SU1560058A3 - Method of producing peptides - Google Patents

Abstract

The invention relates to the preparation of peptides of the general formula: I: @ (II) where R ₁ is C ₂ -C ₁₀ alkyl, cyclohexyl, cyclohexylmethyl

R ₂ -H

R ₃ --NH-CH (CH ₃ ) -COOR ₅

R ₄ - H, C ₁ -C ₆ -alkyl

R ₅ - H, C ₁ -C ₆ -alkyl, benzyl, which can be used in medicine. The purpose of the invention is to obtain new, more active peptides. The method involves the acylation of a compound of formula II, where R ₂ , R ₂ and R ₄ have the indicated meanings, with a compound of the formula R ₁ -CO-HAL, where R ₁ has the indicated values HAL is halogen, and functional groups not participating in the reaction may be protected with subsequent, if necessary, selective removal of protective groups. 1 tab.

Description

The invention relates to a method

obtaining peptides - new biological active compounds that can be used in medicine.

The purpose of the invention is a method for producing new peptides with higher immunostimulating activity,

Example 1 M-Izovaleryl-O-gamma-glutamyl-gliai-D-alanine

1A "Hydrophore salt of complex benzyl esyr glish-D-ala" NIN.

To a cold (0 ° C) solution of 100 ml of methylene chloride containing 10 (57) N-tert-butyloxycarbonylglyne 20 g (57 mmol) sopi

P TOLUOLSULF ACID COMPLEX

Lovoy Ebir D-lodzina and 5577 g (57 mmol) of triethylamine 8 doarp rt 12.3 g (60 mmol) of diiiklshex utcarbothiimitsa. The resulting reaction mixture is allowed to warm to room temperature. After 18 h, the mixture was filtered and the KOHITPHTPIIPV-South filtrate was removed under vacuum. Os-ag ht DT (.S-K

L

S

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entrap in 200 ml of ethilidate and the organic layer is washed with 2.5% hydrochloric acid, water, saturated sodium bicarbonate solution and brine solution. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure. To the resulting oil, 200 ml of dioxane saturated with hydrogen chloride are added. After 30 minutes, 400 ml of diethyl ether were added and the resulting product was filtered through a field of nitrogen. The yield of 10.9 g (70% -).

Jb. I-tert-Butoxycarbonyl-B-gamma-glutamyl (alpha-benzyl ether) is an oxysuccinamide ester.

To 1500 ml of methylene chloride containing 50 g (143 mmol) of N-tert-butoxycarbonyl-D-gamma-glutamic acid alpha-benzyl ester and 17.3 g (150 mmol) of N-hydroxysuccinimide, are added 30.9 g (15 mmol) of d-cyclohexylcarbodiimide and the resulting reaction mixture is allowed to stir at room temperature for 18 hours. The solids are filtered and the filtrate is concentrated under vacuum. The residue is triturated with diethyl ether and the solids are filtered under a layer of nitrogen. Yield 43.7 g (68%).

1C. The hydrochloride salt of the benzyl ester is D-gamma-glutamyl (alpha-benzyl) -glycyl-D-alanine.

A solution containing 4.3 g (9.45 mmol) of N-tert-butoxycarbonyl-D-gamma-glutamip (alpha-benzyl

ether) -oxysuccinamide ester, 2.71 g (9.92 mmol) of the hydrochloride salt of the benzyl ester of glycyl-D-alanine and 1.0 g (9.92 mmol) of triethyl-amine in 100 ml of methylene chloride are left to stir with room temperature for 18 hours and then concentrated in vacuo. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with 2.5% hydrochloric acid, water, 10% potassium carbonate and brine. The organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure. The residue is treated with 200 ml of dioxane saturated with hydrogen chloride, and left to stir for 2 hours. This solution is concentrated to dryness.

vacuum conditions, and the residue is triturated with diethyl ether. The solids are filtered under a layer of nitrogen. The yield of 3.41 g (73%).

Id. M-Isovalerip-B-gamma-glutamc-glyiip-B-alanine.

1 $ solution of J f 0 t (2.03 mmol.) D-gamma-glutamyl benzyl ester hydrochloride (alpha benzyl ester glycyl-O alanine and 6J 6 mg (6.09 mmol) of triethylamine in 50. ml of methylene chloride 480 mg (4.06 mmol) of isovalerianic acid chloride are added and the reaction mixture is stirred at room temperature for 80 hours. Methylene chloride is evaporated under vacuum and the residue is dissolved in ethyl acetate. The resulting solution is washed with 2.5% hydrochloric acid , water, 10% potassium carbonate, water, and brine solution. The anicic phase is dried over magnesium sulphate and concentrated under vacuum.The residue is triturated with simple diethyl ether, filtered under a layer of nitrogen (910 mg) and 700 mg dissolved in 50 ml of methanol. To this solution is added 200 mg - palladium hydroxide and this mixture are agitated under a hydrogen atmosphere at a pressure of 50 pounds per square inch for 3 hours. The catalyst is filtered and the solvent is removed in vacuo. The residue is dissolved in water and lyophilized to form 364 mg. The yield of the target product is 65%.

YNR spectrum (DMSO-dfe) ppm: 8.25-8.05 (t, 3N); 4.33-4, P (t, 2H); 3.72 (d, J 6 Hz, 2H); 2.21 (t, J 8 Hz, 2H); 1.88-1.68 (t, 1H); 2.08-1.9 (t, 4H); , 1.28 (d, J 8 Hz, 3N); 0.9- (d, j 7 gi, 6H),

Example 2. Using the corresponding acid and the hydrochloride salt of benzyl ether D-gamma-glutamip (el-benzyl ether) -glycyl-O-analyte as starting materials and performing the procedure described in Example ID, compounds were obtained listed in table. 1. All compounds are obtained with a yield of 30-75%.

Example 3. (8) -Methylheptanoyl) -O-gamma-glutamyl-b-alanyl-B-alanine.

BEHIND. Complex benzyl esier N-tert-butoxycarbonyl-b-alanyl-B-alanine

To a solution of 23.0 g (0.121 mol) of H-tert-butoxy-carbonyl-L-alanine, 42.6 g (0.121 mol) of p-toluene-sulphonic acid salt of D-alanine benzyl ester and 17 ml (0.121 mmol). triethylamine in 400 ml of cold (0 ° C) methylene chloride was added dropwise 25.0 g (0.121 mol of dicyclohexylcarbodiimide in 100 ml of methylene chloride. After stirring overnight at room temperature

100 ml of methylene chloride, cooled to 2.0 g (9.64 mmol) of diiiclohexylcarbodiimide in 20 ml of the same solvent are added. After stirring overnight at room temperature, the solids are filtered and the filtrate is concentrated under vacuum. The residue is treated with 150 ml of Etc-acetate, the solids are filtered and the filtrate is washed with 1% hydrochloric acid, 10% carbonate, potassium, water and brine. Ohr

the solids are filtered and the filtrate 55 is dried over sodium sulfate and concentrated to form a white solid, which is triturated with ether to give 4, J g of the desired product. 3D. The hydrochloride salt of the complex benzyl eLira B-gamma-glutamyl (alLa-benzyl eACx) -L-lanyl-D-alanine.

25K suspension 4.1 g (7.2J mmol)

N-tert-bu-yuxi-carbonip-B-gamma-glutamyl (alfa-benzyl ester) -L-alanyl-B-alanine complex benzyl ester in 50 ml of dioxane is added J 00 ml

30 dioxane sprinkled with hydrogen chloride and the reaction mixture is stirred for 3 hours at room temperature. The solvent is removed in vacuo and the residue is powdered with diethyl ether. Output 3.5 g

Here Benzyl ester of (3) -methylheptanoyl-B-gamma-glutamyl- (alpha-benzyl eLir) -T.-alanyl-D-alanine.

To 1.0 g (1.98 mmol) of a complex benzyl B-gamma-glutamyl (alpha-benzyl) -L-alanyl-B-alanine and 0.833 ml (5.93 mmol) of triethyl 45 amine in 50 ml of methylene chloride was added 390 mg (2.37 mmol) of 3- (5) -methylheptanone chloride and the reaction mixture was stirred under a layer of nitrogen for 45 minutes. The reaction mixture is concentrated to an oil. The residue is dissolved in 400 ml of ethyl acetate, which is washed with L% hydrochloric acid solution, J 0% potassium carbonate solution, water and brine solution. The organic phase is separated, dried over magnesium sulfate and concentrated to an oil. The residue is triturated with diethyl ether and the resulting solids are filtered under a layer of nitrogen, 16.0 g. An additional 12.7 g of the expected product is crystallized on (Limate.

