwise to the mixture while stirring. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed with dilute hydrochloric acid, water, an aqueous solution of sodium bicarbonate and a saturated saline in the sequence indicated. The ethyl acetate solution was dried and concentrated under reduced pressure to remove the solvent. The residue was purified by chromatography on silica gel (solvent: chloroform: ethyl acetate 4: 1) to give benzyl ether (4-isobutyryloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino-Tn • butyric acid (3.6 g, 59.2% as a colorless, viscous oil.

IR (film), -5

ms cop

 3350, 1730

1650. Mass spectrometry, 1p / e: 393 (M

2. Benzyl ester (isobutyryloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino-H H-butyric acid (3.4 g) was dissolved in methanol (34 ml and palladium black was added to it 30 mg.) The mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. After completion of the reaction, the reaction mixture was filtered to remove unreacted particles and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane and obtained (4

924

butyryloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino N-butyric acid (2.0 g, 76.3%) in the form of colorless prisms, m.p. 73-75 s. IR (Nujol),

 "Same

cm

,

3320, 1715, 1610. Mass spectral metrology, t / e: 303 (), s + 37.2 ° (C 1, ethanol).

This product is recrystallized from a mixture of ethylacetate and isopropyl ether to give colorless prism crystals with m.p. 82-83 ,, 4 ° (s 1, et nol).

3. (4-Isobutyryloxy-3, 35-dimethyl-2-hydroxy-n-butyryl) amino-1-n-butyl acid (1.0 g) was dissolved in ethanol (20 ml) and hydroxide was added to it Calcium (0.15 g) and water (2 ml); the mixture was stirred at room temperature for 40 minutes. The reaction mixture was filtered to remove non-dissolved particles and the filtrate was concentrated under reduced pressure. The residue was treated with n-hexane

5 and obtained 1) (4-isobutyryloxy-3.3. Dimethyl-2-hydroxy-n-butyryl) amino calcium calcium butyrate (0.85 g, 80.0%) as a colorless powder. + 28.3 ° (C 1, ethanol). Example 2. 1. Analogously to Example 1.1, using benzyl ester (2,4-dioxy-3, 3-dimethyl-n-butyryl) amino-n-butyric acid (5.0 g), tetrahydrofuran (55 ml) pyridine (3 g) and isovaleryl chloride

5 (2,1), benzyl ester of (4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino-n-butyric acid (4.0 g, 63.5%) was obtained in as a colorless viscous oil. IR (nui-

° ol) ,, „d, 3350, 1730, 1650. Mass spectrometry, t / e: 407.

2. Analogously to Example 1.2, using benzyl ester of (4-isovaleryloxy-3, 3-dimethyl-2-ox cy-n-butyryl) amino H-butyric acid (3.8 g), methanol (38 ml) and pallium black (30 mg), obtained (4-isovaleryloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino-n-butyrate (2.1 g, 70.9%) as colorless prisms, mp 84-86 0. IR (nuy-)

ol),

Max

-one

cm-: 3300, 1720, 1610.

IMU COP.

Mass spectronetry, t / e: 317 (M), Id + 34.1 ° (C 1, ethanol). 5 3. Analogously to Example 1.3, using (4-isovaleryloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino-n-butyric acid (1.0 g).

ethanol (20 ml), calcium hydroxide (0.13 g) and iodine (2 ml) obtained (D-isovaleryloxy-3, 3-dimethyl 2 OxyH butyryl) amino N calcium butyrate (0.84 g , 79.2%) in the form of a powder.

 + 26.1 ° (C 1, ethanol).

Example 3. 1. Analogously to Example 1.1, using D-4-N benzyl ester (2,4-dioxy-3,3-dimethyl-n-butyryl) AminoJ H-butyl acid (5.0 g), tetrahydrofuran (55 ml pyridine (3 g) and isohexanoyl chloride (2.3 g), obtained the benzyl ester D-4 N - (4-isohexanoyloxy 3,3-dimethyl 2-hydroxy-n-butyryl) amino-n-t asl - Acidic acid (4.8 g, 73.1%) as a colorless viscous oil. IR (Nuy

ol) ,, cm 3350, 1730, 1650. Mass spectrometry, T / e: 421 (M). 2. Analogously to example 1.2. using benzyl ester (4- -isohexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino1-n-butyric acid (4.0 g), methanol (40 ml) and palladium black ( 40 mg), (4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino-n-may-

lonic acid (2.9 g, 92.2%) as a colorless, viscous oil. IR (film), Mo ,, 3330, 1720, 1610. Mass spectrometry, t / e: 331 (), s + 31.6 ° (C 1, ethanol).

