Method of producing derivatives of perhydrothiazepin or acid-additive pharmaceutically acceptable sa

专利摘要:
Compounds of formula (I): (wherein: R1 represents an optionally substituted alkyl, cycloalkyl, aryl, partially hydrogenated aryl or heterocyclic group; R2, R3, R4 and R5 represent hydrogen or an optionally substituted alkyl, cycloalkyl, aralkyl, aryl, heterocyclic or heterocyclic-alkyl group or any adjacent pair thereof form a cyclic structure, at least one not being hydrogen; A represents a bond, or a methylene, ethylene, oxymethyl or thiomethyl group; B represents an alkylene, alkylidene, cycloalkylene or cycloalkylidene group; and n is 0, 1 or 2) and salts and esters thereof are hypotensive agents.
公开号:SU1435151A3
申请号:SU853886502
申请日:1985-04-09
公开日:1988-10-30
发明作者:Янагисава Хироаки；Исихара Садао；Андо Акико；Каназаки Такуро；Коике Хироюки；Тсудзита Есио
申请人:Санкио Компани Лимитед (Фирма)；
IPC主号:

专利说明:


cm
The invention relates to a method for producing new, biologically active perhydrotyazepine derivatives of the general formula
COOR, S..R
CHjCH
.
eleven)
SNG
Cun
where ft, hydrogen, phenyl, naphthyl,
thienyl, buffet1 {15
Rj is hydrogen, C, -C-alkyl, phenyl, benzyl, thienip, provided that both R, 4 and R, j cannot be hydrogen-,
RJ is hydrogen, C, -C4-alksh120, or their acid-addition, pharmaceutically acceptable salts, which can be used to treat humans and other animals suffering from increased blood pressure. 25
The purpose of the invention is to develop a method for producing perhydrotyazepine derivatives of general formula I.
The invention is illustrated by the examples below, in which Q describes the preparation of the starting, intermediate and target compounds, including the isolation and / or preparation of their individual isomers. In nuclear magnetic resonance spectra, which are given in some examples, the abbreviation Ph stands for phenyl group. All values for optical rotation are measured using sodium D-line, i.e. all values are given in the form - Cotjjj.
Example 1. Ret Butyl | Shfa- (R) - (1-Toxycarbonyl-3-phenylpropylamino) -5-oco-3; (R) -phenyl-lephydro--1,4-thiazepin-4-Sh1-acetate.
1a, 2- (R) -tert-Bytoxycarbonyl-amino-2-phenyl-methanol.
Under ice-cooling, 10.5 g of di-tert-butyl pyrocarbonate are added to the mixture consisting of 6 g of 1) - (-) - alpha-phenylglycinol and 6 ml of triethylamine, 50 dissolved in 100 mp of methylene chloride, and the mixture was stirred for 15 hours at room temperature. The resulting reaction solution is further concentrated by 55 evaporation under reduced pressure, the residue is dissolved in ethyl acetate and water ... The formed ethyl acetate
35
40
)
ten
15
,
20 25

-
50 55
35
40
the layer is separated, washed with an aqueous solution of potassium hydrogen sulfate and with an aqueous solution of sodium bicarbonate, and then dried with anhydrous magnesium sulfate. The solvent is distilled off to give the title compound as crystals. This compound is then washed with a small amount of diisopropyl ether and cyclohexane to obtain as a result of the purified compound in the amount of 9.9 g. The compound has mp. 136-.
NMR spectrum (CDCl + sufficient (CT) C,) 0 to dissolve the product) o, ppm: 1.36 (9H, singlet, tert-butyl) {3.6-3.75 (3N, g multiplet, 4.3-4.7 (1H, multiplet, Ph-CIb-N) i 6.34 (1H, broad doublet, J 7 Hz, W); 7.20 (5H, singlet, phenyl protons) .
1b. 1 (R) -TpeT-ByTOKCHkap6oHmiaMH-but-2-methanesulfonyloxy-1-phenylzane.
To a solution containing 9.9 g of 2 (R) -tert-butoxycarbonyl-amino-2-phenylthanol, prepared as described in step a, dissolved in 120 ml of methylene chloride, is added dropwise first, 11 ml of pyridine, and then 6, 6 ml of methanesulfonyl chloride, the addition is carried out at room temperature. The mixture was stirred for 15 hours at room temperature, and then the solvent was removed by distillation. The residue obtained is dissolved in ethyl acetate and water and the resulting ethyl acetate layer is separated; the ethyl acetate layer; washed with an aqueous solution of potassium hydrogen sulphate and with an aqueous solution of sodium bicarbonate, and then dried with anhydrous magnesium sulphate. the solvent is separated by distillation. The resulting crystalline residue is collected by filtration and washed with small amounts of diisopropyl ether and cyclohexane to give the title compound in the amount of 12.2 g, i.e. 108-109 ° C.
Nuclear Magnetic Resonance Spectrum (CDCl 3), ppm: 1.42 (9H, singlet, trut-butyl) J 2.84 (3N, singlet,) i 4.36 (2H, doublet, J 5 Hz, C-CHg -0) 7-5.4 (2H, multiplet -, -.- H-CH-Ph) i 7.27 (5H, singlet, phenyl protons).
1s. Benzhydryl ester of (I) -tert-butoxycarbonylamino-2-phenylethyl-H-phthaloyl-L-cysteine,
Sodium bicarbonate in an amount of 7.26 g is added under an atmosphere of gaseous nitrogen to a mixture consisting of 11.7 g L-cysteine p-toluenesulfonate and 8.8 g K-ethoxycarbonylphthalimide,
C HjCH -), 7.5–7.9 (AH, multiplet, phthaloyl protons).
Id. S- 2 (K) -Amino-2-phenylstil -N-β-phthaloyl-L-cysteine trifluoroacetate.
50 ml of trifluoroacetic acid are added, under ice-cooling, to a solution containing 9.9 g of (E) -tert-borated ester benzhydryl ester dissolved in 80 ml of Qtoxycarbonylamino-2-phenylethyl-N-dimethyl forma, and the mixture is stirred-phthalo -L-cysteine, obtained as for 3.5 hours at 90-100 ° C. The reaction mixture is then cooled and dissolved in a mixture consisting of ethyl acetate — is reacted for 2 hours at tata and an aqueous solution of acidic sulphate. Received in
indicated in stage c and dissolved in 50 ml of anisole. The resulting mixture
Fata Kali. The resulting aqueous layer is further oxidized, and then the resulting ethyl acetate layer is separated. The separated ethyl acetate wash layer, the reaction solution was concentrated by evaporation under reduced pressure, and then simple diisopropyl is added to the residue.
C HjCH -), 7.5–7.9 (AH, multiplet, phthaloyl protons).
Id. S- 2 (K) -Amino-2-phenylstil -N-β-phthaloyl-L-cysteine trifluoroacetate.
50 ml of trifluoroacetic acid are added under ice-cooling to a solution containing 9.9 g of (E) -tert-butoxycarbonylamino-2-phenylethyl -H-phalloht-b-cysteine benzhydryl ester, obtained as is reacted over 2 hours. h at room temperature. Received in
toxycarbonylamino-2-phenylethyl -H- -phthalosht-L-cysteine, obtained as subjected to reaction for 2 h at room temperature. Received in
indicated in stage c and dissolved in 50 ml of anisole. The resulting mixture
the result, the reaction solution is concentrated by scrubbing under reduced pressure, and then simple diisopropyl is added to the residue.
sulphate and 2o ether and the target compound are then-dried with anhydrous magnesium sulphate by filtration as an intermediate. Next, 8.6 g of diphenyl (powder) was added in an amount of 8.6 g. This diazomethane. The resulting mixture of intermediate was subjected to cycling for 1 hour in a stream of nitrogen gas, and then the solvent was removed by distillation. The precipitate formed is dissolved in 140 ml of dimethylformamide and then 2 (R) -t-butoxycarbonylamino-2-methanesulfonyloxy-1-phenyletalization is added in the next step without purification.
1e. 5-Oxo-3 (K) -phenyl-6 (K) -phthal-imidoperhydro-1,4-thiazepine.
To a solution containing 8.6 g of S-2 (R) -amino-2-phenyl-1-N-phthalo-I-L on obtained as described in stage 3, in an amount of 12.2 g and sodium carbonate in an amount of 12.2 g. the mixture is stirred for 16 hours at 70 ° C. in a stream of nitrogen gas. The reaction mixture is then dissolved in ethnyl acetate and water, the ethyl acetate layer thus formed is separated, washed with an aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The solvent used was distilled off, and the resulting residue was chromatographed on a column filled with silica gel, using as eluent a mixture of ethyl acetate and cyclohexane in a volume ratio of 1: 4. The result is 9.9 g of the title compound, which is an amorphous material.
Nuclear Magnetic Resonance Spectrum (CDC1,), S, ppm: 1.34 (9H, singlet, tert-butyl); 2.88 (2H, wide doublet, J 6 Hz, S-CH), 3.28 (2H, wide doublet, J 8 Hz, S-CH,); 4.6-5.5 (3N, multiplet,, NH, N — CH — CO, Ph — CH — N), 6.9l (1H, singlet, CHPh); 7.23 (UN; singlet, () GOS); 7.28 (5H, singlet.
thirty
-cysteine trifluoroacetate, obtained 40
go as indicated in step d and dissolved in 50 ml of dimethylformamide and 200 ml of methylene chloride is added dropwise at room temperature
, 9.8 g diphenylphosphorylazide and then 35 grams 6.1 ml of K-metstmorpholine is added.
The resulting mixture is stirred for 16 hours. The solution is then concentrated by evaporation of methylene chloride, and the target substance is separated as crystals by adding 100 ml of ethyl acetate and then adding an aqueous solution of sodium chloride to the resulting reaction mixture, which is further shaken and stirred. . The crystals are then separated by filtration and washed with water and an insignificant amount of ethyl acetate, resulting in 2.25 g of the compound indicated by the title, mp. 280-282 ° C.
Nuclear Magnetic Resonance Spectrum ((CD) 2SO), 8, .m.d .; 2.95 (2H, wide doublet, J 7 Hz, SCHj)} 3.40 (2H, wide doublet, J 6 Hz, 55 SCHj); 5.0 (1H, wide quartet, J 7 Hz, NH-CHPh) -, 5.50 (1H, wide triplet, J 6 Hz) -; 7.1 - 7.5 (5H, multiplet, phenyl proto45
50
2o the ether and the target compound are wiped out by filtration in the form of an intermediate product (powder) in the amount of 8.6 g.
after 25 without purification.
1e. 5-Oxo-3 (K) -phenyl-6 (K) -phthal-imidoperhydro-1,4-thiazepine.
To a solution containing 8.6 g of S- 2 (R) -amino-2-phenyl 1-N-phthalo I-L30
-cysteine trifluoroacetate, obtained0
go as indicated in step d and dissolved in 50 ml of dimethylformamide and 200 ml of methylene chloride is added dropwise at room temperature
, 9.8 g of diphenylphosphorylazide and then 5 is added 6.1 ml of K-metstmorpholine.
The resulting mixture is stirred for 16 hours. The solution is then concentrated by evaporation of methylene chloride, and the target substance is separated as crystals by adding 100 ml of ethyl acetate and then adding an aqueous solution of sodium chloride to the resulting reaction mixture, which is further shaken and stirred. . The crystals are then separated by filtration and washed with water and an insignificant amount of ethyl acetate, resulting in 2.25 g of the compound indicated by the title, mp. 280-282 ° C.
Nuclear Magnetic Resonance Spectrum ((CD) 2SO), 8, .m.d .; 2.95 (2H, wide doublet, J 7 Hz, SCHj)} 3.40 (2H, wide doublet, J 6 Hz, 5 SCHj); 5.0 (1H, wide quartet, J 7 Hz, NH-CHPh) -, 5.50 (1H, wide triplet, J 6 Hz) -; 7.1 - 7.5 (5H, multiplet, phenyl proto5
0
14
here), 7.7 (1H, broad doublet, J = 7 Hz, NH); 7.77 (4H, singlet, phthaloyl protons).
If. tert-Butyl alpha-5-oxo-ZSH -) - phenyl-6 (K) -phthalimidoperhydro-1,4-β-thiazepin-4-yl acetate.
270 mg (50 wt.%) Of a suspension consisting of sodium hydride in mineral oil is added to a solution containing 5 ml of hexamethylphosphoric triamide and 1.9 g of 5-oxo-3 (S-phenyl-6 (R) - phthalimidoperhydro-1,4-thiazole, prepared as described in step e and dissolved in 20 ml of dimethylformamide. The mixture thus obtained is stirred for 5 minutes at room temperature. Next, 1.8 l of tert. -butyl bromoacetate. The resulting mixture is stirred for 1 hour at room temperature, after which it is made further by adding suspension of sodium hydroxide in oil, 55 wt.%, and this suspension is added in a quantity of 0.2 g, and 1 g of tert-butyl bromoacetate is also added. The mixture is stirred for an additional 1 h at room temperature. Next, ethyl acetate is added to the heel mixture, the mixture is washed with an aqueous solution of sodium chloride and then dried with anhydrous magnesium sulfate, after which the solvent is distilled off. The resulting residue is chromatographed on a column filled with silica gel, using as eluent mixture consisting of fl ylacetate and methylene chloride in a volume ratio of research institutes equal to 1:40. As a result, 1.65 g of the title compound is obtained in the form of an amorphous substance. NMR spectrum (CBCI 3), b, ppm. 1.3 (9H, singlet, tert-butyl) {2.8-4.0, (6H, multiplet,); 5.30 (1H, broad doublet, J 8 Hz, -CH-Ph); 5.72 (1H, doublet of doublets, J 4 and 7.5 Hz, N-CH-CO) i 7.30 (5H, singlet, phenyl proton 7.45-7.85 (4H, multiplet, phthaloyl protons).
1g. tert-Butyl alpha-6 (R) -amino-5-oco-3 (R) -phenylperhydro-1, 4-tiazepin-4-yl acetate.
0.7 ml of methylhydrazine is added to a solution containing 1.65 g of tert-butyl alpha 5-oxo-3 (R) -phenyl-6 (R) phthalimide-perhydro-1.4
5 Q

five
0
five
sixteen
-thiazepin-4-yl acetate, prepared as described in step If, dissolved in 20 ml of methylene chloride, and the resulting mixture was allowed to stand at room temperature for 2 hours. Then, the solvent and an excess amount of methylhydrazine are distilled off by distillation. the residue is dissolved in 10 ml of methylene chloride in 1 ml of methanol. The resulting solution is allowed to stand for 12 hours at room temperature, after which the solvent is separated by distillation. Next, a small amount of methylene chloride is added to the resulting residue, and the precipitate formed is filtered off. The filtrate is chromatographed on a column filled with silica gel, and a mixture consisting of methanol and methylene chloride in a ratio of 1:20 is used as eluent. As a result, 1.1 g of the title compound are obtained in the form of an amorphous substance.