3B. The hydrochloride salt of the benzyl ester of L-alanyl-B-alanine.

A suspension of 28.7 g of N-tert-butoxycarbonyl-b-alanyl-B-alanine benzyl ester is taken in 150 ml of dioxane saturated with hydrogen chloride. This mixture is stirred for 4 hours at room temperature. The solvent is removed in vacuo and the residue is triturated with diethyl ether. The resulting solids are filtered, redissolved in methylene chloride, and the solution is concentrated to a volume of J50 ml. Ether and solids are added and filtered under a layer of nitrogen. Yield 22.0 g (35%).

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AP N-tre-50 benzyl ester is poured from 150 ml of ethyl acetate and the organic butoxycarbonyl-B-gamma-glutamyl (the al-phase is washed with 10% chloris-benzyl ester) -L-alanyl-B-alanine.

To a suspension of 5.0 g (9.64 mmol) of dicyclohexylamine al-AA-benzyl CEP, ether L-tert-butoxycarbonyl-B-gamma glutamine and 2.76 g (9.64 mmol) of the hydrochloride salt of the complex benzyl ester b-alanyl V-alanine in

thirty

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hydrochloric acid, 10% rasp by the thief of potassium carbonate, water and brine solution. The organic phase is dried over sodium sulfate and concentrated to dryness. The residue is triturated with ether and filtered under a layer of nitrogen. Yield 900 mg.

3F. N- 3- (5U MethylheptanosH) gamma-glutamyl-b-alanyl-B-alanine.

A mixture of 200 mg of palladium hydroxide on carbon and 900 mg of (S) -methylheptanyl JD-gamma-glutamyl (alpha-benzyl) -L-alanyl-B-alanine benzyl ester in 50 ml of methanol is shaken under an atmosphere of hydrogen at 50 pounds per 1 square. inch to- for 1 hour. The catalyst is filtered and the solvent is removed in vacuo. Water is added to the residue and removed under reduced pressure to form 492 mg of product as a white solid, m.p. 165 - 168 ° C.

 NMR spectrum (DMSO-d), parts per ppm, 8.21-7.98 (t, 3N); 4.41-4.1 (t, 3N); 2.3-2.06 (t, 4H); 2.06-1.56 (t, 6H) j 1.43-1.02 (m, MO); 1.02-0.73 (ms6H)

Example 4. N-p-SJ, U-Tgil-hexanoip-B-gamma-glutamyl (alcBa-n-butyl egyr) -glycyl-B-alanine.

4a. The salt N-tert-butoxycarbonyl-D-gamma-glutamyl-Sylph-n-butyl ether) dicyclohexylamine.,

A solution of 39.5. G (, 0, J72 col) of C-tert-butoxycarbonyl-B-glutamic acid anhydride in 75 ml of dry tetrahydrofuran is added dropwise to the solution of 47 ml (0.5J6 mol ) and 34.3 ml (0, J72 mol), dicyclohexylamine in 300 ml of ether at 0 ° C. The reaction mixture is allowed to stir at 0 ° C for 3 hours and kept in a refrigerator for a night. The solids are filtered, suspended in ethanol, filtered, get 43,3,

4B. B-gamma-glutamyl (alpha-n-butyl alcohol) -glycyl-D-alanine hydrochloride salt of benzyl ester.

The product obtained in Example 4A (10, g, 0.021 mol) and 6.7 g (0.024 mol) of the hydrochloride salt of the benzyl ester of glycyl-B-alanine are suspended in 200 ml of methylene chloride under a layer of nitrogen and cooled to 0 ° C. Dicyclohexylcarbodiimide (4.25 g, 0.021 mol) was added to this suspension and the mixture was allowed to warm to room temperature overnight. The urea by-product is filtered and the solvent is removed in vacuo. The residue is treated with ethyl acetate and filtered. Filtrate sequentially

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0

five

0

five

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washed with water, 2, 5% hydrochloric acid, water, 10% potassium carbonate solution and brine. The organic phase is dried over sulphate, magnesium, the solvent is removed. under vacuum, and the residue is dissolved in 300 ml of dioxane saturated with hydrogen chloride. After stirring for 4 hours at room temperature, the solvent is removed, and the residue is triturated in a mixture of ethyl acetate and hexane (1: 1) and liptitrated. Output 7.4 g

. 4C. (S, R) -ethylhexanoyl-D-glutamyl (alaAn-butyl ether) -glycyl-B-a-lanine.

460 mg (283 mmol) 3- (S, R) was added to the product obtained in Example 4B (1.0 g, 2.35 mmol), 0.99 ml (7.05 mmol) of triethylamine and 50 ml of methylene chloride. -ethylhexanoyl chloride, after which the reaction mixture is stirred overnight under a layer of nitrogen. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. The organic phase is successively washed with 10% hydrochloric acid, water, .. 10% potassium carbonate and brine. The organic phase is separated, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is dissolved in 10 ml of ethanol and shaken with J70. Mg J 0% palladium hydroxide in an atmosphere of hydrogen at an initial pressure of 50 Moon per 1 square inch for 1.5 hours. The spent catalyst is filtered off and the solvent removed under vacuum. Yield 100 mg.

NMR spectrum (DMSO-d), ppm: 8.18 (d, J 6 Hz, 1H); 8.10 (d, j 6 Hz, 1H); 8.02 (t, J 5 Hz, 1H); 4.28-4.10 (ha, 2H); 4.00 (t, J 6 Hz, 2H); 3.78-3.56 (m, 2H) ;. 2.18 (t, J 6 Hz, 2H); 2.02 (d, J 6 Hz, 2H); 2.00-1.60 (t, 3N); 1.58-1.42 (t, 2P); 1.28-1.08 (t, 8H); 1.24 (d, j 6 Hz, 3N); 0.92-0.76 (t, 9H).

Example 5. As a result of applying the procedure described in Example 4- and using the necessary reagents as starting materials, the compounds shown in Table 1 were obtained. 2

Example 6. Compound ethyl eLir (R, S) -til-hexanoip-B-gamma-glutamyl-glipyl-O-alanine.

91560058

6A. Hydrochloride salt complex

D-gamma-glutamine-mil (alpha-benzyl ether) -glycylCh) alanine ethyl ester.

To a suspension of 14.8 g (0.0285 mol) of the salt of dicyclohexylamine of alpha-benzyl ester of N-tert-butoxy-carbonyp-D-gamma-glutamic acid and 6 g (0.0285 mol) of the hydrochloride salt of ethyl ethyl ester of glycyl- D-alanine in 200 ml of methylene chloride was added 5.6 g (0.0270 mol) of dicyclohexylcarbodiimide, after which the mixture was stirred under nitrogen overnight, the urea was filtered and the solvent was removed under vacuum. The residue is treated with 300 ml of ethyl acetate, filtered, and the filter is washed successively with 2.5% hydrochloric acid, water, 10% kalach carbonate solution, and brine. The organic phase is separated, dried over magnesium and concentrated under vacuum. The residual oil is dissolved in 450 ml of dioxane saturated with hydrogen chloride. This solution is stirred for

Benzyl ester (S) - methylheptanoyl-B-gamma-glutamyl (al

2 h, after which the solvent is removed

under vacuum conditions. The residue, which is transformed with -, fa-benzyl ether) glycyl (CH) -alanine, is powdered with ether (30.8 g) is suspended in 300 ml of the absolute and is filtered. Output 11.2 g.

6B. Ethyl ester of N-Q3- (R, S) -ethylhexanoyl-B-gamma-glutamal-glycyl-D-alanine.

To the product obtained in Example 6A (1.0 g, 2.35 mmol) and 0.98 ml (6.98 mmol) of triethylamine in 30 ml of methylene chloride, under a nitrogen atmosphere, add 378 w (2, 33 mmol.) 3- (D, S) -ethylhexanoic chloride. After stirring at room temperature for 1.5 hours, this mixture is poured into 100 ml of ethyl acetate, after which the organic Laza is successively washed with a 10% potassium carbonate solution and brine.

lute ethanol in a 2-liter autoclave ve. To this suspension is added 5% palladium carbon (1.54 g, moistened with 50% water). After that, the mixture is hydro.