Example 4. 1. Analogously to Example 1.1, using benzyl ester (2,4-dioxy-3, 3-dimethyl-n-butyryl) amino-n-butyric acid (4.0 g), tetrahydrofuran (45 ml), pyridine (2.4 g) and pivaloyl chloride, benzyl ester is obtained (4-pivaloyloxy-3,3-dimethyl--2-hydroxy-n-butyryl) aMHHoJ-H-butyric acid (3.0 g, 47.6 %) as a colorless viscous oil. IR (film)

max 3350, 1730, 1650. Mass spectrometry, t / e: 407 ().

2. Analogously to Example 1.2, using benzyl ester of (4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amine H-butyric acid (2.8 g), methanol (28 ml) and palladium black (30 mg), obtained D-4- (4-pivaloyloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino 2 -n-butyric acid (1.1 g, 50, 4%) as colorless crystals, after recrystallization from a mixture of ethyl acetate and n-hexane, m.p. 79-82 ° C. IR (nuy

 five

.rt.

ten

, ° - msi; from 3350, 1730, 1710, 1610. Mass spectrometry, t / e: 317 (M).

Example 5. 1. Analogously to Example 1.1, using benzyl ester (2,4-dioxy-3,3-dimethyl-n-butyryl) amine n-butyric acid (4.0 g), tetrahydrofuran ( 45 ml), pyridine (2.4 g) and 3,3-dimethyl-n-butyryl chloride (2.0 g), received bisyl ester G) -4-k-G4- (3,3-dime - Tyn-butyryl) -oxy-3,3-dimethyl--2-hydroxy-n-butyryl amino-n-butyric acid (3.7 g, 71%) as a colorless, viscous oily substance. IR (film), 1, 3350, 1730, 1650. Mass spectrometry, t / e: 421 (M).

2. Analogously to Example 1.2, using benzyl ester -4-H - “- - (3,3-dimethyl-n-butyryl) -oxy-3,3-dimethyl-2-hydroxy-n-butyryl amino-n- oil acid (3.5 g), methanol (35 ml) and palladium black (40 mg), 5 obtained D-4- | N- 4- (3,3-dimethyl-n-butyryl) -oxy-3,3-dimethyl-2-hydroxy-n-butyryl amines-n-butyric acid

0

(2.2 g, 79.7%) in crystals,

0 | 0l),

colorless 102-104 ° C. IR (Nui - 1735, 1715,

m.p.

 Max, 3340, 1610. Mass spectrometry, t / e: 331 (M), + - - - ° and m

32.0 (C 1, ethanol). II p and measure 6. 1. Analogously to example 1.1, using benzyl 5 ether (-2,4-dioxy-3, 3-dimethyl-n-butyryl) amino | -n-butyric acid (4.0 g), tetrahydrofurac (45 ml), pyridine (2.4 g) and 2-ethyl-n-butyryl chloride (2.0 g) gave 0 benzyl ester 1) (2- ethyl-n-butyryl) -oxy-3,3-dimethyl-2-OK-si-n-butyryl} amino-n-oil

(2.5 g, 47.9%) as an oil-free. IR (film).

five

acids

color viscous

MqKc

 3350, 1730, 1650. Mass spectrometry, t / e: 421 (M).

2 Analogously to Example 1.2, using benzyl ester - (2-ethyl-n-butyryl) -oxy-3,3-dimethyl

Tyl-2-hydroxy-n-butyryl amino) -n-butyric acid. (2.4 g), methanol (24 ml) and palladium-black (30 mg), received D-4- {N- 4- (2 -stil-N-butyryl) -oxy-n-butyryl amino-n-oil -

Acidic acid (1.7 g, 90.1%) as a colorless, viscous oil. IR (film), „g.j., cm-: 3350, 1730, 1710, 1645. Mass spectrometry, t / e: 331

(M), MC - 25.9 (C .1, ethanol).

3. Analogously to Example 1.3, using (2 ethyl N-butyryl) -oxy-3.3-dimethyl-2-hydroxy-n-butyryl amino | -n-butyric acid (1.0 g), ethanol (20 ml ), calcium hydroxide (130 mg) and water (2 ml), received (2-ethyl H butyryl) -oxy 3, 3-dimethyl-2-hydroxy-n-butyryl amino-n-butyrate calcium (0 , 81 g, 76.6%) as a colorless powder. o (.1 o + 24.7 ° (C 1, ethanol).