NMR (CDC1,) 5, ppm: 1.38 (9H, singlet, tritubutyl); 2.09 (2H, broad singlet, NHj); 2.7-3.4 (3N, multiplet,); 3.64 (2H, AB: quartet, uS 0.47 ppm, J 18 Hz,), 4.47 (1H, doublet of doublets, J 5 and 7 Hz, H N-CH-CO), 5, 36 (1H, doublet of doublets, J 2 and 10 Hz, N-CH-Ph), 7.40 (5H, singlet, phenyl protons).
1h. tert-Butyl alfa- (6 (R) - (1--ethoxycarbonyl-3-phenylpropylamino) -5-oxy-3- (R) -phenyl perhydro-1,4-thiazepin-4-Sh1 acetate.
Sodium carbonate in an amount of 2.4 g is added to a mixture consisting of 1.1 g tert-butyl alpha-6 (R) - -amo-5-oco-3- (R) -phenylpyrgydro -1.4- thiazepin-4-yl | acetate, obtained as in stage g, and 1.4 g of ethyl 2-bromo-4-phenylmethyl butyrate, dissolved in 15 ml of dimethylformamide, and the resulting mixture is stirred for 15 hours at. The reaction mixture is further dissolved in the acetate acetate with a water -, - m solution of sodium chloride. The resulting ethyl acetate layer is separated, washed with water and dried with anhydrous magnesium sulphate, after which the solvent is separated by distillation. The residue obtained is chromatographed on a column filled with silica gel, and as
eluent is a mixture consisting of ethyl acetate and methylene chloride in a ratio of 1: 9. The result is tert-butyl alpha-b (E) (R) -E-hydroxycarbonyl-3-phenylpropane I-amino-3; hd-oxo-3- (R) fIpIpherhydro-1, 4-tiazepin-4-yl | acetate from the first fractions in the form of an oil substance and its output is 0.53 g.
NMR (CBC1) .8, h, ppm: 1.25 (3N, triplet, J = 7 Hz, ... CHj) i 1.37 (9H, singlet, tert-butyl), 1.75-2.2 (2H , multistit,) 2,5-. 4.4 (11H, multiplet, PhCH- -,
Cp-gH-NH-CH-CHi-S-CH ,, N-CHj. SO); 4.15 G5J, quartet, J 7 Hz, COiCH CH,); 5.22 (1H, broad doublet, J 8.5 Hz, N-CH-Ph) j 7.23 (5H, singlet, phenyl protons); 7.31 (5H, singlet, phenyl protons).
From the following fraction, 0.60 g of tert-butyl alpha-BSK) -p- (S) - -ethoxycarbonyl-3-phenylprosham-2-oxo-3 (K) phenylperhydro-1,4-thiasepin-4- is obtained. W1 | acetate, which is an oily substance.
NMR (CDC1,), ppm: 1.27 (3N, triplet, J 7 Hz,,); 1.36 (9H, singlet, tert-butyl); 1.8-2.25 (2H, multiplet,), 2.5-4.3 (11H, multiplet, PhCHj,
co-CH-jra-CH-CHj -s-CHj,);
, 15 (2H, quartet, J 7 Hz,
ten
15
20
25
thirty
nents are added to the condensate. The resulting mixture was thoroughly mixed by shaking and then the resulting aqueous layer was separated. Next, ethyl acetate is added to the aqueous layer, the pH is adjusted to 2.8 by the addition of 3N hydrochloric acid. The resulting ethyl acetate layer was then separated, and the resulting aqueous layer was further extracted twice with ethyl acetate. All extracts in ethyl acetate are then combined and these combined extracts are dried with anhydrous magnesium sulphate. The solvent is distilled off and, as a result, the title compound is obtained in the form of a solid amorphous material; the yield is 270 mg.
NMR (SOSHOZ, ppm: 1.25 (GZ, triplet, J 7 Hz,,); 1.8-2.35 (2H, multistit, PhCHj CH), 2.5 4.55 (YUN, multiplet , PhCH, —CO — CH — —NH — CH — CH, j, —S — CH, j ,,) i 4.12 (2H, quartet, J 7 Hz, CO,) -, 5.17 (1H, broad doublet, J 8.5 Hz), 7.17 (5H, singlet, phenyl protons); 7.22 (5H, singlet, phenyl protons).
Example 3. Alpha- {b (E) (5) -ethoxycarbonyl-3-phenylproshamino | - -5-oxo-3 (U-phenylperhydro-1,4-thiazepine-4-pcs. Acetic acid (compound 27).
0.60 g of tert-butyl alpha-b- (K) 5, 26 (1H, broad doublet, J 8.5 Hz, fl (S) -ethoxycarbonyl-3-phenylpropyl-N-CH-Ph) J 7, 18 (5H, singlet, phenyl-amino-5-oco-3- (R) -fluorohydrogen protons) j 7.29 (5H, singlet, phenyl protons).
Example 2. Alpha- | 6 (R) - - (R) -ethoxycarbonyl-3-phenylpropano-amino-5-oxo-3 (K) -phenylperhydro-1,4-α-thiazepin-4-B11 acetic acid.
0.53 g of tert-butyl alpha-r6 (R) 40
- 1,4-thiazepin-4-yl 1-acetate is treated in the same manner as described in example 2 to obtain the title compound in the form of a solid amorphous substance. Yield 0.21 g
- 1 (R) -stoxocarbonyl-3-phenylpropyl-amino-5-oxo-3 (R) -phenylperhydro-, 4-thiazepin-4-yl | acetate, prepared as described in Example 1, is dissolved in 5-7n anisole and this solution is then reacted with 6 ml of trifluoroacetic acid for 2 hours at room temperature, after which the reaction product is subjected to condensation (evaporation by evaporation under reduced pressure. Then 20 ml of water, 0.9 g of sodium bicarbonate, a small amount of ethyl acetate are added and a large amount of diisopropyl ether, i.e. these compounds
50
55
NMR (CDCl1) S, ppm; 1.28 (3N, triplet, J 7 Hz, C02.) I 1.9– 2.4 (2H, multiplet,), 2.5–3.8 (9H, multiplet PhCH, CH –Z – CH,, N-CH-CO); 4.65 (1H, broad triplet, J 4.5 Hz, N-CHCO); 5.19 (1H, broad doublet, J 8.5 Hz, N-CH-Ph) (J 7.14 5H, singlet, phenyl protons); 7.22 (5H, singlet, phenyl protons); 8.90 (2H, broad singlet, NH).
Example 4. Alpha b (R) R) - -carboxy-3-phenylpropylamino-5-oxo-3 (K) -phenylperhydro-1, 4-thiazepine-4-yl acetic acid.
0
five
0
five
0
nents are added to the condensate. The resulting mixture was thoroughly mixed by shaking and then the resulting aqueous layer was separated. Next, ethyl acetate is added to the aqueous layer, the pH is adjusted to 2.8 by the addition of 3N hydrochloric acid. The resulting ethyl acetate layer was then separated, and the resulting aqueous layer was further extracted twice with ethyl acetate. All extracts in ethyl acetate are then combined and these combined extracts are dried with anhydrous magnesium sulphate. The solvent is distilled off and, as a result, the title compound is obtained in the form of a solid amorphous material; the yield is 270 mg.
NMR (SOSHOZ, ppm: 1.25 (GZ, triplet, J 7 Hz,,); 1.8-2.35 (2H, multistit, PhCHj CH), 2.5- 4.55 (YUN, multiplet, PhCH, -CO-CH- -NH-CH-CH, j, -S-CH, j ,,) i 4.12 (2H, quartet, J 7 Hz, CO,) -, 5.17 (1H , broad doublet, J 8.5 Hz,), 7.17 (5H, singlet, phenyl protons); 7.22 (5H, singlet, phenyl protons).
Example 3. Alpha- {b (E) (5) - -ethoxycarbonyl-3-phenylproshamino | - -5-oxo-3 (U-phenylperhydro-1,4-thiazepine-4-pcs. Acetic acid (compound 27).
0.60 g of tert-butyl alpha-b- (K) - fl (S) -ethoxycarbonyl-3-phenylpropyl-amino-5-oxy-3- (R) -phenylphenylpropyl
 - fl (S) -ethoxycabonyl-3-phenylpropyl-amino-5-oco-3- (R) -phenhydrophydro-
40
- 1,4-thiazepin-4-yl 1-acetate is treated in the same manner as described in example 2 to obtain the title compound in the form of a solid amorphous substance. The yield is 0.21 g.
NMR (CDCl1) S, ppm; 1.28 (3N, triplet, J 7 Hz, C02.) I 1.9– 2.4 (2H, multiplet,), 2.5–3.8 (9H, multiplet PhCH, CH –Z – CH,, N-CH-CO); 4.65 (1H, broad triplet, J 4.5 Hz, N-CHCO); 5.19 (1H, broad doublet, J 8.5 Hz, N-CH-Ph) (J 7.14 5H, singlet, phenyl protons); 7.22 (5H, singlet, phenyl protons); 8.90 (2H, broad singlet, NH).
Example 4. Alpha b (R) R) - -carboxy-3-phenylpropylamino-5-oxo-3 (K) -phenylperhydro-1, 4-thiazepine-4-yl acetic acid.
17t) mg alpha- {6 (K)) - ethoxycar bonyl-3-phenylprophachamino-5-oxo-3 (K) -phenylperhydro-1 i 4-thiazepine-. The 4-yl acetic acid obtained — as described in Example 3 — was dissolved in 0.8 ml of a 1% aqueous solution of sodium hydroxide, and the resulting solution was allowed to stand for 18 hours at room temperature. Next, 0.8 ml of 1N hydrochloric acid is added dropwise to this reaction product to a pH of 2.0. The title compound is precipitated as a powder after this addition is added dropwise. The resulting powder is then separated and washed with a small amount of water and ethyl acetate, to give 70 mg of the title compound.
NMR, ppm: 1.7-2.1 (2H, multiplet,,), 2.4-3.4 (7H, multiplet, PhCH, j, N-CH-CO,,) ; 3.5 (2H, singlet,) -, 4.33 (1H, wide triplet, J 5 Hz, N-CHGO) j 5.30 (1H, wide doublet, J 9 Hz, N-CH-Ph) j 7.23 (5H, singlet, phenyl protons), 7.39 (5H, singlet, phenyl protons).
to 200 ml of a methylene chloride solution containing 25.3 g of 01, -2-amino-1-β-phenylethanol and 45 ml of triethylamine, and the resulting reaction mixture is kept for 12 hours at room temperature. Next, this reaction mixture is condensed by drying under reduced pressure, and
10 then water and diisopropyl ether are added to the resulting condensate.
The resulting mixture is thoroughly mixed and as a result,
15 The title compound, an insoluble, crystalline product, i.e. 123-124 ° C. The yield is 20.6 g. The obtained crystals are filtered off. The formed organic layer in the filtrate is separated and washed with an aqueous solution of potassium hydrogen sulphate and then with an aqueous solution of sodium bicarbonate. The resulting solution was dried with anhydrous magnesium sulphate, and then the solvent was distilled off. The crystals of the title compound are collected by filtration and washing.
Dimension 5. Alpha-b (K) (S) - 30 ° with a mixture consisting of simple iso-carboxy-3-phenylpropylamino-5-ox-3-(R) -phenylper hydro-1, 4-thiaz epin-4-yl1 acetic acid.
165 mg alpha gb-p- (5) -ethoxycarbonyl-3-phenylpropylamino-5-oxo-3 (R) -phenylperhydro-1 4-thiazepin-4-yl 1 acetic acid, prepared as described in example 3 , is treated according to Example 4, thereby obtaining 100 mg of the title compound, which is a solid.
NMR ((CD,) SO) 5 ppm: 1.65- 2.2 (2H, multiplet) i 2.4- 3.4 (7H, multiplet, PhCH ,, N-CH-CO, CH SCUJ; 3.55 (2H, singlet, NCH5, CO); 4.55 (1H, broad triplet, J 5 Hz, N-CHCO) S 5.38 (1H, doublet, J 9 Hz, N-CH- Ph) i 7.25 (5H, singlet, phenyl protons) j 7.41 (5H, singlet, phenyl protons).
Example 6. Tert-Butyl alpha- (6) -1-ethoxycarbonyl-3-phenyl-pro-amine- (5-ox-2-phenyl-perhydro-1, 4-thiazepin-4-yl) acetate.
6a. 2-tert-Butoxycarbosh1pamino -1-phenylethanol.
28 g of tert-butoxycarboschazide are added at room temperature
35
40
45
50
55
propyl ether and petroleum ether, resulting in an additional 18.7 g of product.
NMR ((CD,) SO) 5, ppm: 1.40 (9H, singlet, tert-butyl) {3.15 (2H, multiplet, C-CH,), 4.61 tlH, multiplet, Ph -CH-C), 5.12 (1H, doublet, J 4 Hz, OH); 6.00 (1H, wide triplet Ш); 7.24 (5H, singlet, phenyl protons).
6b. 2-tert-Butoxycarbonylamino--1-chloro-1-phenylethane.
A mixture of 3.7 ml of pyridine and 2.2 ml of methanesulfonyl chloride is added dropwise to a 35 ml solution containing 3.5 g of 2-tert-butoxycarbonylamino-1-phenyl-ethanol, prepared as described in at stage a, in methylene chloride, and the reaction mixture thus formed is allowed to stand for 12 hours at room temperature. The reaction mixture was then concentrated by scrubbing under reduced pressure, and the resulting residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer formed is separated, first washed with water, and then washed with water. 1435151
ten
to 200 ml of a methylene chloride solution containing 25.3 g of 01, -2-amino-1-β-phenylethanol and 45 ml of triethylamine, and the resulting reaction mixture is kept for 12 hours at room temperature. Next, this reaction mixture is condensed by drying under reduced pressure, and
water and diisopropyl ether are then added to the resulting condensate.
The resulting mixture is thoroughly mixed and as a result,
the title compound is an insoluble crystalline product, i.e. 123-124 ° C. The yield is 20.6 g. The resulting crystals are filtered. The formed organic layer in the filtrate is separated and washed with an aqueous solution of potassium hydrogen sulphate and then with an aqueous solution of sodium bicarbonate. The resulting solution was dried with anhydrous magnesium sulphate, and then the solvent was separated by distillation. The crystals of the title compound are collected in the residue by filtration and washing with a mixture consisting of simple
0
five
0
five
propyl ether and petroleum ether, resulting in an additional 18.7 g of product.