-53 genesis is carried out at a pressure 4 times the atmospheric pressure, during which the absorption of hydrogen is completed. The catalyst is separated by Ailtration first on paper and then on porous nylon with a pore size of 0.45 µm using 100-150 ml of ethanol for transfer and rinsing. The filtrate, combined with the wash liquors, is applied to a wet white solid, which is dissolved in 150 ml of hot absolute ethanol mixture.

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Rila at a ratio of 1 ilO, is clarified by hot ailtration, boiled to 35 ml, slowly cooled to room temperature, granulated and filtered to form a crystalline, dense, non-electrostatic product indicated in the title. Yield 20.1 g (94%).

The organic phase is separated, dried with narsulfate magnesium and concentrated in vacuo. The white solid residue is dissolved in 30 ml of methanol and palladium hydroxide in an atmosphere of hydrogen at an initial pressure of 50 pounds per square meter. inch. After 2 hours, the catalyst Ailtruyut, Ailtrath is concentrated to dryness. The residue is taken up in-powder using simple ether and filtered. Yield 275 mg (35%).

ten

NQR spectrum (DMSO-SC), hours per million; 8.26 (d, J 8 Hz, 1H); 8.14-8.02 (t; 2H); 4.31-4.00 (t, 2H); 4.06 (q, J - 10 Hz, 2H); 3.78-3.60 (t, 2H); 1.17 (t, J 8 Hz, 2H); 2.08-1.65 (t, 1H); 2.08 (t, J 8 Hz, 2H); 1.82-1.53 (t, 3N); 1.40-0.96 (t, 5H); 1.23 (d, J - 6 Hz, 3N); 1, 14 (s, J 10 Hz, 311); 0.90-0.64 (t, 6H).

Example 7. By using the appropriate reagents as starting materials and following the procedure described in the example, the compounds shown in Table 2 were obtained. 3

Example 8. The procedure described in Example 6 was repeated using the appropriate reagents as starting materials, with the exception of hydrogenation, whereby the compounds shown in Table 2 were obtained. four.

Example 9. Crystalline (S) -methylheptanoyl-B-gamma glutamyl-glycyl-B-alanine.

Benzyl ester (S) - methylheptanoyl-B-gamma-glutamyl (alpha-benzyl ether) glycylCH) -alanine (30.8 g) is suspended in 300 ml of abs

lute ethanol in a 2-liter autoclave. To this suspension is added 5% palladium carbon (1.54 g, moistened with 50% water). After that the hydro mix

genesis is carried out at a pressure 4 times the atmospheric pressure, during which the absorption of hydrogen is completed. The catalyst was separated by Ailtration, first on paper, and then on porous nylon with a pore size of 0.45 µm using 100-150 ml of ethanol for transfer and washing. The filtrate, combined with the wash liquors, is applied to a wet white solid, which is dissolved in 150 ml of a hot mixture of absolute ethanol.

Rila at a ratio of 1 ilO, is clarified by hot ailtration, boiled to 35 ml, slowly cooled to room temperature, granulated and filtered to form a crystalline, dense, non-electrostatic product indicated in the title. Yield 20.1 g (94%).

IR Spectrum (Nujol Paste), 3340; 3300; 2900; 2836; 1725; 1656; 1628; 1580; 1532; 1455; 1410; .1370; 1280; 1240; 1216; 1175.

This crystalline product, 9.4 g), is further purified by dissolving in 1000 ml of acetone by heating under reflux for 1 hour. This solution is cooled to room temperature and seeded with a trace amount of the indicated crystals. After stirring for 6 hours, the title product was isolated by filtration by washing with a minimum amount of acetone and dried under vacuum at 35 ° C. Yield 7.25 g. Identically added 10.5 ml of sjollohexanone in 40 ml over 1 hour. tetrahydrofuran and the reaction mixture is stirred at room temperature overnight. The reaction mixture is poured into water and extracted with diethyl ether. Organic Bazu washed with 1N. sodium hydroxide solution, water and brine. The organic phase is separated, dried over magnesium sulfate and concentrated under reduced pressure.

The residue is dissolved in 250 ml of the metatic characteristics infrared - "with nola", treated with 1.5 g of 10% hydro.

th spectrum.

Example 10. Complex benzyl-esc esier M-Ј3- (U-methyl-4-heptenoyl J-D-gamma-glutamyl (alpha-benzyl esier) -glycylCH3-alanine.

As a result of performing the procedure described in Example 10 and using 2.77 g (5 mmol) of the hydrochloride salt of the D-gamma-glutamip (alpha-benzyl esyr) -glycyl-B-alanine gasoline ester and the acid chloride obtained from 747 mg, (5 mmol) of 3- (H) methyl 4-heptenoic acid, the title compound is obtained.

Example 11. (R) -methyl-4-heptanoyl j-D-gamma-glutamyl-tl-iyl-D-alanine.

A mixture of 500 mg of the product obtained in Example 10 and 26 mg of 5% palladium carbon (moistened with 50% water) in J25 ml of ethanol is agitated in a hydrogen atmosphere at an initial pressure of 4 times the atmospheric pressure. for 2.5 hours. The catalyst is filtered and the solvent is removed in vacuo. The product obtained is purified in accordance with the procedure described in Example 9, while it is, in all respects, identical to the product obtained in the same example.

Production Method A. Piclohexyl acetyl chloride.

A1. Ethylcyclohexyl acetate,

Sufficient hexane is added to 4.9 tons of 60% sodium hydride in oil to dissolve the oil. To an oil-free sodium hydride under nitrogen is added 1 00 ml of dry tetrahydrofuran, and then a solution of 22.2 ml of triethylphosphonoacetate in 80 ml of dry tetrahydrofuran. After stirring at room temperature and palladium on carbon, after which the mixture is stirred in a hydrogen atmosphere at a pressure of 50 pounds per square inch for 4 hours. The catalyst

filtered, and the filtrate concentrated in vacuo. The residue is distilled at 45-50 ° C and a pressure of 0.4 Torr to form 15.4 g (yield 90% j of the desired intermediate product.

A2 „Giclohexylacetyl chloride.

15.2 g of potassium hydroxide was added to 100 ml of methanol containing 15.4 g of ethylcyclohexyl acetate, after which this solution was heated under reflux for 3 hours. The methanol was removed under vacuum and the residue was treated with water. The solution is extracted with diethyl ether and then acidified with 10% hydrochloric acid. The acidified solution is extracted with fresh ether, the organic phase is separated and washed with water and brine. Removal of the solvent after drying allows a liquid residue to be obtained.

This residue is dissolved in 60 ml of methylene chloride and treated with 18 ml of oxalyl chloride. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under vacuum and the residue was distilled at 45-50 ° C and 0.4 Torr to form 12.5 g of product (yield 86%).

The method of obtaining B.

In the result of performing the general procedure described in the method of preparing A, the use of triethylphosphonoyate acetate and the corresponding aldehyde or ketone as the starting materials, the acid chloride shown in Table 2 is obtained. five.

The method of obtaining C.

C. 6-Methylheptanoyl with 1,3-hydroxy-4-methyl-1-pentyl.,

6.3 ml of isobutyraldehyde in 30 ml of tetrahydrofuran was added dropwise to 90 ml of a 0 M solution of methyl bromide in tetrahydrosoburan cooled to 5 ° C, after which the mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was added to a saturated solution of ammonium chloride and extracted with ether.

The ether extracts are combined by washing with hydrochloric acid and extracted with a saturated solution of ammonium chloride, a saturated solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent is removed in vacuo to give 6.0 g of the expected product.

C2. 6-methyl-4-heptanoic acid ethyl ester.

A mixture of 18.2 g of 3-hydroxy-4-methyl-1-pen-25 potassium oxide. After mixing

Tena, 200 ml of triethyl orthoformate and 500 ml of p-toluenesulphonic acid are treated with 400 ml of toluene and heated to reflux over molecular sieves 4A for 24 hours. The solvent is removed in vacuo and the residue is distilled. A fraction distilled at 45-64 ° C and a pressure of 0.5 Torr affords 7.5 g of the expected product.

NW. Complex ethyl eLir 6-methyl-heptanoic acid.

To 7.5 g of 6-methyl-4-heptenoic acid ethyl ester in 75 ml of methanol was added 700 mg of 10% palladium hydroxide on carbon, after which this mixture was agitated under a hydrogen atmosphere under a pressure of 50 Lunts.

per 1 sq. inch for 1.5 hours. Catalyst. Preparation method E. 3- (5) - ethyl filter is filtered, and the solvent is successful in aluminum. under vacuum conditions to form 5.7 g of the expected product. C4. 6-Methylheptanoyl.