Example 7.1. D-4 ll-l benzyl ester 2,4-dioxy-3,3-dimethyl-n-butyryl) amino1 H-butyric acid (4.0 g) was dissolved in tetrahydrofuran (30 ml) and added to it is pyridine (2 ml). A solution of acetyl chloride (1.2 g) in tetrahydrofuran (5 ml) was added dropwise to the mixture while cooling with ice. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with dilute hydrochloric acid, water, an aqueous solution of sodium bicarbonate and brine in the order indicated. The ethyl acetate layer was dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (solvent: chloroform: ethyl acetate 4: 1) to give the benzyl ester, (4-.acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino-3-butyric acid (2.3 g, 50.9% as a colorless viscous oil. IR (film), 5 ,,,, ..,., Cm

.

3350, 1730, 1650. Yass spectrometry t / e: 365 (M).

2. Benzyl ester of (4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl) amio-butyric acid (2.0 g) was dissolved in methanol- (20 ml and added to the mixture palladium black (20 mg). The mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. After the reaction was completed, the reaction mixture was filtered to remove insoluble particles and the filtrate was concentrated under reduced pressure. Received - (4-acetoxy-3j 3-dimethyl-2-hydroxy) -n-

0

ten

-butyryl) amino-n-butyric acid (1.38 g, 91.6%) as a colorless, viscous oil. IR (film),, tt 3350, 1720, 1640. Mass spectrometry, t / e: 275 (M), oc in + 33.1 ° (С 1, ethanol).

Example 8. 1. Analogously to Example 7.1, using benzyl ester (2,4-dioxy-3, -3-dimethyl-n-butyryl) amino-n-butyric acid (4.0 g), tetrahydrofuran (35 ml ), pyridine (2 ml) and propionyl chloride (1.4 g), gave benzyl ester (4-propionyl-3-3, 3-dimethyl-2-oxy-n-butyryl) amino | -n • butyric acid (2.2 g, 46.9%) as a colorless, viscous oil. IR (film), ake, 20 cm: 3350, 1730, 1650. Mass spectrometry, t / e: 379 (M).

2. Analogously to Example 7.2, using (4-β-propionyloxy 3, 3-dimesh-1-2-ca-2-C-n-butyryl) amino-n-butyric acid benzyl ester (2.0 g), methanol (20 ml) palladium black (20 mg), obtained D-4-N- (4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino1-n-butyric acid (1.46 g, 96, 7%; in the form of a colorless viscous oil. IR (film), max, 3350, 1720, 1640. Mass spectrometry, t / e: 289 (M), o (, l + 30.0 (C 1, ethanol) .

Example 9.1. In analogy to Example 7.1, using benzyl ester (2,4-dioxy-3, 3-dimethyl-n-butyryl) amino-n-butyric acid (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml ) and n-butyryl chloride (1.6 g), obtained the benzyl ester (4-n-butyrsh1ok si-3,3-dimetsh-2-oxy-n-butyryl) amino-n-may / fH XX- . "..

thirty

five

 of lactic acid (2.9 g, 59.6%) as a colorless, viscous oil. IR (film), 3370, 1730, 1650. Mass spectrometry, t / e: 393 (M),

Ы / °

+ 27.6 (C 1, ethanol). 2. Analogously to Example 7.2, using benzyl ester of (4-n-butyryloxy-3,3-dimesh-1-2-hydroxy-n-butyryl) amino-n-butyric acid (2.0 g), methanol (20 ml) and palladium-black (20 mg), received. D-4-fN- (4-n-butyrdl-rx-3,3-dimethyl--2-ok si-n-butyryl) amino n butyric acid (1.48 g, 96.0%) as a colorless viscous oil. IR (film).

m. s - 1720, 164P. Mass spectrometry, p / e: 303 (M), IB - 30.2 ° (with I, ethanol).

Example 10 1. Analogously to Example 7.1, using (2, A-flHt-iKCH-B, 3-dimethyl-n-butyryl) amino-n-butyric acid benzyl ester (A, O g) , tetrahydroluran (35 ml), pyridine (2 ml) and. n-valyl chloride (1.8 g), obtained benzyl ester (4-n-valeryloxy- -3.3 dimethyl-2 oxy-n-butyryl) amino H-butyric acid (3.0 g, 59 , 5%) in the form of colorless crystals, etc. 34-35 ° C. IR (Nujol) ,,, cm 3370, 1730, 1650. Mass spectrometry, t / e: 407 (M).