NMR ((CD,) SO) 5, ppm: 1.40 (9H, singlet, tert-butyl) {3.15 (2H, multiplet, C-CH,), 4.61 tlH, multiplet, Ph -CH-C), 5.12 (1H, doublet, J 4 Hz, OH); 6.00 (1H, wide triplet Ш); 7.24 (5H, singlet, phenyl protons).
6b. 2-tert-Butoxycarbonylamino--1-chloro-1-phenylethane.
A mixture of 3.7 ml of pyridine and 2.2 ml of methanesulfonyl chloride is added dropwise to a 35 ml solution containing 3.5 g of 2-tert-butoxycarbonylamino-1-phenyl-ethanol, prepared as described in at stage a, in methylene chloride, and the reaction mixture thus formed is allowed to stand for 12 hours at room temperature. The reaction mixture was then concentrated by scrubbing under reduced pressure, and the resulting residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer formed is separated, first washed with water, and then washed with water.
a solution of potassium hydrogen sulphate and then an aqueous solution of sodium bicarbonate. The resulting solution is dried with anhydrous magnesium sulphate. The solvent is then separated by distillation. The resulting residue is subjected to column chromatography using silica gel, using this mixture consisting of ethtacetate and xlcclohexane in a volume ratio of 15:85 as eluent. The result is 0.75 g of the title compound as crystals having m.p. 57-59 ° C.
NMR (CDCl 2), ppm: 1.44 (9H, singlet, tert-butyl), 3.4-3.7 (2H, multiplet,) 4.2-5.15 (2H, multiplet, W, PhCHCl); 7.30 (5H, (Singlet, phenyl protons).
6c. Benzhydryl ester 8- (2-tert-butoxycarbonylamino-1-phenylstil) -N-phthaloylcysteine.
The benzhydryl ester of -Y-phthaloyl-T-cysteine is prepared from 5.0 g of L-cysteine p-toluenesulfonate, 3.8 g of N-ethoxycarbonylphthalimide, 2.9 g of sodium bicarbonate and 3.3 g of diphenyldiazomethane using methods similar to example 1c.
5 g of sodium bicarbonate are added to 60 ml of the solution containing the compound obtained, and 3.9 g of 2-tert-butoxycarbonylamino-1-chloro-1-phenyl-ethane, obtained as described in step b, in dimethylformamide, and the resulting mixture stirred at 65 ° C for 40 hours. The resulting reaction mixture was further diluted with ethyl acetate, washed with an aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent is distilled off, the residue is chromatographed on a column filled with Si.
using a mixture consisting of ethyl acetate and cyclohexane in a ratio of 1: 3 as the solvent. The result is the compound indicated in the title as a solid amorphous substance, the output is 4.0 g.
NMR (CDCl 3) & ppm: 1.36 (9H, singlet, tert-butyl) 3.15-3.7 (4H, multiplet,); 4.10 (1H, broad triplet, J 9 Hz, S-CH-Ph); 4.6-5.2 (2H, multiplet, NH, N-CH-CO); 6.87 and 6.89 (together 1H, both singlet CHPh J; 7.24 (UN,
g c
o
5 n
0
five
0
five
51:
singlet, phenyl protons of benzhydryl); 7.29 (5H, singlet); 6.6 - 6.9 (4H, multiplet, phthaloyl protons).
6d. 5- (2-Amino-1-phenylethyl) -Y-β-phthaloylcysteine.
A mixture consisting of 40 ml of trifluoroacetic acid with 30 ml of an anisole solution containing 4.8 g of 5- (2-tert-butyroxycarbonylamino-1-phenylethyl) -K-phthaloylcysteine benzhydryl ester, prepared as described in in stage c, it is allowed to settle for 4 hours at room temperature, and then the reaction product is concentrated by evaporation under reduced pressure. The resulting, in the form of a residue, the oil substance is washed by decanting using diisopropyl ether. After washing, 50 ml of water is added to the resulting solution, and then 5 g of sodium bicarbonate is added with stirring, and as a result, the title compound is dispensed in an amount of 2.4 g. This product is separated. then subjected to the subsequent cyclization reaction in step e without further purification.
be. 2-Phenyl-6-phthalimidoperhydro -1,4-thiazepin-5-one.
830 mg of 1-hydroxybenzotriazole monohydrate and 1.13 g of N, N -dicyclohexylcarbodiide are added to 40 ml of dimethylformamide solution containing 2.0 g of S- (2-amino-1-phenes-Ethyl) -N-β-phthaloylcysteine obtained as described in step d. The resulting mixture is stirred for 4 hours at room temperature, then 300 ml of ethyl acetate are added to the reaction mixture thus obtained. The insoluble material is separated by filtration, and the resulting filtrate is washed with water and then dried with anhydrous magnesium sulfate. The solvent is distilled off and the result is a title compound in crystalline form. The resulting crystals are collected by filtration and washed with a small amount of ethyl acetate and diisopropyl ether, resulting in 2.0 g of the title compound. This compound softens at about 200 ° C and melts at 240-247 s.
13. 14
 NMR ((SV,) ,, 80) 8Gch./million: 3.9-4.4 (5H, multiplet, Ph-CHS-, -CHj, N-), 5.38 (1H, doublet of doublets, J 3 and 9 Hz, N-CHCO); 7.41 (5H, singlet, phenyl protons); 7.93 {4H, singlet, phthaloyl protons); 8.18 (1H, broad triplet, J 6 Hz, NH).
6f. tert-Vutyl alpha- (5-OXO-2- -phenyl-6-phthalimidoperhydro-1,4-thiazepin-4-yl) acetate.
0.35 g () of a sodium hydride suspension in oil is added, and then 2 g of tert-butyl bromoacetate are added to 20 ml of a dimethylformamide solution containing 1.9 g of 2-fench 1-6-phthalimoperhydro-1,4-thiazepin-5 -one obtained as described in step e, and the resulting mixture was stirred for 1 hour at room temperature. Next, the resulting reaction mixture is diluted with ethyl acetate, washed with water and dried with anhydrous magnesium sulfate. The solvent is separated by distillation, and the residue is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of ethyl acetate and methylene chloride in a ratio of 1:20, and as a result two diastereomers are separated. from the carbon atom in the 2-position. The isomer, which is subjected to zylation first and in an amount of 1.3 g, is called diastereomer A and is a crystalline powder softening at a temperature of about 100 ° C and having a T.
NMR (CBC1) 8, ppm: 1.47 (9H, singlet, tert-butyl); 2.8-4.8 (7H, multiplet, N-CH-CH-S-, N-CHj-CO, S-CH-Ph-CHj), 5.68 (doublet of doublets, J 2 and 10 Hz, N -CH-CO) i 7.40 (5H, singlet, phenyl protons)} 7.65-8, (4H, multiplet, phthaloyl protons).
Then, the next isomer is eluted, in an amount of 0.4 g, which is named as diastereomer B and is a solid amorphous substance,
NMR (CDC1,) S, ppm: 1.40 (9H, singlet, tert-butyl) j 2.45-4.50 (7H, multiplet, N-CH-CH-S, S-CH -CH Ph) i 5.52 (1H, doublet of doublets, J 6 and 9 Hz, N-CH-CO); 7.2-7.5 (5H, multiplet, phenyl protons);
 , five
0
five

five
eleven
7.6-7.8 (4H, multiplet, phthalic
protons).
6g. tert-Butyl alpha- (6-amino-5-oo.xo-2-phenylperhydro-1,4-thiazepine-yl) acetate, obtained from diastereomer A in step f.
1.3 g of the diastereomer A of tert-butyl alpha- (5-oxo-2-fench1-6-phthalimidoper-hydro-1,4-thiazepin-4-yl) acetate, prepared as described in step f, are subjected to dephthaloyl.isation with using methylhydrazine according to the procedure described in example 1g, resulting in 0.66 g of the title compound as an amorphous solid. .
NMR (CDC1,) & h / ppm: 1.46 (9H, singlet, t-butyl); 2.05 (2H, broad singlet, W); 2.4-4.5 (8H, cartoon, -N-CH-CH a SCH-CH -, N-CHj CO); 7.29 (5H, singlet, phenyl protons).
6h. tert-Butyl alpha- (6-amino-6-oxo-2-phenylperhydro-1,4-thiazepin-4-yl) acetate, obtained from the diastereomer B in step f.
0.4 g of the diastereomer B of tert-butyl alpha- (5-oxo-2-phenyl-6-phtapimidoperhydro-1,4-thiazepin-4-Sh1) acetate, prepared as described in step f, is subjected to dephthaloization using methylhydrazine and using the procedure described in example 1g, resulting in 0.22 g of the title compound as an amorphous solid.
NMR (CDC1 :,) S, ppm: 1.41 (9H, singlet, t-butyl); 2.13 (2H, broad singlet, NHi) i 2j7-3.1 (3N, multiplet, C-CH -S-CH-Ph), 4.10- 4.50 (5H, multiplet, N-CH- CO, N-CH -G-Ph) i 7.36 (5H, singlet., Phenyl protons).
6J .. tert-Butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -5-ox-2-phenylperhydro-1,4-thiazepine-4-acetate.
0.66 g of the tert-butyl alpha- (6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4 yl) acetate isomer, prepared as described in step g, is N-alkylated using 0, 84 g of ethyl 2-bromo-4-phenylbutyrate, in accordance with the procedure described in example 1h. The compound obtained is chromatographed on a column filled with silica gel, using a mixture of co15 as eluent.
consisting of ethyl acetate and methylene chloride in a ratio of 1:20. From the first fraction, 0.28 g of tert-butyl alpha-b- (1-ztoxycarbonyl-3-phenylpropylamino) -5-oco-2-phenylperiphydro-1,4-thiazepin-4-yl 1 acetate is obtained in the form of an oil .
NMR (CDC1,) 5, ppm: 1.25 (EH, triplet, J = 7 Hz, 1.47 (9H, singlet, tert-butyl); 1.8-2.25 (2H, multiplet, Pb -CE JV ,,), 2.4-4.5 (14H, multiplet, Ph-CH, CO-CH-NH 2., (9H, singlet, tert-butyl) j 1.8-2.25 {9H , multiplet, PhCHj CI.) 2.6-4.5 (14H, multiplet, PhCH, CO — CH — NH — —CH — CH j, -, S — CH — CH, j, COj CH j CH,) -, 7.26 (5H, singlet, phenyl protons) - 7.36 (5H, singlet, phenyl protons).
From the fraction that is eluted by the second one, 0.08 g of another isomer is obtained due to the asymmetric carbon atom at the 6-position, obtained as indicated above, which is an oil.
NMR (CDCl 2), ppm: 1.25 (3N, triplet, J 7 Hz, C02.,); 1.44 (9H, singlet, tert-butyl) - 1.8-2.25 (2H, multiplet,), 2.4-4.5 (14H, multiplet, PhCH. CO-CH-Shch15
-CH-CH S-CH-CH ,, NCHjCO,, CH3),
7.25 (5H, singlet, phenyl protons); 7.33 (5H, singlet, phenyl protons).
From the second fraction, the resulting elution, receive
0.26 g of another isomer, due-jg -CH-CH, -S-Ql-CH NCH (CO); a go / asymmetric carbon atom of 7.26 (5H, singlet, phenyl proto-6-position of the compound obtained), 7.34 (5H, singlet, phenyl, as indicated above and representing co-protons). is an oil. Example 7. Alpha-b- (1-etoKNMR (CDCLj), ppm: 1.25 (ZN, 25 sikarbonsh-3-phenylpropylamino) -5-about-triplet, J 7 Hz,) i 1.46 co-2-phenylperhydro-1,4-thiazepin-4- (9H, singlet, tert-butyl), 1.8-2.25 (2H, multiplet, Ph-CH CH); 2.5-4.5 (14H, multiplet, Ph-CHj., CO-CH-N-CH-CH-3-CH-CHg, N-CH, pO, .Ciyi ;.
7.26 (5H, singlet, phenyl protons), 7.34 (5H, singlet, phenyl protons).
6J. tert-Butyl alpha-f6- (1-ethoxy-carbon-1-3-phenyl-propylamino) -5-oxo-2-phenyl-perhydro-1, 4-thiazepin-4-yl-sanna in Example 2, and to obtain an acetate. specified
The tert-butyl alpha- (b-amino-5g-oxo-2-phenylperhydro-1, 4-thiazepin-4-yl) acetate isomer in an amount of 0.22 g, prepared as described in step h, is subjected to N-alkylated using 0.28 g of ethyl 2-bromo-4-phenylbutyrate using the same procedure as described in Example 1h.
The product obtained is chromatographed on a column filled with silica gel. A mixture consisting of ethyl acetate and methylene chloride in a volume ratio of 1:20 is used as eluent. From the fraction that
- ethyl acid
tert-Butyl alpha-b- (1-z toxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl acetate in an amount of 0.28 g, prepared as described in example 61 (first fraction), deturbatized with trifluoroacetic acid using a technique, opiva header, in the form of amorphous hard40
One substance, in the amount of 0.18 g
NMR (0001) 6 ppm: 1.25 (3N, triplet, J 7 Hz, CO ,,) 1.8-2.25 (2H, multiplet) J 2.5-4.6 (13H , multiplet, РЬШ, CO-CH-NH-CH-CH -S-CH-QJj, -, N-CH.CO,) ;, 7.25 (4H, singlet, phenyl protons); 7.34 (5H, singlet, phenyl protons).
Example 8. Alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxy-2-phenylperhydro-1,4-thiazepin-4-yl-acetic acid.
0.26 g of tert-butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamine) -5-oxo-2-phenylperhydro-1,4-thiazepine-4-yl} acetate, obtained as described 50
eluted first, 0.14 g of tert-butyl alpha-b- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2-fe0, 26 g of tert-butyl alpha-6- (1--ethoxycarbonyl) 3-phenylpropylamine-5-oxo-2-phenylperhydro-1,4-thiase-4-yl} acetate, obtained as op
nilperhydro-1,4-thiazepin-4-Sh1 acetamine in Example 61 (second fraction).
that
in the form of butter.