E1. 3- (K) -methylglutaric acid monomethyl ester.

In a 5 liter four-necked flask, As a result of the procedure, 50 equipped with a stirrer and an electrode for the pH described in Preparation Method A2, adjusting the pH, pouring 5.7 g of ethyl methyl alcohol 6.0 liter of 0.01 buffer solution potassium phosphate with a pH of 7.0 followed by the addition of 150 mg of the pig liver esterase and 150 g of dimethyl-3-methylglutarate. The pH of this mixture is maintained at 6.85 by the periodic addition of a 10% potassium carbonate solution. Through

lots get 2.0 g of the target product, t.il. 30-34 ° C at a pressure of 0.5 Torr,

Production Method D. 2-Methylhepta-nocchloride.

D1. 2-methylheptanoic acid.

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5.4 ml of n-heptenoic acid was added to a cold (0 ° C) solution of 100 ml of dry tetrahydrofuran containing 11.8 ml of dry diisopropylamine and 55 ml of a 1.6 M solution of n-butyl lithium, after which the mixture was left for stirring at room temperature for 1 hour. The resulting solution is cooled to 0 ° C and

7.2 ml of methyl iodide. The reaction mixture is stirred at room temperature under a layer of nitrogen for 1.5 h, and then poured into 10%

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diethyl ether (ml). The extracts are combined, washed with 10% hydrochloric acid, water, 20% sodium bisulfate and brine solution, then dried over magnesium sulfate and. The solvent is removed in vacuo, and the residue (5.61 g) is diluted in methanol containing 5.1 g of rv po0

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overnight, the methanol is removed, and the residue is dissolved in 150 ml of water. The aqueous layer was washed with simple air (2 ml) and acidified with 10% hydrochloric acid. The product obtained is extracted with ether, washed with 20% sodium bisulfate solution and brine, and then dried over magnesium sulphate. Removal of the ether affords 5.0 g of the product as a yellow liquid.

D2. 2-Methylheptanoyl.

As a result of using 5 g of 2-methylheptanoic acid and 7.6 ml of oxalyl chloride and applying the procedure described in production method A2, 3.3 g of the desired product are obtained, b.p. 32-34 ° C at a pressure of 0.6 Torr.

There are 2.5 liters of 0.01 potassium phosphate buffer solution with a pH of 7.0 followed by the addition of 150 mg of pig liver liver esterases and 150 g of dimethyl 3-methylglutarate. The pH of this mixture is maintained at 6.85 by the periodic addition of a 10% potassium carbonate solution. Through

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2.5 hours, the reaction mixture is acidified with 10% hydrochloric acid until a pH of 2.0 is reached, after which the product is extracted with simple diethyl ether. The extracts are combined, dried over magnesium sulfate and concentrated in vacuo to give 114 g of the expected product.

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liloxy) pentanoate in 125 ml of ether. The reaction mixture was stirred for 1 hour at 0 ° C, and then 8.4 g of water, 8.4 ml of 15% sodium hydroxide solution and 25.5 ml of water were added dropwise. The solids are filtered, the organic phase is separated and washed with water, 2.5% chloro (f -1.48 ° (CH3CO, C 0.086 g / ml), 1P rice with homogeneous acid and solution

E2. 1 ethyl-3- (K) -methyl-5-hydroxypenta- nate.

To 114 g of monomethyl eAir of 3- (K) -methylglutaric acid in 61 5 ml of dry tetrahydroluran, cooled, to 0 ° C, 391 ml of a 2 M solution of borane dimethyl sulfide in tetrahydrofuran are slowly added. After the addition is complete, the reaction mixture is stirred overnight at at a temperature of about 2.5 m. The reaction mixture is cooled and 50 ml of water are slowly added. The reaction mixture is extracted (3 X100 ml) with ether. The extracts were combined, washed with water, saturated sodium bicarbonate solution and brine solution, then dried over magnesium sulfate. Removal of the solvent affords 37 g of the expected product.

EZ. methyl 3- (K) -methyl-5- (t ret-butyldimethylsilyloxy) pentanoate.

To a solution of 37 g (0.253 mol) of methyl 3- (K) -methyl-5-hydroxypentanoate and 37 g (0.543 mol) of imidazole in 500 ml of dimethylformamide were added 37 g of (O, 249 mol) tert-butyldimethylsilyl chloride after which the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted (4 x 100 ml) with simple air. The combined extracts are washed with 10% hydrochloric acid saturated with rastrassol. The organic base is dried over magnesium sulfate and concentrated under vacuum to form 46 g of product.

 E5. 3- (I) -Methyl-5- (tert-butyldimethylsilyloxy) -3-pentanal.

To 56.3 g of oxalyl chloride in 300 ml of dry methylene chloride, cooled to -60 ° C and under nitrogen at atmosphere, are added dropwise

74.81 g of dimethyl sulfoxide in 100 ml of dry methylene chloride. After 15 minutes, 92.0 g of 3- (S) -methyl-5- (tert-butyldimethyl-25-lyloxy) -pentanol in 250 ml of the same solvent is added dropwise. After 30 minutes, 206.1 g of triethylamine, which is at -60 ° C, is added, followed by removal of the cooling bath.

3Q The reaction mixture is stirred at room temperature for 5 hours, then it is drunk into water and extracted with methylene chloride. The extracts are washed with 2.5% hydrochloric acid, saturated sodium bicarbonate solution, water, and brine solution, and then dried over magnesium sulfate. The solvent is removed, the residue is dissolved in a simple and washed again and dried as previously described. Removal of the ether affords 90.9 g of the expected product.

E6. 5- (S) -Methyl-7- (tert-butyldime35

40

thief of sodium bicarbonate, water, and rapsyl-yloxy) -2-heptene. by brine assembly, and then dried; To a suspension, 80 g (0.2155 mol)

over magnesium sulfate. Removal of the growth methyl bromide trigene-ethylFosbuni in

The solvent allows to obtain 121.78 g 800 ml of dry tetrahydro Auran, an oily product, after distillation of which 107.12 g of pure product are obtained, b.p. 80-81 ° C at a pressure of 0.4 Torr.

E4. 3- (5) -Methyl-5- (tert-butyldimethylsilyloxy) -1-pentanol.

53.5 g (0.206 mol) of methyl 3- (S) -methyl-5- (tert-butyldimethyl) are added to 8.5 g (0.224 mol) of lithium aluminum hydride in 250 ml of diethyl ether under a layer of nitrogen.

005816

liloxy) pentanoate in 125 ml of ether. The reaction mixture was stirred for 1 hour at 0 ° C, and then 8.4 g of water, 8.4 ml of 15% sodium hydroxide solution and 25.5 ml of water were added dropwise. The solids are filtered, the organic phase is separated and washed with water, 2.5% chloro rice figurine with common acid and solution

-

brine. The organic base is dried over magnesium sulfate and concentrated under vacuum to form 46 g of product.

 E5. 3- (I) -Methyl-5- (tert-butyldimethylsilyloxy) -3-pentanal.

To 56.3 g of oxalyl chloride in 300 ml of dry methylene chloride, cooled to -60 ° C and under nitrogen, is added dropwise

74.81 g of dimethyl sulfoxide in 100 ml of dry methylene chloride. After 15 minutes, 92.0 g of 3- (S) -methyl-5- (tert-butyldimethyl-5-yloxy) -pentanol in 250 ml of the same solvent is added dropwise. After 30 minutes, 206.1 g of triethylamine, which is at -60 ° C, is added, followed by removal of the cooling bath.

Q The reaction mixture is stirred at room temperature for 5 hours, then it is drunk into water and extracted with methylene chloride. The extracts are washed with 2.5% hydrochloric acid, saturated sodium bicarbonate solution, water, and brine solution, and then dried over magnesium sulfate. The solvent is removed, the residue is dissolved in a simple and washed again and dried as previously described. Removal of the ether affords 90.9 g of the expected product.