2. Similarly to Example 7.2, using benzyl ester of (4-H-valeryloxy-3, 3 dimethyl-2-oxyl-n-butyryl) amino-n-butyric acid (2.6 g), methanol (30 ml) and palladium black (30 mg), received D-4-N (4-n-valeryloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino - n-butyric acid (1, 9 g, 93.8%) as a colorless viscous oil. IR (captured by mothers 3350, 1720, 1640. M;) ss spectrometry, t / e: 317 (M), L 1 + 31.8 ° (C 1, ethanol).

3.1) (4-Valeryloxy-3,3-di-methyl-2-hydroxy-n-butyryl) amino-n-butyric acid (0.9 g) was dissolved in methanol (10 ml) and L-lysine was added to it (0.41 g). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was treated with n-hexane

and the resulting powder was collected by filtration. The L-lysine salt of (4-varyloxy-3, 3-dimethyl--2-hydroxy-n-butyryl) amino-n-butyric acid (1.13 g, 86.3%) was obtained as a colorless powder, t. P. Software-PZ with + 25,5 ° (C 1, ethanol).

4. (4-n-valeryloxy-3, 3-dmethyl-2-yc s-n-butyryl) amino-n-butyric acid (1.0 g) was dissolved in methanol (10 ml) and calcium hydroxide was added to it (0.12 g) and water

(5 ml). The mixture was stirred at room temperature and then concentrated under reduced pressure. Ethanol was added to the residue, and the mixture was concentrated to dryness under reduced pressure. Got

fO

15

0

five

0

five

(4-n-valeryloxy-3,3-dimethyl-2-Oxy-n-butyryl) amino-calcium n-butyrate (1.0 g, 94.3%) as a colorless powder.

Example 11. 1. Analogously to Example 7.1, using benzyl ester (2,4-dioxy-3, 3-dimethyl-n-butyryl) amino-n-butyric acid (4.0 g), tetrahydrophane (35 ml ), pyridine (2 ml) and n-hexanoyl chloride (2.0 g), benzyl ester (4-n-hexanoyl-3-3, 3-dimethyl-2-hydroxy-n-butyryl) was obtained amino n-butyric acid (3.2 g, 61.4%) as a colorless viscous oil. IR (film), |, d, 3370, 1730, 1650. Mass spectrometry, t / e: 421 (M).

2. Similar to Example 7.2, using (4-, -hexanoyloxy-Z.Z-dimethyl-2-hydroxy-n-butyryl) amino-n-butyric acid benzyl ester (2.0 g), methanol (20 ml) and palladium black (20 mg), obtained (4-hexanoyl-3,3-dimethyl-2-hydroxy-n-butyryl) amino H-butyric acid (1.35 g, 85.9%) as a colorless viscous oils. IR (nnetika), mox 3350, 1720, 1640. Mass spectrometry, t / e: 33 (M), Ce lp + 27.6 ° (C I, ethanol).

3. Similar to Example 10.3, using D-4-FN- (4-n-hexanoyloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino-n-butyric acid (1.0 g), L-lysine (0.44 g) and methanol (10 ml), received L-lysine salt

- (4-n-hexanoyloxy-3,3-dimethyl-2-α-oxy-n-butyryl) amine of o-butyric acid (1.3 tons, 90.2%) as colorless

powder oh

etc. 131-134 s.

Ys 25.1 (C 0.5, ethanol). Example 12, 1, as in Example 7.1, using benzyl ester (2,4-dioxy-3, 3-dimethyl-n-butyl) amino-n-butyric acid (4.0 g), tetrahydrofuran (35 ml) , pyridine (2 ml) and n-heptanoyl chloride (2.2 g), gave the benzyl ester (4-n-heptane-yloxy-3,3-dimethyl-2-oxy-n-butyryl) amino-n- oil acid (2.5 g, 46.4%) as a colorless, viscous oil. IR (foam) -, 3370, 1730, 1650, Mass spectrometry, t / e :.