NMR (CDClO) Y, ppm: - 1.25 (3N, triplet, J 7 Hz, 1.41
sixteen
(9H, singlet, t-butyl) j 1.8-2.25 {9H, multiplet, PhCHj CI.) 2.6-4.5 (14H, multiplet, PhCH, CO — CH — NH — CH — CH j , -, S-CH-CH, j, COjCHjCH,) -, 7.26 (5H, singlet, phenyl protons) -, 7.36 (5H, singlet, phenyl protons).
From the fraction that is eluted by the second one, 0.08 g of another isomer is obtained, due to the asymmetric carbon atom at the 6-position, obtained as above, which is an oil.
NMR (CDCl 2), ppm: 1.25 (3N, triplet, J 7 Hz, C02.,); 1.44 (9H, singlet, tert-butyl) - 1.8-2.25 (2H, multiplet,), 2.4-4.5 (14H, multiplet, PhCH. CO-CH-Shch15
jg —CH — CH, —S — Ql — CH NCHj, CO); 7.26 (5H, singlet, phenyl protons), 7.34 (5H, singlet, phenyl. - protons). Example 7. Alpha-b- (1-ethoxycarboxy-1-3-phenylpropylamino) -5-oxy-2-phenylperhydro-1,4-thiazepin-4-
sled in example 2, and with the resulting compound indicated
- ethyl acid
tert-Butyl alpha-b- (1-z toxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl acetate in an amount of 0.28 g, prepared as described in example 61 (first fraction), subjected to detritialization using trifluoroacetic acid using a technique, opiv title, in the form of amorphous solid
One substance, in the amount of 0.18 g
NMR (0001) 6 ppm: 1.25 (3N, triplet, J 7 Hz, CO ,,) 1.8-2.25 (2H, multiplet) J 2.5-4.6 (13H , multiplet, РЬШ, CO-CH-NH-CH-CH -S-CH-QJj, -, N-CH.CO,) ;, 7.25 (4H, singlet, phenyl protons); 7.34 (5H, singlet, phenyl protons).
Example 8. Alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxy-2-phenylperhydro-1,4-thiazepin-4-yl-acetic acid.
0.26 g of tert-butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamine) -5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl} acetate, prepared as described
 but in example 61 (second fraction).
deturbated using trifluoroacetic acid according to a procedure similar to
described in example 2, resulting in a compound of the title indicated in an amount of 0.17 g. This compound was a solid amorphous product.
NMR (CDCl5), 8 ppm: 1.26 (3N, triplet, J 7 Hz,,) i 1.8-2.25 (2H, multiplet, PhCHj CH), 2.5-A, 6 (13H, multiplet, PhCH, CO-CH-NH-CH-QHj -S-CH-CHj-, N-CH, j, CO, COiOT,); 7.25 (5H, singlet, phenyl protons); 7.36 (5H, singlet, enyl protons).
Example 9. Apfa-b- (1-ethoxycarbonyl-3-phenylpropylamino) -5-ox-2-feshperhydro-1,4-thiazepin-4- -yl acetic acid (compound 29).
0.14 g of tert-butyl alpha | b- (1--ethoxycarbonyl-3-phenylpropylamino) -5-oxo 2-fensh1perhydro-1,4-thiazepine-4-Sh1 acetate, prepared as described in Example 6j (first fraction), is detritortized using trifluoroacetic acid in accordance with the procedure described in Example 2 and, as a result, obtaining the title compound in an amount of 0.09 g. This compound is a solid, amorphous product.
NMR (CDC1,) S, ppm: 1.25 (3N, triplet, J = 7 Hz, COH 2 CH,), 1.8-2.25 (2H, multiplet) i 2.5-4.5 (13H, multiplet, PhCH, CO-52J-NH-CH-CHj -S-CH-CH, N-CHj.-CO, COCHj CH,); 7.25 (5H, singlet, phenyl protons) J 7.35 (5H, singlet, phenyl protons).
Example 10. Alpha-b- (1-ztoxycarbonyl-3-phenylpropylamino) -5-oxy-2-phenylperhydro-1,4-thiazepine-4-chylacetic acid.
0.08 g of tert-butyl alpha-b- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenyl-perhydro-1,4-thiazepine-4-yl-1-acetate obtained as described in Example 6j (second fraction), was subjected to detretbutillation with trifluoroacetic acid using the procedure described in Example 2, to give the title compound in an amount of 0.05 g. This compound is a solid amorphous substance.
NMR (СРС1,) 5, ppm: 1.26 (ЗН, triplet, J 7 Hz,,); 1.8-2.55 (2H, multidlet,) j
five
0
2.5-5.1 (13H, multiplet, CO — CH — NH — CH — CH j —S — CH — CH -,,, 7.25 (5H, singlet, fenipic protons), 7.34 (5H , singlet, phenyl protons).
Example 11. Alpha-6- (1-carboxy-3-phenylproshamino) -5-oxo-3-α-phenes1-perhydro-1,4-thiazepin-4-yl 3 acetic acid.
0.18 g of apa-b- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl | acetic acid, prepared as described in example 7, is hydrolyzed using an aqueous solution of sodium hydroxide using the same procedure as described in example 4. The result is the title compound, in the form of a powder, in an amount of 0.14 g .
NMR ((CD,) SO) -S, ppm: 1.75-2.15 (2H, multiplet;, PhCHDSYA), 2.55-4.6 (11H, multiplet, PhCH, 5 -CH- NH-CH-QH T SH-CHlV NCH (CO); 7.30 (5H, singlet, phenyl protons); 7.40 (5H, multiplet, phenyl protons).
Example 12. Alpha-b- (1-carboxy-3-phenylpropylamino) -5-hydroxy-2-phenylperhydro-1,4-thiazepin-4-yl acetic acid.
0.17 g of alpha-6- (1-ztoxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenyl-perhydro-1,4-thiazepin-4-yl 3 acetic acid, prepared as described in example 8, is subjected to hydrolysis using caustic soda, according to the procedure described in Example 4. The result is a title compound, which is a powder. The yield is 0.13 g.
NMR ((, H./MN: 1.75- 2.1 (2H, multiplet, PhCHjCH ,.)} 2.55- 4.50 (11H, multiplet,
—CH — N — CH — GH S — CH — CH,); 7.27 (5H, singlet, phenyl protons) 7.38 (5H, singlet, phenyl protons).
Example 13. Alpha-b- (1-carboxy-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-thiazepn-4-yl acetic acid.
90 mg of alpha-Gb- (1-ethoxycarbonyl-r3-phenylpropylamino) -5-oco-2-phenyl-perhydro-1,4-thiase pin-4-yl-2-acetic acid, prepared as described in example 9, is subjected to hydrolysis with aqueous hydroxide solution
0
five
0
0
sodium according to the procedure described in Example 4, thereby obtaining the title compound. This compound is a powder, the yield is 70 mg.
NMR ((CDj) SO) S, ppm: 1.7-2, (2H, multistep,); 2.55- 4.5 (11H, multiplet, PhCHj, —CH — NH — CH — CH —S — CH — CH,); 7.27 (5H, singlet, phenyl protons); 7.40 (5H, singlet, phenyl protons).
Example 14. Alpha- 6- (1-carb hydroxy-3-fensh1propylamino) -5-oxo-2- -phenylperhydro-1,4-thiazepine-4-sh1 acetic acid (compound 30).
50 mg of alpha-b- (1-ethoxycarboxy-1-3-phenylproshamino) -5-oxo-2-phenyl-perhydro-1,4-thiazepin-4-B1 acetic acid, prepared as described in example 10, is subjected to hydrolysis using an aqueous solution of sodium hydroxide in accordance with the procedure described in Example 4, thereby obtaining the title compound. The resulting product is a powder, the yield is 40 mg.
NMR (() S, ppm: 1.7-2.1 (2H, multiplet,); 2, (9H, multiplet, PhCH ,, -CH-NH-CHT -CH-S-CH-CHj) ; 3.97 (2H, AB quartet 0.27 ppm, J 19 Hz); 7.26 (5H, singlet, phenyl protons), 7.40 (5H, singlet, phenyl protons).
Example 15. tert-Butyl alpha-b (R) - (1 -toxycarbonyl-3-phenylpropylamino) -5-oxo-3 (S) - (2-thienyl) - perhydro-1,4-thiazepin-4- silt | acetate.
15a. 2 (5) -tert-butoxycarbonyl but- (2-thienyl) ethanol.
5 g of B- (2-thienyl) glycinol is subjected to tertbutoxycarbonylation in accordance with the procedure described in Example 1a, to give 6.5 g of the title compound and having so pl. 79 ° C.
NMR (CDC1,) S, ppm: 1.43 (9H, singlet, tert-butyl), 2.78 (1H, triplet, J 6.5 Hz, OH) 3.81 (2H, doublet of doublets, J 5.0 and 6.5 Hz CH ,.); 4.98 (1H, doublet of triplets, J 5.0 and 7.0 Hz, N-CH-CO) i 5.34 (1H, broad doublet, J 7 Hz, NH); 6.95 (2H, multiplet, protons in the N3 and C4 positions of the thiophene ring),
ten
15
0
five
7.20 (1H, multiplet, proton in the C5 position of the thiophene ring).
15b. 1 (S) -tert-butoxycarbonyl-amino-1- (2-thienyl) -2-methanesulfonyl-oxethane.
7.07 g of 2- (3) -tert-butoxycarbonyl-amino-2- (2-thiensh1) ethanol, prepared as described in step q, is methanesulfonylated according to the procedure described in example 1b. The result is 8.25 g of the compound indicated in the preform having a mp. 116 ° C.
NMR (CDC1) &, ppm: 1.45 (9H, singlet, tert-butyl) i 2.94 (3N, singlet, CH, SO,) -, 4.42 (2H, doublet, J 4 Hz ,) 5.0-5.4 (2H, multiplet, -Sh-CH-thienyl); 6.8-7.25 (3N, multiplet, protons of the thiophene ring).
15c. Benzhydryl ester of (t) -terbite-botoxycarbonylamino--1- (2-thienyl) ethyl-K-phthaloncysteine. . Loil-1-cysteine complex benzp dryl ester is prepared from 11.7 g L-cysteine p-toluenesulfonate, 8.8 g N-ethoxycarbonylphthalimide, 7.26 g sodium bicarbonate and 8.6 g diphenyldiazomethane, and the process is carried out according to the procedure described in Example 1c. The resulting product is reacted with 11.8 g of 1 (S) -terto-botoxycarbonylamino-1- (2-thienyl) -2-methanesulfonoxyethane, prepared as described in step b, and the result is the compound indicated in the title, in the amount of 13.7 g, which is a solid amorphous product.
NMR (CDC1,) 5, ppm: 1.40, (9H, singlet, tert-butyl), 2.8-3.4 (4H, multiplet, CH —S — CHj) 4.8-5, 2 (3N, multiplet, NH, N-CH-CO, K-CH-thienyl), 6.5-7.2 (3N, multiplet, protons of the thiophene ring) 6.80 (1H, single t, COiCHPh, j) j 7.11 and 7.18 (together YUN, each singlet, benzhydryl phenyl protons); 7.4-7.8 (4H, multiplet, phthaloyl protons).
15d. (5) -amino-2- (2-thienyl) ethyl 3-N-phthaloyl cysteine trifluoroacetate.
Benzhydryl ester of 5 5-G2 (5) -t-butoxycarbonyl-amino-2- (2-thienyl) ethyl-N-phthaloyl cysteine, in an amount of 15.6 g, prepared as described in step c, is subjected to pe0
five
0
five
0
4ctions with trifluoroacetic acid in accordance with the procedure described in Example 1 Id. The result is 12.8 g of the compound indicated in the title: | yuvke. This product is further subjected to
JeaKipiH cyclization in stage e without additional purification. I 15th. 5-Oxo-6 (K) phthalimido-3 (8) - 4- (2-thienyl) perhydro-1,4-thiazepine. I 8- {2 (8) -Amino-2- (2-thienyl) ethyl) -N-phthaloyl-cestine rifluoroacetate, in a salt amount of 12.8 g, obtained as a) at stage d, is subjected to a condensation and cyclization reaction using diphenylphosphide azide in accordance with the procedure described in Grimer 1e, resulting in a compound of the title indicated in an amount of 2-2.5 g, which is m.p. 254-255 ° C.
NMR (CDC1) 5, ppm: 2.8-3.15 (4H, multiplet, CH, -5-CH, g); 4.8- | 5.65 (2H, multiplet, N-CH-CO, N-CH-gtienyl) i 6.9-7.6 (3N, multiplet, | protons of the thiophene ring) 7.87 | (4H, singlet, phthaloyl protons). I 15f. tert-Butyl alpha-5-oxo-I-6- (R) -phthalimido-3 (S) - (2-thienyl) per-hydro-1,4-thiazepin-4-yl3 acetate.
5-Oxo-b- (R) -phthalimido-3- (S) - (2- -thienyl) perhydro-1,4-thiazepine in an amount of 1.3 g, obtained as described in step e, is reacted with tert -butyl bromoacetate in accordance with the procedure described in the example of If, resulting in a compound indicated in the title in the amount of 0.99 g. This compound is a crystalline product having m.p. 211-212 C.
NMR (CDC1,), ppm: 1.36 (9H, singlet, tert-butyl) {2.8-4.2 (6H, multiplet, CH —H-CH,), 5.4-5, 9 (2H, multiplet, N-CH-CO, N-CH- -thienyl), 6.9-7.45 (3N, multiplet, thiophene ring protons) j 7.6- 8.0 (4H, multiplet, phthaloyl protons).
15g. tert-Butyl alpha-b- (K) - -amino-5-oxo-3 (S) - (2-thiesh) perhydro-1,4-thiazepin-4-yl3 acetate.
tert-Butyl alpha-5-oxo-6 (E) -phthalimido-3 (S) - (2-thienyl) perhydro-1,4-thiazepin-4-yl acetate, in an amount of 1.18 g, cured as described in step f, subjected to the reaction of diphthopoxy zacyis using methyl hydrazine in accordance with the procedure described in
five
0
re 1g. The result is 0.77 g of the title compound, which is a solid amorphous substance.
NMR (CDC1,) S, ppm: 1.38 (9H, singlet, tert-butyl) i 2.41 (2H, broad singlet, NH); 2.7-3.65 (4H,. Multiplet, CH -8-SND), 3.68 (2H, AB quartet, U5 0.48 ppm, J 17 Hz, 4.33 (1H, doublet of doublets , J 6.0 and 7.0 Hz, W-CH-CO) 5.44 (1H, doublet of doublets, J 2.5 and 9.0 Hz, N-CH-thienyl); 6.93 (2H, multiplet , protons in and C-positions of the teofen ring) 7.26 (1H, multiplet, proton in the C-position of the teofen ring).