E6. 5- (S) -Methyl-7- (tert-butyl dime 5

0

After addition to O C, 165.7 ml of a 1.3 M solution of n-butyl lithium (0.2155 mol) in the same solvent was added. After 2 hours, 45 g (0.1 96 mol) of 3- (H) -methyl-5- (tert-butyldimethylsilyloxy) -pentanol in 200 ml of dry tetrahydrofuran is added dropwise to the reaction mixture. The reaction mixture is allowed to stir for 2 hours at room temperature, and then poured into water and extracted

simple ether. The combined extracts are washed with water and brine solution, then dried over magnesium sulfate. Removal of the solvent under vacuum conditions yields a yellow oil, from which, after distillation, 37.4 g of product are obtained, b.p. 74-79 ° C at a pressure of 0.2-0.1 Torr.

E7. 3- (S) -Methyl-1-heptanol.

To a solution of 74.8 g of 5- (5) methyl-7- (tert-butyldimethylsilyloxy) -2-heptane in 500 ml of methanol was added 7.5 g of 10% palladium hydroxide on charcoal, after which this mixture was agitated under a hydrogen atmosphere for 1.5 hours at a pressure of 50 pounds per square inch. The catalyst is filtered off and the solvent is removed in vacuo. Exit 30 g

E8. 3- (S) -Methylheptanoic acid.

To 10 g of 3- (S) -methyl-1-heptanol in 175 ml of acetone, 90 ml of Jones reagent at 15-20 ° C are added dropwise over 45 minutes. After 15 minutes, 15 ml of isopropanol are added and stirring is continued for 30 minutes. The reaction mixture was poured into water and the resulting product was extracted with ether. The extracts are combined, washed with water, sodium bisulfate solution and dissolving solution.

la and then dried over magnesium sulphate. Removal of the solvent affords 10 g of the product as a liquid, b.p. 84-88 ° C at a pressure of 0.4 Torg. eLs -4,46 ° (СН3ОН, С - 0,105 g / ml).

E9. 3- (S) -ethyl heptanoyl chloride.

As a result of performing the procedure described in the method of producing A2, using 5.0 g of 3- (5) -methylheptanoic acid and 7.5 ml of oxalyl chloride, 2.9 g of the desired acid chloride are obtained, b.p. 29-32 ° C at a pressure of 0.25 Torr.

Biological tests of the compounds obtained were carried out.

The test procedure in which the sampled mice treated with C.H / HeN was used is shown below. Mice were acclimatized for 5 days before the start of the test, and then they were injected subcutaneously (S C) or various solutions (100; 10; 1 and 0.1 mg / kg) of the test compound or Pleybo (Saline without pyrogenic preparation) in volume of 0.2 ml. Re

five

0

0

The injection pressure depended on the infectious microorganisms used: 24–0 hours before infection with Klebsiella pneumoniae in normal mice; 3, 2 and 1 day before infection with Escherichia co-11 or Staph. aureus in immunocompromised mice. Infection was made intramuscularly (JP) in the case of E.coli and Staph. aureus.

A volume of 0.2 ml was used for infection. Mortality was recorded after 7 days in the case of K. pneumoniae and after 3 days in the case of infection with two other microorganisms.

Cooking culture.

K.pneumoniae, E.coli or Staph. aureus. the culture is isolated in pure form from frozen blood on a brain brain extract (BHI) agar. Three colonies are taken from the culture on Petri dishes grown for 18 hours and placed in 9 ml of heart brain extract broth, the broth cult-uru is incubated for 2 hours at 37 ° C in a circular rocking chair, then 0.2 ml is transferred to the surface of several oblique agar with a brain brain extract. After growing for 18 hours at 37 ° C

beveled agars are washed with heart-brain extract broth, the culture density is adjusted with the aid of Spectronic 20, after which appropriate dilution is made until the infection level is reached in normal rainforests at the appropriate dose resulting in the death of 90% of individuals.

The test results are shown in Table. 6

The tests carried out showed that in the tested doses, the proposed compounds show no signs of toxicity, i.e. can be classified as low toxic.

Claims (1)