435 (K), - -

2, Analogously to Example 7.2; using benzyl ester lr-4-N- (4 H-teptanoyloxy-3, 3 dimethyl- -ok--. si-butyryl) aMHHoJ -n-butyric acid (1, 8 g), methanol (20 ml ) and palladium black (20 mg), received - (4-n-heptanoyloxy 3,3-di methyl 2 oxy N butyrnl) amine-n-butyl nuk) acid (1.3 g, 91.1 %) in the form of colorless oil in whom. IR (capturing

K -1), max. 3330, 1720, 1640 Mass spectrometry, t / e: 345 (M), W + 30.2 ° (C, ethanol). Example 13, 1. Similarly to Prmer 7.1, using D-4-N- (2,4-dioxy-3, 3-dimethyl-n-boor-tiryl) amino-N-butyric acid benzyl ester (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and n-octanoyl chloride (2.4 g), ig- (4-n-octanoyloxy-3, 3-dimethyl-2 oxy-n-butyryl) aMHHoJ benzyl ester was obtained (n 2.2 g, 39.6%) in the form of best oil in whom oil. IR (film)

 mo.x spectrometry, t / e: 449 (M).

2. Analogously to example 7.2. using benzyl ester of (4-H-octanoyl-3, 3-dimethyl-2-hydroxy-n-butyryl) amino H-butyric acid (1.4 g), methanol (20 ml) and palladium-evuk mobile (15 mg), got D-4-

(4-n-octanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amino -1H-butyric acid (1.05 g, 93.8%) as a colorless, viscous oil. IR (film)

"Dicc ° spectrometry, n / e: 359 (M),

M + 27.4 ° (1, ethanol).

Example 14. 1. Similar to Example 7.1, using benzyl ester (2,4-dioxy-3, 3-dimethyl-n-butyryl) amino H-butyric acid (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and n-nonanoyl chloride (2.6 g) ,. (4-n-nonanoyloxy-3, 3-dimethyl-2 -o-s-n-butyryl) amino-n-butyric acid benzyl ester (3.9 g; 68.0%) was obtained as colorless zky oil. IR (film) -. «P. "3370 1735, 1650. Mass spectrometry, t / e: 463 (M).

2. Analogously to Example 7.2, using (4-n-nano-nanoyloxy-3, 3-dimethyl-2-oxyl-n-butyryl) amino-n-butyric acid benzyl ester (2.0 g), methanol ( 20 ml) and palladium black (20 mg), received D-4-N- (4-n-nonanoyloxy-3, 3-dimethyl-2-hydroxy-n-butyryl) amino-n-oil

acid (1.4 g, 86.9%) as a colorless, viscous oil. IR (film) mphs cm: 3330,1720,1640. Mass spectrometry, t / e: 373 (M-), + 26.2 (s 1, ethanol).

3. Analogously to Example 10.3, using D-4-N-4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl) amy-HoJ-n-butyric acid (o, 9 g), methanol (10 ml) and t-lysin (o, 35 g), obtained the lysine salt O - 4-N- (4-n-nonanoyloxy-3, 3-dimethyl-2-oxy-n-butyryl) ) amino-butyric acid (l, l5 g, 91.8%) as a colorless powder, etc. .

TC 22.9 ° (with 0.5, ethanol).

Biological activity.

Experiment 1.

Used SD rats male individuals weighing 200 g at the age of 7 weeks starving overnight (one group of 4 rats). Each rat was orally administered a suspension (2 ml) of the test compound in a solution (0.5%) of carboxymethylcellulose by means of the gastric complex (dose of the test compound: 389 W mol / kg corresponds to 100 mg / kg of calcium hopantenate). One or two hours after the drug was injected, the rats were killed by cutting through the carotid arteries and blood was collected. The blood of each rat was centrifuged (2800 rpm, 15 min) to determine the blood plasma. The concentration of gopaitenoic acid in plasma (0.1 ml) was determined by gas chromatography and mass spectrometry.

The results are presented in table 1.

Experiment 2.

Male rats weighing 200 g at the age of 7 weeks starving overnight (one group 4 rats) were tested on rats. Each rat was orally administered a suspension (2 ml / test compound in 0.5% carboxymethylcellulose solution ( The dose of test compound 389.4 Schmol / / kg corresponds to 100 mg / kg calcium hopantenate. Two or three hours after the compound was administered, the brain was removed and washed with saline. A larger volume of water was added to the brain 9 times, the mixture was homogenized. at 1 minute with ice cooling and then centrifuged at 10,000 rpm at a temperature of 1 hour. The concentration of hopantenic acid in the supernatant (1 ml corresponds to 0.1 g of the brain) was determined using gas chromatography spectrometry. The results are presented in Table 2. The same compounds were tested as in Experiment 1.