15h. tert-Butyl alpha-6- (R) - (1- -ztoxycarbonyl-3-phenylpropylamino) -5-oxo-3 (S) - (2-thienyl) perhydro-1,4-β-thiazepin-4-yl Accetate .
344 mg of tert-butyl alpha-b (R) - -amino-5-oxo-3 () - (2-thienyl) perhid5 ro-1,4-thiazepine-4-shG acetate, prepared as described in step g, are subjected to N-alkylation reactions with 406 mg of ethyl 2-bromo-4-phenyl butyrate, in accordance with the procedure
Q described in example 1h. The product obtained as a result of this reaction is chromatographed on a column filled with silica gel, and a mixture consisting of ethyl acetate and methylene chloride in a mixture is used as a solvent.
 volume ratio equal to t: 20. As a result, this compound is divided into two isomers: Isomer A and Isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached). Isomer A (in which the carbon atom attached to the phenyl group has the R configuration) is first vilified and is an oily compound. This isomer is obtained in an amount of 0.17 g.
50
NMR (CDC1) (,, ppm: 1.25 (MN, triplet, J 7.5 Hz, 1.40 (9H, singlet, tert-butyl); 1.7 - 2.25 (2H, multiplet , PhCHj CH -); 2.5-4.35 (14H, multiplet, -CH-NH protons of the thiazepine ring, 5 N-CH ,,) i 5.43 (1H, doublet of doublets, J 2.0 and 9, 0 Hz, N-CH-thienyl); 6.9-7.4 (3N, multiplet, thiophene ring protons) J
23
7.20 (5H, singlet, phenyl protons).
Isomer B (in which the carbon atom attached to the phenethyl group has the S-configuration) is eluted second. This isomer was an oily compound, the yield of which was 0.17 g.
NMR (CDC1,) S, ppm: 1.28 (EG, singlet, J 7.5 Hz,); 1.39 (9H, singlet, tert-butyl); 1.8 - 2.2 (2H, multiplet,) 2.55 - 4.2 (12H, multiplet, Phra CH —CH — NH, protons of the thiazepine ring, .N — CH,), - 4.16 (2H, quartet, J 7.5 Hz, COiCJ, j.CH-j), 5.45 (1H, doublet of doublets, J 2.5 and 10.0 Hz, K-CH-thienyl), 6.95-7.45 (MN, multiplet, protons of the thiophene ring); 7.20 (5H, singlet, phenyl protons).
Example 16. Alpha-Gb (E) - -I1 (8) -ethoxycarbonyl-3-phenylpropyl-thiazepin-4-yl acetic acid- (compound 40).
90 mg of alpha-b- (K) (8) -ethoxycarbonyl-3-phenylpropylamino-3-5-oxo-3 (S) - (2-thienne) perhydro-1,4-thiazepin-4-yl | acetic acid, prepared as described in example 16, is subjected to hydrolysis with aqueous
A solution of sodium hydroxide, in accordance with the procedure described in example 4, resulting in 65 mg of the title compound. This compound is prepared in powder type.
NMR ((CD) SO) &, h / mpn: 1.7-2.1 (2H, multiplet, PhCHj CH2); 2.4-3.8 (7H, multiplet, PhCH CH —CH — N, CH, j —S — CH), 3.67 (2H, singlet,
2Q N-CH2.CO) i 4.46 (1H, broad triplet, J 6 Hz, N-CHCO); 5.58 (1H, doublet-doublets, J 2.5 and 10.0 Hz, N-CH-thienyl); 6.9-7.2 C2H, multiplet, protons in C, - and C-positions
C y-poloamino-5-oxo-3 (8) - (2-thiens 1) perhydric – 25 thiophene ring); 7.27 (5H, singlet, phenyl protons); 7.62 (1H, doublet, J 5 Hz, proton to the thiophene ring).
Example 18. tert-Butyl alpha-2 "(1-butoxycarbonyl-3-phenylpropylamino) -5-oxo-2-phenylperhydro-1,4-β-thiazepine-4-shu acetate.
0.34 g tert-butyl alpha- (6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl) acetate, prepared as pointopro-1, 4-thiazepin-4-yl-acetic acid .
160 ml of isomer B tert-butyl alpha b (I) - (1-ethoxycarbon-1-3-phenyl-propylamino) -5-oxo-3 (S) - (2-thien-1) - perhydro-1,4-thiazepin-4- silt | The acetate prepared as described in Example 15h is subjected to the reaction of detretutylation with rifluoroacetic acid according to the procedure
As described in example 6g, the title compound is obtained in the amount of 118 mg, which is a solid amorphous product.
NMR ((CPR) 50) 5, h / mpn: 1.29 (MN, triplet, J 7.5 Hz :, 1.9-2.35 (2H, multiplet, PCHCH2CH); 2.45 -4.2 (9H, multippet, PCHH, -QH-N, CH -S-QH, N-CH,) i 4.26 (2H, quartet, J 7.5 Hz, CO-CH CH, 5.03 (1H, broad triplet, J 6, OHz, kN-CH-CO); 5.62 (1H, doublet of doublets, J 3.0 and 11.0 Hz, L-CH-thienyl); 6.9-7, 3 (2H, multiplet, protons in the C, - and C-positions of the thiophene ring) i 7.32 (5H, singlet, phenyl protons); 7.67 (1H, doublet, J - 5 Hz, proton in C5-- thiophene ring).
45
50
55
N-alkylation with 0.45 g of butyl 2-bromo-4-fench1 butyrate according to the procedure described in example 1h. The product thus obtained is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of ethyl acetate and methylene chloride in a volume ratio between these components equal to 1:40. As a result, the title compound is divided into isomer A and isomer B, the presence of which is due to the asymmetric carbon atom to which the phenethyl group is attached.
Isomer A, which is first eluted, is an oily substance, the yield is 0.13 g.
NMR (CDClI) S, ppm: 0.7-1.1, (3N, multiplet, CH from normal-butyl); 1.46 (9H, singlet, tert-butyl), 1,1-L, 3 (7H, multiplet,
Example 17. Alpha | 6 (K) - -D (8) -carboxy-3-phenylpropylaminoZ-5-oxo-3 (S) - (2-thienyl) perhydro-1,4
5151
24
-thiazepin-4-yl acetic acid- (compound 40).
90 mg of alpha-b- (K) (8) -ethoxycarbonyl-3-phenylpropylamino-3-5-oxo-3 (S) - (2-thienne) perhydro-1,4-thiazepin-4-yl | acetic acid, prepared as described in example 16, is subjected to hydrolysis with aqueous
A solution of sodium hydroxide, in accordance with the procedure described in example 4, resulting in 65 mg of the title compound. This compound is prepared in powder type.
NMR ((CD) SO) &, h / mpn: 1.7-2.1 (2H, multiplet, PhCHj CH2); 2.4-3.8 (7H, multiplet, PhCH CH —CH — N, CH, j —S — CH), 3.67 (2H, singlet,
2Q N-CH2.CO) i 4.46 (1H, broad triplet, J 6 Hz, N-CHCO); 5.58 (1H, doublet-doublets, J 2.5 and 10.0 Hz, N-CH-thienyl); 6.9-7.2 C2H, multiplet, protons in C, - and C-positions
25 thiophene ring); 7.27 (5H, singlet, phenyl protons); 7.62 (1H, doublet, J 5 Hz, proton to the thiophene ring).
C y-poloN, syng2 (1H,
40
 but in example 6g, is reacted
45
50
55
N-alkylation with 0.45 g of butyl 2-bromo-4-fench1 butyrate according to the procedure described in example 1h. The product thus obtained is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of ethyl acetate and methylene chloride in a volume ratio between these components equal to 1:40. As a result, the title compound is divided into isomer A and isomer B, the presence of which is due to the asymmetric carbon atom to which the phenethyl group is attached.
Isomer A, which is first eluted is an oily substance, the yield is 0.13 g.
NMR (CDClI) S, ppm: 0.7-1.1, (3N, multiplet, CH from normal-butyl); 1.46 (9H, singlet, tert-butyl), 1,1-L, 3 (7H, multiplet,
(CH) CH, NHJ. 2,3-4,4 C13H, multiplet,, proton of the thiazepine ring,, CbjCH CCH,), CH,) i 7.17 (YUN, singlet, protons of two-phenyl groups).
Then isomer B is eluted, represented by | which is an oily substance, its amount is 0.12 g. NMR (CDCl), ppm: 0.7-1.1
SN, multiplet, CH nor-butyl);
, 46 (9H, singlet, t-butyl); 1.1 components, equal to 1:40. As a result, the product is divided into two isomers: Isomer A and Isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached).
Isomer A (in which the carbon atom attached to the phenethyl Q group has the R-configuration) is eluted first, it is an oily substance, the composition is 25 (7H5 multiplet, (CH) CH) l 78 mg.
IjhCHjCHi, NH) i 2.3-4.4 (13H, multi-NMR (CDCl) 5, ppm: 0.7-1.1 ppet, protons ty- 15 (3N, multiplet, CH} from norm-zepine ring, butyl); 1.1-2.25 (6H, multiplet,
c6, CH2. (CJ), CH, 1.40 (EN, singlet tert-butyl); 2.5-4.3 (14H, multiplet, PCHCH CH -CH-W, protons
(CH.j) CH); 7, 15 (Yun, singlet, protons of two phenyl groups).
Example 19. Alpha-b- (1-buty-thiazepin-4-yl acetate, half the OO method of Example 18, was subjected) to deturbatilation with trifluoroacetic acid, in accordance with the procedure described in Example 1, resulting in 78 mg of the title compound, which is a solid amorphous material,
NMR (CDC1,) S, ppm: 0.7-1.1
xycarbonyl-3-phenylpropylamino) -5-2o-thiazepine ring, N — CH j —CO, oxo-2-phenyl perhydro-1,4-thiazepine- (CH 2) CH) J 5.44 (1H, doublet 4 or 1 acetic acid-doublets , J 2.5 and 9.5 Hz, N-CH-thie, 12 g of isomer B tert-butyl alpha-nyl) J 6.9-7.4 (3N, multiplet, proto-b- (1-butoxycarbonyl 3-phenylpropyl thiophene ring), 7.20 (5H, mino-5-oxo-2-phenyl-perhydro-1,4-25 singlet, phenyl protons).
Isomer B (in which the carbon atom attached to the phenethyl group has an δ configuration) is eluted second. This product is a 3Q oily substance, its yield is 100 mg.
NMR (CDCl 2), ppm: 0.8-1.1 (MN, multiplet, СН from norm-butyl); 1.15-2.2 (6H, multiplet,
-, -, , Cd2.CHjCH) CH. ,,) -, 1,
1 (ZN, multiplet, SI, from n-butyl) i (9H, singlet, tert-butyl); 2.5-4.3 l, 1-1.8 (4H, multiplet, COGCH CH CHR; (14H, multiplet, FhCH H -CH-NH, 11.95-2.5 (2H, multiplet., PCHH protons thiazepine ring, | 2.5-4.7 (13H, multiplet,, (SNDSN), 5.43 (1H, | PhCH CH CH-N, protons of thiazepine., wide doublet, J 9 Hz, N-CH -thienyl), 6.9-7.4 (3N, multiplet, protons of the thiophene ring), 7.20 (5H, singlet, phenyl protons).
Example 21. Alpha-Gb (K) - - {(8) -butoxycarbonyl-3-phenyl-amino-5-oxo-3 (S) - (2-thienyl) perhydro-1,4-thiazepin-4- Il-acetic acid.
100 mg of isomer B tert-butyl al--1,4-thiazepin-4-yl acetate, obtained (K) - (1-butoxy-carbonyl-3-phenoxy as described in Example 15g, subpropylamine) -5 -oxo-3 (S) - (2-thieves the reaction of N-alkylation with water); perperhydro-1,4-thiazepin-4 yl 2 -acetate, prepared as described in Example 22, is reacted with trifluoroacetic acid in order to remove - chromatographic on a column using its tert-butyl group, forming a mixture as eluent, washing is carried out in accordance with the procedure described in c. example 2. As a result of this treatment receive
ьца, CO, ONg (CH.) CH3); 7.18 (YUN, singlet, protons of two phenyl groups)
Example 20. tert-Vutyl alpha b (R) - (1-butoxycarbonyl-3-phenylpropylamino) -5-oxo-3 (S) - (2-thienyl) - perhydro-1,4-thiazepin-4-yl acetate.
345 mg of tert-butyl alpha-b (E) -ami-HO-5-OXO-3 (S) - (2-thienyl) perhydro 450 ml butyl 2-bromo-4-phenyl butarate in accordance with the method of example 1h. Reaction product further
45
consisting of ztiratel acetate and methylene chloride in the ratio between these components is 1:40. As a result, the product is divided into two isomers: Isomer A and Isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached).
Isomer A (in which the carbon atom attached to the phenethyl group has the R-configuration) is eluted first, it is in the range 143515128
60 mg of the compound indicated in the title-1.47 (9H, singlet, tert-butyl), 1.7 hours and representing solid-2.2 (2H, multiplet,); 2,4-dy amorphous material. 4,2 (13H, multiplet, PhCH2.CHj CHCO-NH, NMR ((005) 30) & h / mn: 0.90protons of the thiazepine ring of CHHSSN) ,,, (( ZN, wide triplet, J 7 Hz, CH, N-CH -CO2); 4.12 (2H, quartet, J from n-butyl); 1.1-1.8 (4H, multi-7.4 Hz,); 1.19 (5H, singlet,,) 2.0-2.3, phenyl protons). (2H, multiplet,.,), 2.5-4.3 Example 23. Alpha-b (R) - (11H, multiplet, PhCH CH2-CH-N, s - GI) ethoxycarbon-1-3-phenylpropyl - CKjSCR,, (j) amino) -3 (K) -of) O1 gal-5-oxoperhydro-5.03 (1H, broad triplet, J 5 Hz, -1,4-thiazepin-4-sh1 acetic acid. N-CH-CO ); 5.62 (1H, doublet of doublets, 0.32 g of tert-butyl apfa- | 6 (Yu-; J 3.0 and 10.0 Hz, -CH-thienyl) -, 6.95- - 1 (S ) -ethoxycarbonshl-3-phenylprosh-7.3 (2H, multiplet, proton at 15 amino-3 (R) isopropyl-5-octo-prophydro-CJ and C-positions of thiophene.-1,4-thiazepin-4-yl acetate , prvdstav-rings) J 7.30 (5H, singlet, phenyl-containing isomer B and synthesized protons) 7.67 (1H, doublet, J as described in Example 22, 5 Hz, Proton at 5 the position of the thiofere-subjected to the reaction of detretbutilirov new kolitsa) .20 using trifluoroacetic acid Example 22. tert-Butyl alpha, you, according to the method, opi-6. (K) - (1-this sikarbonil-3-Phenylpro-toboggan in Example 2. As a result popilamino) -3 (R) -izopropsh1-5-oksoper-shuchayut 260 mg of the compound of this
hydro-1,4-thiazepin-4-Sh1 acetate (co-in the title and representing
unity 206). 25 solid amorphous material.