Thus, the compounds obtained under the conditions of the proposed method are low toxic and have a higher immunostimulating activity than the known compound FK-156. Invention Formula The method of producing peptides of the general formula O E, -CNH  ---about II ONL (СН2) 2СОЖЖ-С-В3 AT 2 nineteen e R.f - C., - C (0-alkyl, cyclohexip, cyclohexylmethyl; R, is hydrogen; R3 - -NH-CH-COOR5 CE3 Rf is hydrogen, C -C-alkyl, R is hydrogen, C -C-alkyl, benzyl, differing in the fact that the unity of the general formula 1560058 by g n with jq u Н2И I СООВ СН / ь about I ii (CH2) 2CONHCH-C-R3 , where Rj, R3 and P4 have the indicated values, ABOUT   C02H (CH2) 2 CONHCH2 CONHCHC O 2H CH5 n3 (cis) n3 (cis) (EMSO-dt) 8.17-8.22 (m, 2H); 4.35-4.13 (m, 2H); 3.83 (d, J - 6 FIT, 2H) i 2.22 (t, J - 6 Hz, 2H); 2.15 (t, J 6 Hz, 2H); 2.08-1.65 (ha, 2H); 1.45-1.18 (m, 17H); 0.90 - (t, J 7 TV, 3H) 110 (DTtSO-dc) 8.2-8.08; (m, 2H); (decomposition - 8.02 (d, J 9 Gp, 1H); e) 4.3-4.1 (m, 2H); 3.72 (d, J 7 Hz, 2H); 2.53-2.40 (m-, 1H); 2.22 (t, J 9 Hz, 2H); 2.1 -1.7 (m, 2H); 1.28 (d, J 9 Hz, 3H); 1.08-0.9 (m, 6H) GGO (DfTSO-d) 8.3-7.9 (m, 3H); (decomposition - 4.33-4.17 (m, 2H); - 3.72 tion) (d, J - 5 Hz, 2H); 2.32, 1 (m, 2H); 2.10-1.0 (m, 16H) 110 (Df SO-de) 8.25-8.05 (m, (decomposition - NN); 4.35-4.22 (m, 2P); δ) 3.72 (d, J 6 Ki, 2H); 2.22 (t, J 8 Gu, 2H); . 2.12 (t, J 8 Hz, 2P); 2.08-1.77 (m, 2H); 1.55 20 subjected to apilirovdniya compound common formula R1-CO-Hal, where R. has the indicated meanings; On 1 - halogen, moreover, functional groups that are not involved in the reaction can be protected with the subsequent, if necessary, selective removal of protective groups. .Priority on the basis of 5 n akam: 11.25.85 when R is hydrogen; I r - hydrogen. . 08/27/86 with R4 - R f-kil. Table 1 type of: CH3 (CIS) 4CH3 (CIS) 4CH3 CH5 (CH2) zCCHCH2 (b) CH2CHS (CHjCH CF (CHjCUjCH HCK 1g Continued table. one (q, J 8 Gp, 2H); 1.28 (d, j 8 gi, 3F); 0.88 (t, J = 7 Hz, 3N) 190 (DMSO-d) 8.33-8.0 (n, decomposition of ZN); 4.35-4.1 (m, 2H); ie) 3.7 (d, J 6 Gu, 2H); 2.17 (t, J 8 Hz, 2H); 2.1 (t, J 8 Hz, 2H); 2.05-1.63 (m, 2H); 1, 48 -, (t, J 7 Hz, 2H); 1.2-1.1 (m, 7H); 0.85 (t, J 7 Hz, ZN) 180 (D2P) 4.42-4.28 (m, 2H) j decomposition - 3.91 (g, 1H); 2.4 (t, ie) J 7 Hz, 2H); 2.27 (t, J 7 Hz, 2H); 2.22-1.94 (n, 2H); 1.65-1, 55 (m, 2H); 1.39 (d, J 8 Hz, 3N); 1, 34-1, 17. (n, 8H); 0.73 (m, 3H) (DMSO-dc) 8.27-8.03 (n, 3P); 4.32-4.1 (m, 2P); 3.72 (d, j 6 gi, 2H); 2.22 (t, J 10 Gu, 2H) g 2.27-1; 68 (m, 6H); 1.42-1.0 (m, JOP); 0.94-0.8 (n, 6H) () 8.22-8.0 (m, 3H); 4.32-4.1 (m, 2H); 3.8-3.6 (m, 2H) r 2.28-1, 68 (m, 6P); 1.6-1, 0 (m, 12H) r 0.94-0.7 (m, 6H) (DMSO-d6) 8.29-7.97 (m, 3H); 4.33-4.1 (m, 2H)} - 3.81-3.59 (m, 2H); 2.32-1, 65 (and, -6H); 1.65-1, 17 (m, 8H); 1.02-0.68 (m, 6H) (DMSO-dt) 8.3-8.0 (rt, 3H); 4.32-4.1 (m, 2H); 3.85-3.62 (m, 2H); 2.21 (t, J 8 Hz, 2H); 2.02 (d, J 8 Hz, 2P); 2.01-1.9 (m, 1H); 1.85-1.5 (m, 8H); 1, 28 (d, J 8 Hz, 3K) j 1.28-0.8 (m, 5H) (DMSO-dt) 8.18-8.0 (m, 3H); 4.31-4.1 (m, 2H) r 3.84-3.6 (m, 2H); 2.22 (t, J 6 Hz, 2H); 2.4) 7 (d, J 8 Hz, 2P); 2.03-1.7 (m, 3P); 1.4-1.15 (m, 11H); 0.87 (t, J 6 Hz, 6P) 23 NU (СН3СНа) gSNSn СН5 (СН,) 3СНСН2 q, s) CH5 CH5 (CH2) 2CHCH2 (R, S) (sn3) 4sn (cis) 3СН5 CH5 (CH2) 4.CHCR .S) CHSCH2 СН3 (СН2) 5СНСН2 (hell (CH CHCCHJ 156005824 Continued table. one (DMFO-d6) 8.27-7.95 (m, 3N); 4.3-4.1 (m, 2H); 3.78-3.6 (m, 2H); 2.3-1.57 (m, 8H); 1.46-1.13 (m, 8H); 0.84 (t, J 8 Hz, 6H) (DMSO-d6) 8.18-8.0 (m, 3H); 4.24-4.06 (m, 2H); 3.74-3.56 (m, 2H); 2.17 (t, J 9 Gp, 2H); 2.12 2.0 (m, 1H); 2.0-1, 64 (m, 4H); 1, 24 (d, J 6 Gp, 7H); 1.14-0, 98 (m, 2H); 0.81 (d, J 6 Gg. 6H) (DMFO-db) 8.2-8.04 (m, 3H); 4.26-4; 08 (m, 2H); 3.76-3.6 (m, 2H); 2.28- 1.64 (y, 7H) D; 1.4-0.96 (m, 7H); 0.96-0.74 (iti, 6H) (DMSO-dJ 8.24-7.95 (m, 3H5; 4.3-4.08 (m, 2H); 3.81-3.59 (m, 2P); 2.21 (t, J 6 Gp, 2P); 2.11 (t, J 8 PIT, 2H); 2.05 1, 38 (m, 7H); 1.27 (d, J 8 Gyyy, MN); 1.17-1, P (m, 2P); 0.86 (d, JJ 0 Gp, 6H) (DMSO-d6) 8.24-8.0 (m, 3H); 4.33-4.11 (m, 2P) j 3 , 79-3.6 (m, 2H); 2.41-2.29 (tn, 1H); 2.22 (t, J - 8 Hz, W); 2.11-1.66 (m, 2H ); 1.59-1, 43 (m, H); 1.38-1.11 (m, HH); 1.06-0.95 (m, 3H); 0.87 (t, J 6 Hn , ZN) (DrSO-d6) 8.24-8.02 d, 4.32-4.11 (m, 2H); 3.84 3.6 (m, 2H); 2.24 (t, J - 8 Hz, 2E); 2.08 (d, J 8 Hz, 2H); 2.03-1, 63 (4H); 1.44-1.11 (m, 12H) 0.97-0.71 (m, 6H) (DMSO-dt) 8.24-8.04 (m, 3H); 4; 28-4, l (m, 2H); 3.76-3.6 (m, 2H); 2.18 (t, J 6 Hz, 2H); 2.1 J 6 Hz, 2H); 2.04-1.8 (m, 1H); 1, 84-1, 66 (m, 1H); 1.56-1.38 (m, 3H); 25 . ch5 CHS (CH2) 4CHCH2 (R.S) ch5 (СН5) 2СН (СН2) 2 СНСНо (R, s; H3: (CH5) 2CHCH22CHCH2 CH5CH2 CH3 (CH2) 2CHCH2 (K, 5) } -sn2 (sn3sng) 1sn (sleep) 1sn3 CH3 (CH2) 2CH (CH2) 2 (R, s) 156005826 Continued table. one 1.23 d, J 6 Hz, 3N); 1.2-3.06 (m, 3F); 0.82 (d, J 6 Hz, 6K) D 40-d ";) 8.23-7.98 (m, 3N); A, 3-4.13 (m, 2E); 3.81-3.61 (m, 2H); 2.22 (t, J 8 Hz, 211); 2.18-1.68 (ha, 6H); 1.45-1.07 (m, 12H) j 0.98-0.8 (ms 6 (DMSO-dt) 8.37-8.03 (m, 3H); 4; 31-4.1 (m , 2H); 3.78-3.6 (m, 2H); 2.26 (t, J 8 Gi, 2H); 2.2-1.36 (m, 7H); 1.3 (d, J 8 