Experiment 3.

Three male hounds, aged 10 months, were kept without food during the night. Each dog was orally administered a suspension (15 ml) of the test compound (the dosed compound 194.7 Schmol / kg corresponds to 50 mg / kg calcium gopanthenate. Blood samples (2 ml) were taken from the head vein and placed in heparinase tubes after 0.5 , 1.2 and 3 hours after application. Blood was centrifuged (2,800 rpm, 10 minutes) to separate blood plasma. The concentration of hopanthic acid in the blood plasma (0.1 ml) was measured by gas chromatography and mass spectrometry. The results are presented in Table 3. The test compounds are the same as in EC 1 to experiments.

The compounds (1) of the present invention have low toxicity and, therefore, high safety. For example, the proposed compounds (4-isobutyryloxy-3,3-dimepti-2-oxy-n-butyryl) amino-n-butyl-acid and (4-iso valeryloxy-3, 3-dimethyl-2-hydroxy -n-butyryl) amino-H-butyric acid show a maximum tolerance of 2000 mg / kg when tested in mice (this maximum tolerance was determined by administering the test compound to the test, then the number of dead mice was determined 48 hours after treatment; maximum tolerance is

10 is a dose slightly lower than the dose that caused the death of mice).

Thus, the compounds according to the invention are converted to hopanthic acid in vivo after administration of

15 neither do their animals and provide a high concentration of gophentenoic acid in the blood and brain compared to calcium hopantenate with high safety and, therefore, in

20 are useful as drugs for improving brain metabolism in the breakdown of its functions. Comparative data.

5 Using the procedure described in Experiments 1 and 2, we measured the content of grapanthenic acid in the blood plasma and brain after oral administration of the proposed

0 and known (control) compounds. The measurement was taken 30 minutes after administration. The measurement results are shown in Table. 4 and 5.

Test compound 5

BUT

I

UNAEFC-C-CH-SESSION

Note. 1. Compound 1: Isopropyl-3,3 Dimethyl-2-hydroxy-N-butyryl amino-n-oil

-. .,acid.

2. Compound 2: (4-Isovaleryloxy 3, 3 Dimethyl-2-hydroxy-H (-biryl) amino H-butyric acid.

3. Control: calcium (2,4-dihydroxy;; - ,,;: si-3,3-dimethyl-n-butyryl) amino H-butyrate.

4. The relative value is calculated using the following formula:

Level of hopantenic acid (mean + error) c. blood plasma in the group with the test compound applied

Relative value

The level of hopantenic acid is the mean error) in the blood plasma of the control group.

Table I

Note. I. The control is the same as in table. I.

2. The relative value is calculated by

the following formula:

The level of hopantenic acid (moderate) in the medulla in the group with the test compound applied

Relative value

The level of hopantenic acid (mean ± error 1 in the medulla in the control group

Table 3

The level of hopantenic acid s plasma, µg / MP

(CH,) 2CH (CH,). SNSI2 Control

20.81 ± 5, P 29.8815.45 20.06 ± 2.08 10.28tO, 49

(5.10) (4.74) (2.07) (1.31) 20.91 tlO, 25 24.40 t3.74 I6.22 ±, 50 9.50 ± 0.90

(5.12) (3.89) (1.67) (1.2J) 4.08 ± l, 31 6.2812.08 9.68 ± 2.42 .7.83 ± 2.70

(1.0)

(1.0)

(1.0)

(1.0)

Note. 1. The control is the same as in table. I and 2.

2. The relative value is calculated according to the formula described in experiment I.

.Table 2

(1.0)

(1.0)

(1.0)

Table A

Table 5

Claims (1)

METHOD FOR PRODUCING 4-AMINOBUT ACID DERIVATIVE OF GENERAL FORMULA CH ₃ HCOOCH ₂ -C-CH-CONH (CH2 ') ₃ COOH CH ₃ OH where R is a C ₅ -C ₇ straight or branched chain alkyl group, or a pharmaceutically acceptable calcium or lysine salt thereof, characterized in that the 4-aminobutyric acid derivative of the general formula sn ₃ 1рЭОСН ₂ Ч2 ~ СН-СШШ2) zSOOSN _r 'C ₆ H ₅ CH ₃ OH wherein r is as defined above, is subjected to catalytic reconstruct p ment of palladium black in a methanol medium, and if desired, converting the reaction product into a pharmaceutically acceptable calcium salt or lysine. SU,. „1218924>