The procedure described in example 1НМР (CDC1,) 5, ppm: 0.98 (6H,
in steps from a to h, a wide doublet is repeated, J 4 Hz, CH (CH),}
except that as 1.24 (ZN triplet, J is 7 Hz,
the starting material used is D-2-CO CH CH,), - 1.7-2.3 (2H, multiplet,
-amino-3-methyl-1-butanol. As a result, 2); 2.4-4.8 (12H, multiplet,
they receive 2 isomers (due to N-CBH,.,. NgCYC 0 III protons, thiazepine moiety of asymmetric carbon atom, th ring, CH (CH, -N-CHj, -CO) -, 4.15
to which phenethyl is attached (2H, quartet, J 7 Hz,, CH,),
Group). The first isomer (isomer A) 7.12 (5H, singlet, phenyl protons),
is tert-butyl alpha. Example 24. Alpha- {b (E) -p (S) - {b- (R) - l (R) -ethoxycarbonyl-3-phenyl-carboxyphenylpropro1amino} 3 (R) - isopropylamino) -3 (R) -isopropyl-5-oco-propyl-5-hydroxyperhydro-1,4-thiazepineperhydro-1, 4-thiazepin-4-yl acetate, -4-sh1 acetic acid slot.,
and the second isomer (isomer B) is tert-bu
type alpha-6 (R) (8) -ethoxycarbo-1bO mg alpha- {6 (R) (S) -ethoxy-3-phenylpropylamino-3 (R) -isopro-carbonyl-3-phenylpropanolamo j-3 ( R) - peel-5-oxoperhydro-1,4-thiazepin-4 - isopropsh-5-oxoperhydro-1,4-thiaz-ayl acetate, these isomers, represented by lipin-4-yl-1-acetic acid, are oily products. Noah as described in Example 23, the hydro- isomer A. Zuo aqueous solution of hydroxide
NMR (CDCl 3) S ppm: 0.98 (6H, sodium according to the procedure
a doublet of doublets, J 3.0 and 6.5 Hz, which is described in Example 4. In peCH (CE) Y, 22 (3N, triplet, J 7 Hz, as a result of this reaction,
); 1j47 (9H, singlet, tert-certain, specified in the title, in the number of.-Butyl) J 1.6-2.2 (2H, multiplet, 113 mg, representing
Ph CH-iQH), 2.4-4.4 (15H, multiplet, powdered material.
PhCH CH CHCO-NH, protons thiazepine-NMR (() S ppm: 0.97
single salt, CH (CH,) 2, N-CH2. —CO, (6H, doublet, J 6 Hz, CH (CH,) 4) i
SOGCH SN); 7.19 (5H, singlet, fe-J, 7-2.2 (2H, multiplet,.),
yielding protons) .2.3-4.4 (YUN, cartoon, isomer B. PhCHj CH, j CHCO-NH, protons T1 azepine-.
NMR (CDC1,) S, ppm: 1.00 (6H, th ring, CH (CH,);,) -, 3.83 (2H, Singlet, 5 Hz, CH (CH,)), 1.23 years old,) -, 7.25 (5H, singlet
(ZN triplet, J 7 Hz,); phenyl protons).
Example 25. tert-Butyl alpha-b (R) - (1-ethoxycarbonyl-3-phenyl-Yropylamino) -3 (R) -methyl-5-oxoper-I idpo-1,4-thiazepin-4-yl} acetate ,
The procedure described in 4th x from a to h of Example 1 is repeated, except that D-2-amino-1-propanol is used as a starting material. As a result of this procedure, two isomers are obtained (due to the presence of an asymmetric carbon atom to which a phenehyl group is attached). One of these isomers (isomer A) is gret-butyl alpha-b (R) -1 (R) -ethoxy-sarbonyl-3-phenylproshamino-3 (D) -methyl-1-5-oxoperhydro-1, 4-thiazepine-a-yl acetate These isomers are oils.
Isomer A.
NMR (CDC1,) S, ppm: 1.22 (ZN, triplet, J 7 Hz,,) 1.29 1 (ZN, doublet, J 6 Hz, 3-CH.j) -, 1.46 | (9H, singlet, trut-butyl) 1.7-2.2: (2H, multiplet, j); 2.3-4.2 I (YUN, multiplet, Ph, CHj, CH CHCO-NH, protons of the thiazepine ring) -, 3.97 (2H, singlet, N-CH-CO) -, 4.11 (2H, quartet, J 7 Hz,,); 7.19 (5H, singlet, phenyl protons).
Isomer B.
NMR (CDCl1) 8, h, ppm: 1.26 (3N, triplet, J 7 Hz,,); 1.32 (ZN, doublet, Hz, 3-CH3); 1.7-2.3 (2H, multiplet, Ph),, 2, (YUN, multiplet, pH CH CH CHCO-NH, protons of the thiazepine ring); 3.98 (2H, AB quartet & S 0.33 ppm, J 17 Hz,); 4.13 (2H, quartet J 7 Hz, 7.18 (5H, singlet, phenyl protons i).
Example 26 Alfa-6 (R) - - 1 (8); - ethoxycarbonyl-3-phenetroph-1 is a solid amorphous product, the yield of which is 334 mg.
NMR (CDC1) &, ppm: 1.26 (3N, triplet, J 7 Hz,) i J. 32 (ZN, doublet, J 6 Hz, Z-CH,),
1.8-5.0 (15H ,, multiplet,
Ph
15
20
25
CH CH; CHCO-NH, protons of thiazepine 1Q rings,,,), 7.12 (5H, singlet, phenyl protons).
Example 27. Alfar 6 (R) - - 1 (BO-carboxyphenylpropylamino - -3 (R) -methyl-5-oxy-perhydro-1,4-thiase pin-4-yl1 acetic acid.
175 mg alpha Hb (R) - l (8) -ethoxycar bonyl-3-phenylpropylamino-3 (R) -MeTmi-5-oxoperhydro-1,4-thiaz epin-A-yl - acetic acid, prepared as described in Example 26 , is hydrolyzed with an aqueous solution of sodium hydroxide, the reaction is carried out in accordance with the procedure of Example 4. The result is a compound indicated in the title, which is a powdery material, the output of which is 93 mg.
NMR ((CD,) SO) S, ppm: 1.28 (ZN doublet, J 6.5 Hz, 3-CH,); 1.7-2.1 (2H, multiplet, Ph) -, 2.3-4.35 (9H, multiplet, Ph CH CH CH CH-NH, protons of the thiazepine ring); 3.98 (2H, AB quartet, uS 0.28 ppm, J 17 Hz,), 7.26 (5H, singlet, phenyl protons).
Example 28. tert-Bugil alfa- {3 (S) -benzyl-5 (R) - 1 (5) -ethoxycarbonyl-3-phenylpropylamino -5-oxb-perhydro-1,4-thiazepin-A- w / w acetate
The procedure indicated in steps a to h of example 1 is repeated, except that L-2-amino-3-phenyl-1-propanol is used as the starting material. As a result,
35
40
amino -3 (K) -metsh1-5-oxoperhydro-1,4-yielded 2 isomers (due to
-thiazepin-A-yl acetic acid (compound 171).
0.41 g of tert-butyl alpha-r6 (R) - - 1 (8) -ethoxycarbonyl-3-phenylpropnl-amino (3R) -methyl-5-oxoper gndro-1,4-thiazepin-A-yl) acetate, the isomer B, and synthesized as described in Example 25, is subjected to the reaction of decaying with.
50
the asymmetric carbon atom to which the phenethyl group is attached). These isomers are isomer A, which is tert-butyl alpha 3 (8) -benz 1-6 (11) (K) -β-toxycarbonyl-3-phenylpropylamine 6 -5-oxoperhydro-1,4-thiazepine- A-yl | - acetate, and isomer B - tert-butyl alpha 3 (8) -benzyl- (R) (5) -ethoxycarbonate with trifluoroacetic acid in 1-1-3-phenylpropylamino-3-oxo-pero-compliance with the procedure described in hydro-1, A-thiazepin-A-sh1 | acetate. These
the resulting isomers are oily products.
example 2. The result is a connection specified in the header.
which is a solid amorphous product, the yield of which is 334 mg.
NMR (CDC1) &, ppm: 1.26 (3N, triplet, J 7 Hz,) i J. 32 (ZN, doublet, J 6 Hz, Z-CH,),
1.8-5.0 (15H ,, multiplet,
Ph
five
0
five
CH CH; CHCO-NH, protons of thiazepine Q ring,,,), 7.12 (5H, singlet, phenyl protons).
Example 27. Alfar 6 (R) - - 1 (BO-carboxyphenylpropylamino-3 (R) -methyl-5-oxy-perhydro-1,4-thiazepine-4-yl-1 acetic acid.
175 mg alpha Hb (R) - l (8) -ethoxycarbonyl-3-phenylpropylamino-3 (R) -MeTmi-5-oxoperhydro-1,4-thiaz epin-A-yl-acetic acid, prepared as described in Example 26, is hydrolyzed with an aqueous solution of sodium hydroxide, the reaction is carried out in accordance with the procedure of Example 4. The result is a compound indicated in the title, which is a powdery material, the output of which is 93 mg.
NMR ((CD,) SO) S, ppm: 1.28 (3N, doublet, J 6.5 Hz, 3-CH,); 1.7-2.1 (2H, multiplet, Ph) -, 2.3-4.35 (9H, multiplet, Ph CH CH CH CH-NH, protons of the thiazepine ring); 3.98 (2H, AB quartet, uS 0.28 ppm, J 17 Hz,), 7.26 (5H, singlet, phenyl protons).
Example 28. tert-Bugil alfa- {3 (S) -benzyl-5 (R) - 1 (5) -ethoxycarbonyl-3-phenylpropylamino -5-oxb-perhydro-1,4-thiazepin-A- w / w acetate
The procedure indicated in steps a to h of example 1 is repeated, except that L-2-amino-3-phenyl-1-propanol is used as the starting material. As a result, 0
five
0
50
the asymmetric carbon atom to which the phenethyl group is attached). These isomers are isomer A, which is tert-butyl alpha 3 (8) -benz 1-6 (11) (K) -β-toxycarbonyl-3-phenylpropylamine 6 -5-oxoperhydro-1,4-thiazepine- A-yl | - acetate, and isomer B - tert-butyl alpha-3 (8) -benzyl- (R) (5) -ethoxycarbons1-3-phenylpropylamino3-5-oxoper-hydro-1, A-thiazepin-A -sh1 | acetate. These
Isomer A.
NMR (CDC1,) S, ppm: 1.24 (3N, triplet, J = 7 Hz,,); 1.43 (9H, singlet, tert-butyl); 1.7-2.2 (2H, multiplet, Ph,,, 3-4.4 (14H, multiplet, Ph CH CH CH CH-NH-, protons of the thiazepine ring,,) J 4.14 (2H, quartet , J 7 Hz, SB ,,), 7.19 (YUN, singlet, protons of two phenyl groups). Isomer B.
NMR. (CBC1) S, ppm: 1.27 (EH, triplet, J = 7 Hz, ,,) i 1.47 (9H, singlet, tert-butyl), 1.8-2.2 ( 2H, multiplet, Ph) i 2.4-4.4 (14H, multiplet, Ph, CHCO-NH, protons of the thiazepine ring, 3-C1GRH N-CH, -CO); 4.16 (2H, quartet, J = 7 Hz, COiQHjCH,); 7.20 (YUN, singlet, protons of two phenyl groups).
Example 29. Alpha-1 3 (8) -ben-ZSh1-6 (R) - 1 (S) -ethoxycarbonyl-3-phenylpropylamino3-5-oxoperhydro-1,4-β-thiazepin-4-yl acetic acid .
630 mg tert-butyl apfa- | 3 (3) - -benzyl-b (K) - p (8) -ethoxycarboxy-1-3-phenylpropylamino-5-oxoperhydro-1,4-thiazepin-4-sh1 | acetate, which is an isomer B and synthesized as described in example 28 ,. de-treading with trifluoroacetic acid according to the procedure. The resulting reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is dissolved in a mixture of ethyl acetate and water. Formed40
and having so pl. NMR (CDCl,)
In the second step, after the ethyl acetate layer was separated, the title compound was obtained, which was a solid amorphous product, the yield was 438 mg.
NMR (CDCl 3) S, ppm: 1.23 (3N, triplet, J = 7 Hz, CO2.CNHCH5), 1.7-2.3 (2H, multiplet, Ph);
, 4-4,6 (13H, multiplet, P-h 1Ш2 CH CHCO-N-H, protons of the thiazepine ring, 3-CHiPh,) 4.14 (2H, quartet, - J 7 Hz,,); 7.18 (YUN, singlet, protons of two phenyl groups).
Example 30. Alpha-3 (8) -benzyl-b (K) - l (8) -carboxy-3-phenylpropylaminoC-5-oxoperhydro-1,4-thiasepin-4-yl acetic acid.
326 mg of alpha-C (8) -benzsh1-6 (K) - (3) -ethoxycarbonyl-3-phenylpropyl-amino-5-oxoperhydro-1,4-thiazepine-4-Sh11 acetic acid is subjected to hydrolysis using aqueous sodium hydroxide solution.
wash with water and dry with anhydrous magnesium sulphate, and remove the solvent by distillation. The resulting crystalline residue is filtered by filtration using diisopropyl ether. 14.2 g of the title compound are obtained.
109-1.
and ppm: 1.44 (9H, singlet, tert-butyl); 3.05-3.09 (GZ, multiplet,); 5.08 (1H, broad NH); 5.60 (1H, doublet of triple 1TOB, J 4.0 and 8.0 Hz, -CH-OH) j 7.25 8.25 (7H, multiplet, naphthyl protons).
31b. 2-tert-Butoxycarboxylamino -1 -1 chloro- (1-naphthyl) ethane.
To a solution consisting of 12 g
 2-tert-butsycarbonylamino-1- (1-naphthyl) ethanol, prepared as described in step q, in 200 ml of anhydrous methylene chloride, is added at
This reaction was carried out in accordance with the procedure of Example 4. The result is a compound indicated in the title, which is a powder, the yield is 225 mg.