Hz, 5H); 1.26-1.05 (m, 2H); 1.05-0.73 (m, 9H (DMSO-d ;;) 8.23-7.98 (m, 3H); 4.3–4.13 (m, 2H); 3.81–3.61 (m, 2H); 2.21 (t, J 8 Hz, 2H); 2.15–2.0 (m, 2P ); 1.9 (t, J 8 TC, 2H); 1, 85-1, 52 (m, 3H); 1.4-1.22 (m, 3H); 1.22-0.94 (m , 3H); 0.94-0.80 (s, 6H) (DHSO-d6) 8.25-7.98 (m, 3H); 4.3-4.08 (mn, 2H); 3.81 -3.62 (m, 2H); 2.22 (t, J 8 Hz, 2H); 2.06 (d, J 8 Hz, 2H); 2.02- 1.89 (m, 1H); 1 , 87-1, 65 (ha, 2H); 1.41-1, 06 (m, 11H); 0.98-0.7 (m, 6H) () 8.33-7.95 (m, 3H ); 4.3-4.06 (m, 2K); 3.83-3.59 (ta, 2H); 2.21 (t, J "8 Hz, 2H); 2.11 (s, 3H) ; 2.08-1.87 (ra, 1H); 1.87-1, 35 (m, 8H); J, 25 (d, J 8 Ggg, ЗН); 1.22-0.98 (m, ЗН) (D fSO-dc) 8.21-8.0 Xm, 3H); 4.32-4.1 (m, 2H); 3.83-3.6 (m, 2H); 2.21 ( t, J 8 Hz, 2H); 2.11 (t, J and 8 Gi, 2H); 2.05-1.89 (m, 1H); 1.87-1, 67 (m, JH); J, 57-1, 38 (ha SAL 4.38-1.08 (m, 9H); 0.83 J 6 Gg, 6H) (DMSO-dt) 8.24-7.97 (m, 3H 4.33-4.1 (m, 2H); 3.86- 3.59 (m, 2H); 2.35-2.08 ( m, 4H); 2.08-1.9 (m, lH); 27 156005828 Continuation of table 1 CH5 CH2 CH5 (CH2) 4CHCH2-) ch3 СН5 (СН2) 5СНСН2- №, 5) C2H5 СН31СН2) 3СНСН2 CS) Ъ С02Е4 СН (CH2) 2CONHCH2CONHCH (CH3) C02H but 3-Ethylheptanoyl Tie t il 1, 39-1.67 (m, IH); 1.63-1.46 (t, 1H); 1.46-1.02 (t, PN); 0.98-0.73 (t, 6H (DMSO-d6) 8.2-7.94 (t.ZN) 4.26-4.06 (t, 2H); 3.76- 3.56 (t , 2H); 2.16 (t, J 6 Gu, 2H); 2.1-1.84 (t, 3N); 1, 84-1.6 (t, 2H); 1.24 (d, J 6 Hz, 9H); 1, 12-0.92 (t, 3N); 0.92-0.64 6, 9H) (DMSn-dt) 8.23-8.0 (t, 3N) 4.32-4.06 (t, 2H); 3.72 (d, J 8 Hz, 2F); 2.22 (t, J 10 Gu, 2H); 2.16-1.7 (t, 6H); 1.42-1.08 (t, 14P); 0.92-7.0 (m, 6H) (DMSO-dt) 8.2-8.0 (t, 3N); 4.24-4.16 (t, 2H); 3.74- 3.60 (t, 2H); 2.18 (t, J = 7 Hz, 2H); 2.02 (d, J = 7 Hz, 2H); 2.02-1, 6 (t, 3N); 1, 26 (d, j 6 Hz, 3N); 1.26-1.08 (t, 8H); 0.92-0.74 (m, 6F) Tablia 2  6 Hz, 1H); 8.15 (d, J 6 Hz, IH); 8.09 (t, J 6 Gp, 1H); 4.28-4.14 (m, 2F); 3.72 (d, J 6 Hz, 2H); 3.61 (s, 3H); 2.23 (t, Hz, 2H); 2.16-1.70 (m, 6H); 1.34-1.04 (m, 8H); 1, 25 (d, j 7 Hz, 3N); 0.92-0.76 (m, 6H) (DHSO-d6) 8.19 (d, J — 6 Hz, IH); 8.1 1 (d, J 6 Hz, 1H); 8.03 (t, J - 6 Hz, 1H); 4.24-4.10 (m, 2H); 3.74-3.62 Zetylheptanep Ethyl 3-Ethylheptanine Z-typtheptanoip 3-Ethylheptanep 3-Ethylgensano sludge The termination table. 2 nzzzr: teal (m, 2H); 3.57 s, 3F); 2.18. (T, J 9 Hz, 2H); 2.01 (d, J - 6 Hz, 2H); 1.97-1.60 (that, ZN); 1,321, 10 (t, 8H); 1.23 (d, J 7 Hz, ZN); 0, 90-0.72 (t, 6H) (DMSO-de) 8.24-8.02 fa, 4.26-3.96 (t, 211) for 4.04 (q, j 9 Hz, 2H); 3.76-3.56 (and, 2H); 2.17 (t, J -7 Hz, 2K); 2.12-1.63 (t, 6H); 1.74-0.94 (t, 6H); 1.23 (d, J 5 Hz, ZN); 3, 13 (t, J 9 Hz, ZN); 0.88-0.72 (t, 6H) (DMSO-dc) 8.16 (d, J -6 Hz, 1H); 8.09 (d, J 6 Hz, 1H); 8.02 (t, J) - Hz, 1H); 4.22-4.08 (m, 2H); 4.02 (q, J - 7 Hz, 2H); 3.74-3.54 (m, 2H); 2.16 (t, J = 7 Hz, 2H); 2.00 (d, J 6 Hz, 2H); 1.96-1.58 (m, 3H); 1.30-1.08 (rt, 8H); 1.21 (d, J "7 Hz ZN); 1.13 (t, J - 7 Hz, 3N); 0.88-0.70 (m, gobutyl (DMSO-d) 8.14 (d, J 6 Hz, 1H); 8.08-7.98 (m, 2H); 4.20-4.04 (m, 2H); 3.75 (d, J - 6 GP, 2H); 3.68-3.54 (m, 2H); 2.14 (t, J 6 Hz, 2H); 2.08-1.64 (m, 6H); 1.28-0.96 (m, 6H); 1.19 (d, j = 7 Hz, 3N); 0.88-0.70 (m, 12H) gobutyl (DMSO-d) 8.21 (d, J -6 Ki, 1H); 8.14-8.04 (m, 2H); 4.24-4.08 (m, 2H); 3.79 (d, J 6 Hz, 2H); 3.72-3.58 (m, 2H); 2.19 (t, J = 7 Hz, 2H); 2.03 (d, J 6 Hz, 2H); 1.99-1.60 (m, 4H); 1.32-1.10 (m, 8H); 1.23 (d, J 6 Hz, ZN); 0.92-0.72 (ha, 12H) gobutyl (Shbo-dt) 8.18 (d, J 6 Hz, 1H); 8.1 0-8.00 (m, 2H); 4.26-4.08 (m, 2H); 3.79 W, J 6TTPI -Itgge ks ano il - ethylhexanoip -1 ethnheptanoyl -Ethylheptanoyl 2F); 3.72-3.58 (m, 2H); - 2.18 (t, J 6 Hz, 2H); 2.02 (d, J 6 Hz, 2H); 1.98-1, 62 (t, 4H); 1.34 - I, 08 (t, 6H); 1, 23 (d, J - 7 Hz, 3N); 0.96-0.72 (t, W) Ethyl (DMSO-d6) 8.21 (d, J - 7 Gi, 1h); 8.10 (d, j 7 Hz, 1H); 8.05 (t,, T "6 Hz, 1H); 4.26-4.10 (m, 2H); 3.76-3.60 (m, 2H); 3, 59 (s, 3H); 2.18 (t, J - 6 Hz, 2H) j 2.02 (d, J 6 Hz, 2H) $ 2.00-1, 60 (n, 3H); 1.32-1.08 (m, 7F); 0.90-0.72 (m, 6H) Ethyl (DMSO-d6) 8.22 (d, J  7 Gu, 1H); 8.18-8.06 (m, 2H); 4.26-4.10 (ta, 2H); 4.06 (q, J 5 Gu, 2H); 3.78-3.58 (m, 2K); 2.20 (t, J 6 Gi, 2H); 2.04 (d, J 6 Hz, 2H); 2.02-1, 60 (m, 3H); 1.26-1, 20 (m, 7H); 1, 18 (t, J 5 Hz, 3N); 0.90-0.78 (m, 6H) Butyl (DMSO-dJ 8.20 (d, J  7 Hz, 1H); 8.16-8.04 (m, 2H); 4.24-4.06 (m, 2H); 4.00 (t, J 6 Gu, 2H); 3.74- 3.56 (m, 2H); 2.17 (t, L 6 Hz, 2H); 2.12-1, 60 (m, 5H); 1.58-1, 40 (n, 2H); 1, 36-100 (ri, 8H); 1, 21 (d, J 6 Hz, WE); 0.90-0.74 (m, 9H) t: util (DMSO-dt) 8.16 (d, J  7 Hn, 1H); 8.11 (d, j 7 gi, 1H); 8.03 (t, J 5 Hz, 1H); 4.26-4.09 (m, 2H); 3.99 (t, J 7 Hz, 2H); 3.79-3.58 (m, 2H); 2.17 (t, J 6 Hz, 2H); 2.01 (d, J 6 Hz, 2P); 2.00- 1, 60 (m, 3H); 1, 58-1.42 (m, 2H); 1.36-1.08 (m, YUN); 1.24 (d, j 5 Hz, 3N); 0.92-0.72 (ha, 9H) Continued table. 