NMR ((CDj) SO) g, ppm: 1.6-2.2 (2H, multiplet, Ph), 2.4-4.5 Q (13H, multiplet, Ph, CHCO-NH, proton thiazepine ring, N-CH, -CO) -, 7.22 (YUN, singlet, protons of two phenyl groups).
Example 31. tert-Butyl alpha-g (1-ethoxycarbonyl-3-fenshthropyl-amino) -2- (1-n aftil) -5-oxoperhydro-1,4-thiazepin-4-ylT-acetate.
31 a. 2-tert-Butoxycarbonylamino - -1- (1-naphtide) ethanol.
The half-product (raw), which is 2-amino-1- (1-naphthyl) ethanol, obtained by reducing 1-naphthaldehyde cyanohydrin, in an amount of 44 g, using lithium-aluminum 5 hydride, is mixed with 12.8 g tristilamine and di-tert-butyl pyrocarbonate, in an amount of 20 g, in methanol (in an amount of 200 ml). The stirring process is carried out for 1 hour Q at room temperature.
The resulting reaction mixture is concentrated by evaporation under reduced pressure and the resulting residue is dissolved in a mixture consisting of ethyl acetate and water. Formed0
5 The ethyl acetate layer is separated;
and having so pl. NMR (CDCl,)
 the ethyl acetate layer is separated,
wash with water and dry with anhydrous magnesium sulphate, and remove the solvent by distillation. The resulting crystalline residue is filtered by filtration using diisopropyl ether. 14.2 g of the title compound are obtained.
109-1.
and ppm: 1.44 (9H, singlet, tert-butyl); 3.05-3.09 (GZ, multiplet,); 5.08 (1H, broad NH); 5.60 (1H, triplet doublet, J 4.0 and 8.0 Hz, -CH-OH) j 7.258, 25 (7H, multiplet, naphthyl; protons).
31b. 2-tert-Butoxycarboxylamino -1 -1 chloro- (1-naphthyl) ethane.
To a solution consisting of 12 g
2-tert-butsycarbonylamino-1- (1-naphthyl) ethanol, prepared as described in step q, in 200 ml of anhydrous methylene chloride, is added at
1A
33
 C solution consisting of 9.4 g of phosphorus pentachloride in 190 ml of native methylene chloride. The resulting mixture was then stirred for 5 minutes, after which 195 ml of 4% aqueous sodium hydroxide solution was added, the entire portion of the aqueous solution of sodium hydroxide being added at a time, and the mixture was stirred for 30 minutes and cooling is carried out with ice. The resulting methylene sporide layer is separated, washed with a large amount of water and dried with anhydrous magnesium sulphate J, then the solvent is separated by evaporation. The resulting residue of chromate graphite on a column filled with silica gel, as eluent, use a mixture consisting of ethylamine and cyclohexane in a ratio of these components equal to 1: 7. The result is 9.0 g of the compound indicated in the IB title, representing a syrup,
; NMR (CDC1,) &, ppm: 1.43 (9H, | singlet, tert-butyl) j 3.3-4.2 (2H, multiplet, CH,;); 5.00 (1H, broad triplet, NH) i 5.83 (IH, doublet of doublets, J 5.5 and 8.0 Hz, CH-naphtsh1) 7.2-8.3 (7H, multiplet, naphthyl protons) ,
31c. S-2-tert-Butoxycarbonylamino-1- (1-naphthyl) ethyl-N-phthaloylcysteine benzhydryl ester, 1 K solution consisting of 10 g of IL-distein-p-toluenesulfonate and 7.5 g of IN-ethoxycarbonyl phthalimide in 65 ml of dimethylformamide, 6.2 g of sodium bicarbonate are added under nitrogen atmosphere. The resulting reaction mixture is stirred at 90-1OO C for 3.5 hours, then cooled. The reaction mixture is then poured into a mixture consisting of ethyl acetate and an aqueous solution of potassium hydrogen sulphate, in order to oxidize the resulting reaction mixture. The resulting ethyl acetate layer is separated and washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate.
To the resulting solution was added 7.4 g of diphenyldiazomethane, the resulting mixture was stirred for 1 hour under a nitrogen atmosphere. The solvent is then separated by evaporation.
34
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and the resulting residue is dissolved in 60 ml of dimethylformamide. To the resulting solution was added 9.6 g of 2-tert-butoxycarbonylamino-1-chloro-1- (1-naphthyl) ethane, the resulting reaction mixture was stirred at 70 ° C for 16 hours in a stream of nitrogen gas. The resulting reaction mixture is dissolved in a mixture consisting of ethyl acetate and water. The resulting ethyl acetate layer is separated, washed with an aqueous solution of sodium chloride and then dried with anhydrous magnesium sulfate and the solvent is separated by powder.
The resulting residue is chromatographed on a column filled with silica gel, and a mixture consisting of ethyl acetate and cyclohexane in a volume ratio of 1: 4 is used as eluent. The result is the title compound as an amorphous solid, the yield of which is 10.4 g.
NMR (CDCl,), ppm: 1.35 (9H, singlet, tert-butyl) J 3.15-3.8 (4H, multiplet,,), 4.5-5.1 (ZN, multiplet , NH, N — CH — CO, S — CH — naphthyl); 6.61 and 6.70 (together 1H, two-way singlet, CHPh), 6.75 and 8.3 (21H, cartoon, CH (), naphthyl protons, phthaloyl protons).
31d. (S) -2-amino-1- (1-naphthyl) - eth1-H-phthaloylcysteine.
To a solution consisting of 10.4 g of tert-butoxycarboxyamino-1- (1-per; ftyl) ethyl-M-phthaloylcysteine benzhydryl ester in 10 ml of anisole is added 50 ml of trifluoroacetic acid, and the resulting reactive the mixture is stirred for 2 hours at room temperature. Crop-: the solvent is separated by mixing and then 40 ml of ethyl acetate, 30 ml of water and 2 g of sodium bicarbonate are added to the resulting residue with constant stirring. The pH of the reaction mixture was adjusted to 5.8 by the addition of 3N hydrochloric acid. Under constant cooling with ice, the reaction mixture is stirred and the precipitate formed, which is the title compound, is collected by filtration and washed with a mixture consisting of acetone and diethyl ether in a 1: 1 volume ratio between the indicated components. . The result is 5.6 g of the title compound having a mp. 195-199 ° C.
31 e. 2- (1-Naftch1) -5-oxo-6-phthal - imidoperhydro-1,4-thiazepine.
To a solution consisting of 5.5 g S-2-amkno-1- (1-naphthyl) ethyl 3 -N-phthalo header,
; which is a crystalline product; i.e., m.p. , 211-213 C.
NMR (CDC1,) 6 ppm: 1.47 (9H, singlet, t-butyl); 3.0-4.9 TbN, multiplet,,) j 5.30 (1H, doublet, J 9 Hz, N-CH-CO), 5.78 (1H, wide doublet, J 10 Hz,
ilcysteine in 110 ml of dimethylformamide, Q 3 -CH-naphthyl); 7.3-8.35 (11H, naphthyl-add 5.1 g of diphenylphosphoryl azide, essential protons, phthaloyl protons), and 2.6 ml of K-methylmorpholine, and obtained is 31g. The tert-Butsh1Halfa- (6) -amino mixture is stirred for -2- (1-naphthyl) -5-oxoperhydro-1.4-15 hours at room temperature. Next, α-thiazepin-4-yl-acetate, is added to the resulting mixture with g to a solution containing 2.5 g
tert-butyl 2- (1-napht) -5- oxo-6-phthalimidoperhydro-1,4-thiazepine-4- -yl t-acetate, prepared as described in step f, in a mixture consisting of 20 ml of methylene chloride and 2 ml of methanol, 0.77 ml of methylhydrazine is added, and the resulting reaction mixture is allowed to stand for 2 days at room temperature. The reaction mixture is then concentrated by evaporation under reduced pressure, 15 ml of methylene chloride are added to the resulting residue and the mixture is stirred. The resulting residue is filtered and the filtrate is concentrated by extracting under reduced pressure. The resulting residue is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of methanol and ethyl acetate in a volume ratio of 1:20 early. The result is 1.92 g of the title compound, which is a solid amorphous product.
20
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With this stirring, water in an amount of approximately 200 ml, and ethyl acetate, in an amount of approximately 500 ml. The precipitate of the title compound is collected by filtration and then washed with water and ethyl acetate. 3.5 g of the title compound and having a melting point above 300 ° C are obtained. NMR ((CD, j), SO) S, ppm: 2.7-4.6 (4H, multiplet,, N-CH,); 94 (IHj wide doublet, J 8 Hz, S-CH-naphthyl); 5.47 (1H, doublet of doublets, J 3.0 and 8.0 Hz, N-CH-CO), 7.4-8.5 (11H, naphthyl protons, phthaloyl protons). : 31f. tert-Butyl alpha-2- (1-naph tnl) -5-oxo-6-phthalimidoperhydro-1,4-β-thiazepin-4-yl | acetate.
To suspensions comprising 3.4 g of 2 (1-naphthyl) -5-oxo-6-phtapimidoperhydro-1,4-thiazepine, prepared as indicated in step e, in a mixture of 34 ml of dimethylformamide and 100 ml hexamethylphosphoric triamide, tert-butyl bromoacetate in an amount of 2.25 ml is added dropwise and then 609 ml (55% by weight) of the sodium hydride suspension in oil are added in small portions at an additive process and produced in a stream of gaseous nitrogen . After this addition is complete, the resulting reaction mixture is stirred for 16 hours at room temperature, and then
40
45
tert-butyl 2- (1-napht) -5- oxo-6-phthalimidoperhydro-1,4-thiazepine-4- -yl t-acetate, prepared as described in step f, in a mixture consisting of 20 ml of methylene chloride and 2 ml of methanol, 0.77 ml of methylhydrazine is added, and the resulting reaction mixture is allowed to stand for 2 days at room temperature. The reaction mixture is then concentrated by evaporation under reduced pressure, 15 ml of methylene chloride are added to the resulting residue and the mixture is stirred. The resulting residue is filtered and the filtrate is concentrated by extracting under reduced pressure. The resulting residue is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of methanol and ethyl acetate in a volume ratio of 1:20 early. The result is 1.92 g of the title compound, which is a solid amorphous product.
NMR (CDC1) &, ppm: 1.47 (9H, singlet, t-butyl); 2.11 (2H, broad singlet, NH) ", 2.43-4.8 (7H, multiplet, N-CHj-CO, Hj N-CH-CH, S, 5.15 (1H, doublet, J Hz , S-CH-naphthyl), 7.2-8.3 (7H, multiplet, naphthyl runs).
31h. tert-Butyl alpha- {6- (1-ethoxy-anhydrous magnesium sulphate, and ° sycarbonyl-3-amino) -2- (1-naphthyl) -3-oxoperhydro-1 4-thiazepin-4-yl 3 acetate.
 To a solution of a mixture consisting of 803 g of tert-butyl alpha-6-amino-2 (1-naphthyl) -5-oxoperhydro-1,4-thia9epin-4-Sh1 acetate prepared in step g, and 1.13 g of ethyl 2-bromo-4-phenylbutyrate in 10 ml of dimethylformamide, and the solvent is then distilled off. The residue obtained is chromatographed on a column filled with silica gel, and a mixture consisting of cyclohexane and ethyl acetate in a volume ratio of 2: 1 is used as eluent. As a result, 2.6 g of the compound indicated in
heading
; which is a crystalline product; i.e., m.p. , 211-213 C.
NMR (CDC1,) 6 ppm: 1.47 (9H, singlet, t-butyl); 3.0-4.9 TbN, multiplet,,) j 5.30 (1H, doublet, J 9 Hz, N-CH-CO), 5.78 (1H, wide doublet, J 10 Hz,
Z-CH-naphthyl); 7.3-8.35 (11H, naphthyl protons, phthaloyl protons), 31g. tert-Butsh1Galfa- (6) -amino-2- (1-naphthyl) -5-oxoperhydro-1,4-β-thiazepin-4-yl acetate, To a solution containing 2.5 g
tert-butyl 2- (1-napht) -5- oxo-6-phthalimidoperhydro-1,4-thiazepine-4- -yl t-acetate, prepared as described in step f, in a mixture consisting of 20 ml of methylene chloride and 2 ml of methanol, 0.77 ml of methylhydrazine is added, and the resulting reaction mixture is allowed to stand for 2 days at room temperature. The reaction mixture is then concentrated by evaporation under reduced pressure, 15 ml of methylene chloride are added to the resulting residue and the mixture is stirred. The resulting residue is filtered and the filtrate is concentrated by extracting under reduced pressure. The resulting residue is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of methanol and ethyl acetate in a volume ratio of 1:20 early. The result is 1.92 g of the title compound, which is a solid amorphous product.
NMR (CDC1) &, ppm: 1.47 (9H, singlet, t-butyl); 2.11 (2H, broad singlet, NH) ", 2.43-4.8 (7H, multiplet, N-CHj-CO, Hj N-CH-CH, S, 5.15 (1H, doublet, J Hz , S-CH-naphthyl), 7.2-8.3 (7H, ultiplet, naphthyl purlin).
31h. tert-Butyl alpha- {6- (1-ethoxycarbonyl-3-amino) -2- (1-naphthyl) -337
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but; 0.66 g sodium carbonate is added. The resulting reaction mixture was stirred at 80 ° C for 15 hours, then it was dissolved in another mixture consisting of ethyl acetate and aqueous
sodium chloride alignment. The ethyl acetate layer is separated, the washed with water and dried with injected magnesium sulfate, and the solvent is separated by welding. The semi-residual residue is chromatographed on a pad filled with silica gel. A mixture of ethyl acetate and chloromethylene in a volume ratio between these components equal to 30 is used as eluent. As a result of chromatography, the resulting product is divided
two isomers: Isomer A and Isomer B, Lagodar, the presence of asymmetric carbon ohm, to which a phenethyl group is attached.
NMR (CDCl, b) 4. 1.24 (3N, iplet, J 7.5 Hz,,); 46 (9H, singlet, tert-butyl), 1.7-2 (2H, multiplet, Ph CH, CH), 4-4.7 (1ZN, multiplet, Ph $ iCHj., CO-CH-CH S-CH -CH ,,
CHi-CO,,;, CH,) j 5.13 (1H, chic doublet, J 9 Hz, S-CH-naphthyl), 14 (5H, singlet, phenyl proto-n | s)} 7, 2-8.2 (7H, multiplet, naphllic protons).