2 D С02Н shi (CH2) 2CONHCH2CONHCH (CH5) CO2% -Methylheptanoyl - ethylhexanoip -Ethylheptanoyl -Methylheptanoip Isobutyl () 8,24 (d, J -6 Hz, 1H); 8.10-8.00 (m, 2H); 4.30-4.18 (m, 1H); 4.18-4.08 (m, IP); 3.86-3.72 (irt, 2H); 3.72-3.58 (m, 2H); 2.16 (t, J 6 Hz, 2H); 2.12-1.64 (m, 6H); 1, 52-J, -00 (m, 6 H); ; 1, 27 (d, J 7 Gy, 3H); 0.90-0.76 (m, 12H3 Isobutyl (DMSfi-dc) 8.23 d, - J 6 Hz, 1H); 8 08-7.99 (m, 2H); 4.29-4.17 (Rh 4H); 4.17-4.07 (m, 1H); 3.83-3.71 (m, 2H); 3.713 .58 (m, 2F5; 2.15 (t, J rf 7 Ki, 2H); 2.04-1, 60 (m, 4H) j 2.00 (d, J -6 Ki, 2H); 1.31-J, 09 (m, 6H) 5 J, 25 (d, J 6 HZ, 3N); 0.90-0.72 (m, 12H) Isobutyl (ShZO-dj.) 8.23 (d, J 6 Hz, 1H); 8.08-7.98 (m, 2H) i 4.29-4.18 (m, 1H); 4.18-4.07 (tn, 1H; 3.86-3.72 (m, 2P); 3.70- 3.57 (m, 2H); 2.15 (t, J 7 Gi, 2H) ; 2.04-1.59 (m, 4H); 2.00 (d, Hz, 2H}; 1.30-1.11 (m, 8H); 1.25 (d, J 6 Hz, 3N) ; 0.89-0.70 (irt, 12H) Methyl- (DMsn-dt) 8.25 (d, J cyclo-6 Gi, 1H); 8.13-8.00 hexip (m, 2H); 4.32-4.20 (m, 1H); 4.20-4.08 (m, 1H); 3.91-3.76 (tn, 2F); 3.763 .59 (m, 2H); 2.18 (t, J = 6 Hz, 2H); 2.13-1.48 (m, 8H); 1, 36-1, 01 (m, 12H); 1, 27 (d, J 6 Hz, 3N); 1.02-0.76 (m, 8H) Table 3 156005836 Continuation of table 3 3 Zlizi 3-Etipheksanoil 3-Ethylheptanoyl 3-ethylheptanoyl 3-Ethylheptanep 3-Ethylheptanoyl Etipsp- (DMSO-dg) 8.25 (d, J ogyxyl 6 Hz, 1H); 8.13-8.0 (n, 2H); 4.32-4.20 Xt, 1H); 4.20-4.08 (ha, 1H); 3.92-3.74 (t, 2F); 3.74- 3.59 (t, 2HJ; 2.18 (t, J 6 Hz, 2F); 2.09-1.86 (t, 1H); 2.03 (d, J 6 Hz, 2F) ; 1, 82-1, 43 (t, 8H); 1.36-1.01 (t, 9H); 1, 27 (d, J 6 Gu, ZN); 1.01-0.70 (t, 8H) tilcyc- (DMSO-d6) 8.26 (d, J oghexil 6 Hz, 1H); 8.12-8.02 (ha, 2H); 4.31-4.19 (p, 1H); 4 , 19-4.08 (t, 1H); 3.93-3.72 (t, 2F); 3.72- 3.58 (n, 2H); 2.18 (t, J 6 Gi, 2H ); 2.08-1.86 (th, 1H); 2.03 (d, J 6 Ki, 2H); 1, 82-1, 48 (t, 8H); 1, 34-1, 02 (t , 11H); I, 27 (d, J 6 Gi, 3F); 1.00-0.74 (t, 8H) teal (DMSO-dt) 8.25 (d, J  6 Ki, 1H); 8.12-8.00 (m, 2F); 4.28-3.96 (m, 2F); 4.03 (q, j 7 gi, 2H); 3.74-3.56 (m, 2H); 2.16 (t, J 9 Hz, 2H); 2.11-1.62 (m, 6H); 1.32-0.98 (m, 6H); 1.24 (d, j = 7 Hz, 3N); 1, 14 (t, J 7 Hz, 3N); 0.88-0.76 (trt, 6H) Tyl (DMSO-d6) 8.28 (d, J e 6 Hz, 1H); 8.16-8.04 dn, 2HJ; 4.32-4.04 (n, 2H); 4.10 (q, J 6 FIT, 2F); 3.78- 3.64 (IP, 2P); 2.22 (t, J 6 Hz, 2F); 2.11-1.92 (m, JH); 2.07 (d, j 6 gg, 211); 1, 86-1, 64 (p, 2H); 1, 40-1, 14 (m, 8H); 1, 30 (d, j 6 gi, 3N); 1.21 (t, j 6 gi, 3N); 0.94-0.76 (ha, 6F) util (DMSO-d6) 8.27 (d, J  8 Hz, IP); 8.14-8.02 (ha, 2H); 4.32-4.10 (ha, 2F); 4.10-3.94 (m, 2F); 3.78-3.60 (m, 24); 2.18 (t, j 6 gi, 211); 2.04 (d, j 6 gi, 2k); 2.04-1, 62 (m, 3F); 1, 60-1, 46 37 3-8-Methylhepta-Butyl noil 3-5-Ethylheptanoyl Kutil 3-Ethylhexanoip About II Tab  D CH (CH2) 2CONHCH2CONHCH {CH3) C02R5 I 38 Continued table. 3  3 util util util (ha, 2H) J 1.38-1.10 (m, 12H); l, 27 (d, J 6 Hz, ZN) {0.90-0.75 (ha, 9H) (D SO-d6) 8.30 (d, J 8 Hz, IP); 8, J 5-8.04 (t, 2H); 4.45-4.12 (t, 2H) j 4.12- 3.98 (t, 2HJ; 3.78-3.65 (t, 2H); 2.22 (t, J 7 Gi, 2K) ; 2.18-1.69 (t, 7H); 1.61-1.48 - (t, 2P); 1.40-1.11 (t, TI); 0.97-0.80 (ha , 9H) (DMSO-d () 8.22 (d, J 7 Gi, 1H); 8.12-8.0 (n, 2H); 4.4-4.16 (n, 2H); 4, 08- 3.95 (t, 2H); 3.75-3.62 (t, 2H); 2.18 (t, J 6 Hz, 2H); 2; 02 (d, J 6 Hz, 2H); 2.04-1.62 (t, ZN); 1.60-1.46 (t, 2H); 1.38-1, G (t, 15H); 0.9- 0.75 (t, 9H ) (DffSO-d6) 8.28 (d, J 8 Hz, 1H); 8.14-8.04 (t, 2H); 4.34-4.10 (t, 2H); 4.10- , 95 (t, 2H); 3.75-3.62 (t, 2P); 2.9 (t, J "6 Hz, 2H); 2.04 (d, J 6 Hz, 2H); 2, 04-1, 60 (m, 3R); 1.60-1.45 (t, 2H); 1.40-1, 10 (t, 13H); 0, PO-0.76 (t, 9H) Table 4 3-Tgetylheptanoyl Butyl 3-5-Methylhepta-Benzyl but silt (m, 2H) i 2.20 (t, J 6 Hz, 2H); 2.04 (d, J 6 Hz, 2H); 2.00-1.60 (t, ZNZ; 1.60-1.49 (tit, 4H); 1.40-1.10 (t, 15H); 0.95-0.72 (t, 12H) Butyl (DMSO-d) 8.26 (d, J = 7 Hz, 1H); 8.19 (d, J = 7 Hz, 1H); 8.07 (t, J 6 Hz, 1H); 4.32-4.31 (m, 2H); 4.02 (t, J 5 Hz, 4H); 3.79-3.59 (m, 2H); 2S20 (t, J 6 Hz, 2H); 2914-1, 68 (m, 5H); 1.61-1.46 (m, 4H); 1.40-1.06 (m, 13H); 0.95-0.31 (ms 12H) Benzyl (DMSO-d) 8.33, J = 7 Hz, 1H); 8.24 (d, J = 7 Hz, 1H); 8.08 (t, J 5 Hz, 1H); 7.33 (s, 10H); 5.08 (s, 4H) 4.40-4.22 (m, 2H); 3.80-3.60 (m, 2H); 2.21 (t, J 5 Gu, 2H); 2.14-1.64 (y, 5H); 1S26 (d, J = 7 Hz, 3N); 1.22-0.98 Cm, 6H); 0.88-0.73 (m, 6H) 45-4770,6 Y-Cho / 55 25-30 / 0.5 S # Continuation of table 4 50CH3 (sna) 1snsnasn1 (R, S) 30-3470,5 snesn2 No. S 31-35 / Os7 R, D C02R4 QTable 6 Activity of compounds iL- it against Klebe $, ella. in $ sha kЈY (CHjhCONHCHC-Rj K2 pneumonia in Ba1 C mice CHjCCH CIKCHpCHjH D NBCHCOjB CH3  R, s s (svl) 2sp ( H HHCHCOjH 6ne NHfcHCOj H Ahh (CH3) gSN (CH,) 3 R, S CHjCCH jOKC HpCH, - R, S CH. (CHt) 4CH (CB9) CHt R, .3 (CH8) tCH (CH,) tCH (CH,) CH2-H YAVSNSP4 R, S (CH,) 3) GRj - S cnr t B D NHCHCOjB "I, D NBCBCOtB 6v5 at at UBCBCOjH bn D HBCHCQ.R H50 Lodkozh-90 10 but 100 140 Behind iOO 70 60 thirty 50 0 one 50 10 one ". - -eleven 100 80 20 90 40 30 thirty thirty AT at at at 50 podko - 100 25 I0no100 1O 200-100 30 20100100 290  ABOUT 1050 110  ABOUT 1050 140  ABOUT 1080 140 50-100 o 1090 170 100 Subcutaneous - 70 25 1050 130 100- -100 25 1050 120 100- -100 23 1080 140 45 Compiled by V. VolkOBOB Editor V. Petrash Tehred M. Khodanych Corrector L. Patay Order 844 Circulation 317 VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5 Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101 1560058 46 Continued not tav. 6 "I"; ff "" yli "" "i and - .. .h L ± And 80 90 30 ABOUT thirty Subscription