Isomer A is eluted first; it 1 is an oily submenuation, the yield is 0.49 g.
Isomer B is eluted second, it represents an oil form of substitution, the yield is 0546 g,
NMR for isomer B (CDCl), ppm: |, 28 (3N, triplet, J 7.5 Hz,), t, 48 (9H, singlet, tert-butyl), 1.8-, 3 (2H, multiplet, Ph); 2.5-4.8 (13H, multiplet, PhnH 4CH, j.CH-NH, 0-eH-CH 3 CH-CH, CH
, with SNGSn); 5.18 (1N7 oak. J, 9.5 Hz, 3-CH-naphthyl) i 7.21 (5H, singlet, phenyl protons), 35-8.3 (7H, multiplet, naphthyl protons).
Example 22. Alpha-b- (1-3-to-sicarbonyl-3-phenylpropylamino) -2 (1-naphthyl) -5-oxoperhydro-1,4-thiaz-PIN-4-yl acetic acid.
455 mg of isomer B tert-butyl ap- (1-ethoxycarbonyl1-3 phenylpropylamino) -2- (1-naphthyl) -5 oxoperhydrin-t 54-thiazepin-4-sh13 acetate, hem
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The sample as described in Example 31h is dissolved in a mixture consisting of 2 ml of anisole and 2 ml of trifluoroacetic acid. The resulting mixture is further stirred for 4 hours at room temperature, and then it is concentrated by quenching under reduced pressure. Diisopropyl ether is added to the resulting residue while stirring simultaneously. The resulting crystalline powder was collected by filtration, the yield was 447 mg.
The resulting powder is dissolved in a mixture consisting of 2 ml of etipacetate and 2 ml of water. Then, 0.2 g of sodium bicarbonate is added to the resulting solution; The pH of the reaction mixture is adjusted. to 3.5 by adding 3N hydrochloric acid. The resulting precipitate of the title compound is collected by filtration, the yield is 5,216 mg. The resulting ethyl acetate layer is separated and the aqueous layer is extracted with ethyl acetate. The ethyl acetate i solutions were combined and dried with anhydrous magnesium sulphate, and then separated (solvent by combining it to give the title compound as a crystalline material. These crystals (additionally 70 mg) were collected by filtration e using this simple. diisopropyl ether. The melting point of the compound is 201-203 C.
NMR ((CI) j) 2SO) 5 ppm: 1.28 (ZN, triplet, J 7.5 Hz, CO ,,), 2.0-2.4 (2H, multiplet, Ph); 2.5-5.4 (13H, multiplet, Ph, protons of the thiazepine ring, N-CHj-CO, CO ,, CH), 7.32 (5H, singlet, phenyl protons) i 7.2-8.3 ( 7H, multiplet, naphthyl protons).
Example 33. Alpha- 6- (1-carboxy-3-fenschropylamino) -2- (1-nafg: - TyO-5-6xoperhydro-1 j 4-thiazepin-4-; -yl acetic acid.
216 mg alpha-b- (1-ethoxy-carbonyl-3-phenylpropylamino) -2- (1-naphthyl) -5-oxoperhydro 1,4-thiazepin-4-ylZ -. Acetic acid, prepared as described in Example 36, was stirred with 2 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was then stirred for 16 hours at room temperature. Filtered off
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a small amount of insoluble materials and the pH of the filtrate was adjusted to 2 by the addition of 1N hydrochloric acid. The result is a powdered compound that is collected by filtration and then washed with a small amount of water. The result is the connection specified in the title, in the amount of 201 mg,
NMR ((CD,) 2.SO) 5, ppm: 1.7-2.1 (2H, multiplet, Ph); 2.5 - 6.35 (11H, multiplet, Pb,
ten
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34c. S-2 benzhydryl ester of t-butoxycarbonylamino-1- (2- -naphthyl) ethyl -N-phthaloylcysteine.
To a solution of the benzhydrinyl ester of K-phthaloylcysteine, which is obtained by treating 10 g of Lr-cis-stein p-toluenesulfonate, 7.5 g of N-ethoxycarbonylphthalimide, 6.2 g of sodium bicarbonate and 7.4 g of diphenyldiazomethane , in accordance with the methodology.
described in example 31c, and 9.6 g of 2-tert-butoxycarbrylamino-1-chloro--1- (2-naphthyl) ethane (obtained as
the protons of the thiazepine ring, N-CH, fO) were described in step t}, in 80 ml of di- 7.28 (5H, singlet, phenyl proto-methylformamide, 7.3 g of carnage was added), 7.1 -8.3 (7H, naphthyl protons). Example 34. tert-Butyl alpha- - b- (1-ethoxycarbonyl-3-phenylpropyl-amino) -2- (2-naphsh1) -5-oxoperhydro-1,4-thiazepin-4-yl acetate.
34a. 2-tert-Butoxycarboxylate -1- (2-naphsh1) ethanol.
sodium bonata. The resulting reaction mixture is stirred under a stream of nitrogen gas for 18 hours at 2Q. Next, process the resulting reaction solution as described in example 31c. The result is 12.3 g of the compound indicated in the title, which is the half-product (syrup) of 2-amino-1- (sodium carbonate) half-product. The resulting reaction mixture is stirred in a stream of nitrogen-shaped gas for 18 hours at 2 Q. Next, process the resulting reaction mixture. a solution as described in Example 31c. As a result, 12.3 g of the title compound is obtained.
-naphthyl) ethanol, obtained by bo-25 to amorphous substance.
26 g of cyanohydrin 2-naphm-NMR (CDC1,), ppm: 1.37 (9H,
lithium aluminum
hydride, subjected to tert-butoxycarbonylation reaction. As a result, tert-butyl) J 3.2-3.7 (4H, multiplet,,),, 22 (1 triplet, J 4.5 Hz, W-CH-naphthyl), 4.67 (1H, wide, NH); 5.05 (1H, multiplet, N-CH-CO); 6.79 and 7.82 (together 1H, 2 types of singlet, CHPh) 7.0-8.0 (21H, multiplet, SC (naphthyl protons, phthaloyl protons).
those give 16 g of the title compound as a crystalline solid, having so pl. 99-100 ,.
NMR (CDCl}) ppm: 1.43 (9H, singlet, tert-butyl), 3.1-3.75 (3N, multiplet, -Cti, -OH); 4.95 (1H, broad NH), 4.96 (1H, doublet of tTOB, J 4.0 and 8.0 Hz, SD-OH); 7.4- 8.0 (7H, multiplet, naphthyl protons).
34b. 2-tert-Butoxycarboxy-amino -1-chloro-1- (2-naphtsh1) ethane.
16.0 g of 2-tert-butoxycarbonylamino-1- (2-naphtsh1) ethanol, obtained in step a, is chlorinated with phosphorus pentachloride in accordance with the procedure of example 31b, to give the title compound, which represents is a crystalline product having. mp. 97-98 C. The yield is 9.1 g.
NMR (CDCl 3) S, ppm: 1.43 (9H, singlet, tert-butyl) i 3.4-4.0 (2H, multiplet, CH,); 4.93 (1H, broad NH); 5.18 (1H, doublet of doublets, J 6.0 and 7.0 Hz, -CH-naphthyl) 7.45-8.0 (7H, multiplet, naphthyl protons).
40
34c. S-2 benzhydryl ester of t-butoxycarbonylamino-1- (2- -naphthyl) ethyl -N-phthaloylcysteine.
To a solution of the benzhydrinyl ester of K-phthaloylcysteine, which is obtained by treating 10 g of Lr-cis-stein p-toluenesulfonate, 7.5 g of N-ethoxycarbonylphthalimide, 6.2 g of sodium bicarbonate and 7.4 g of diphenyldiazomethane , in accordance with the methodology.
described in step t}, in 80 ml of dimethylformamide, 7.3 g of car-
sodium bonata. The resulting reaction mixture was stirred under a stream of nitrogen gas for 18 hours at. Next, process the resulting reaction solution as described in example 31c. The result of 12.3 g of the compound indicated in the title, which is THERMAL (CDC1,), ppm: 1.37 (9H,
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singlet, tert-butyl) J 3.2-3.7 (4H, multiplet,,),, 22 (1H, triplet, J 4.5 Hz, W-CH-naphthyl), 4.67 (1H, broad, NH); 5.05 (1H, multiplet, N-CH-CO); 6.79 and 7.82 (together 1H, 2 types of singlet, CHPh), 7.0-8.0 (21H, multiplet, SC (naphthyl protons, phthaloyl protons).
34d. 3- 2-Amino-1- (2-naphsh1) ethylZ-N-phthaloylcysteine.
In 12.3 g of the benzhydryl ester of S-2-tert-butoxycarbonylamino-1 - (2-naphtsh1) -ethyl-N-phthaloyl cystiste, obtained as indicated in step g) is subjected to reaction with trifluoroacetic acid in order to remove its tert-butyl group, using the procedure given in Example 31d. The result is (a compound indicated in the title, which is a powdery material, having a melting point of 196-200 C. The yield of this compound is
0 6.6 g
34e. 2- (2-Naphthyl) -5-oxo-6-phtap-imidoperhydro-1,4-thiazepine ..
6.5 g S-f2-amino-1- (2-naphtnl) ethyl | - -N-phthaloylcistein obtained on
5 stage d, is subjected to the reaction of condensation and cyclization, using diphenylphosphoride azide in accordance with the procedure described in example 5
1143
jje 31e. The result is a compound indicated in the title, softening and thickening at temperatures above 270 ° C. H having so pl. 283-285 Co. The yield is 4.25 g.
 NMR ((CDj) SO) 8 ppm: 3.4-4.6 ~ (5H, multiplet, N - CH-CH-S) 15.43 (1H, multiplet, N-CH-CO ) i 7.5-, 4 (11H, multiplet, naphthap protons, phthaloyl protons). I 34f. tert-Butyl alpha- 2- (2-naph- | tyl) -5 oxo-6-phthalimidoperhydro-1,4- | -thiazepin-4-yl acetate. ; 4.15 g of 2- (2-naphthyl) -5-oxo b-phthal-imidoperhydro-1,4-thiazepine, prepared as described in step 6, is treated with tert-butyl bromoacetate in accordance with the procedure described in example 31f . The result is a | compound indicated in the title, 1B in the amount of 3.35 g, representing I as a solid crystalline prod: fcc. 208-209.5 ° C. I NMR (CDClI) S, ppm: 1.47 (9H,; singlet, tert-butyl); 2, (7H., Multiplet,). (naphthyl S-CH ,,); 5.72 (1H, d gb of doublets, J 2.0 and 10.0 Hz, N-CH-CO) 7.3-8.0 (11H, multiplet, naphthyl protons, phthaloyl protons) „
34g. tert-Butyl alpha-3b-amino-2- (2-naphthyl) -5-oxoperhydro-1,4-thiazepin-4-yl I acetate
R /
3.25 g of tert-butyl alpha-2- (2-naphthyl) -5-oxo-6-phthalimidoperhydro-1,4-β-thiazepin-4-Sh1 ace, ata obtained I at stage f, is subjected to the reaction de - I phthaloization using methyl I hydrazine in accordance with the procedure described in example 31g, resulting in 2.6 g of the title compound, which is an amorphous powder,
NMR (AHSC) b, ppm: 1.49 (9H, singlet, tert-butyl); 2.26 (2H, singlet, NHj) i 2.45-4.75 (8H, hlp proton of the thiazepine ring, —N — CH —CO); 7.2-7.9 (1H, multiplet, naphthyl protons, phthalosc protons).
34h. tert-Butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -2- (2-naphthyl) -5-oxoprvhydro-1,4-thiazepine- [-4-yl acetate.
0.85 g of tert-butyl alpha 6-amino-2- (2-naphtsh1) -5-oxoperhydro-1,4-thiazepin-4-yl acetate, obtained in stage g, is subjected to H-alkylro
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using 1.08 g of ethyl 2-bromo-4-phenylbutyrate, in accordance with the procedure described in Example 31h. The resulting product is chromatographed on silica gel using a mixture consisting of ethyl acetate and methylene chloride in a volume ratio of 1:30 as eluent. By chromatography, the reaction product is divided into two isomers: isomer A and isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached).
Isomer A is eluted first, it is an oily substance, the yield of this isomer is 0.47 g.
NMR (CDCl 2), ppm: 1.25 (3N, triplet, J 7.4 Hz, CO,), 1.47 (9H, singlet, tert-butyl); 1.7– 2.2 (2H, multiplet, Ph, 2.4–4.6 (12H, multiplet, Ph CH CH –CH-sh, protons of the thiazepine ring, -); 4.14 (2H, Quartet, J 7.5 Hz,, jCH,); 7.20 (5H, singlet, phenyl protons) i 7.1-7.9 (7H, multiplet, naphthyl protons).
Isomer B is eluted second, it is an oily substance, the yield of this isomer is 0.50 g.
NMR (CDC1,) 5, ppm: 1.27 (3N, triplet, J 7.5 Hz, CO,;, CH2, CH,), 1s47 (9H, singlet, tert-butyl), 1.7 - 2.25 (2H, multiplet, Ph.); 2.5-4.6 (12H, Ph CH, CH2 -CB-NK, protons of the thiazepine ring,), 4.16 (2H, Quartet, L 7.4 Hz,, p; 7.20 (5H, singlet, phenyl protons), 7.1-7.9 (7H, multiplet, naphthyl protons).
Example 35 Alpha-b- (1-ethoxycarbonyl-3-phenylpropylamino) -2- - (2-naphthyl) -5-oxoperhydro-1,4-thiazepin-4-yl-acetic acid.
0.47 g of isomer B tert-butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -2- (2-naphthyl) -5-oxoperhydro-1,4-thiazepin-4-yl acetate, obtained as indicated in example 34h, was subjected to the reaction of detritulizing with trifluoroacetic acid in accordance with the procedure described in example 36, thus obtaining 0.42 g of the compound indicated in the title, which is a crystalline powder
a material softening at a temperature starting from and having a mp. 175-180 ° C.
 NMR ((CD) SO) ppm: 1.30 (3N, triplet, J 7.5 Hz) 2.0-2.35 (2H, multiplet, PhCH-CH.), 2.55 5.2 (13H, multiplet, -CH-N, protons of the thiazepine ring,,); 7.33 (5H, singling years, phenyl protons), 7.2-8.1 (7H multiplet, naphthyl protons).
Example 36. Alpha- 6- (1-carb hydroxy-3-phenylpropane-1-amino) -2- (2-naphthyl-5-oxoperhydro-1, A-thiazepin-4-yl - acetic acid.
200 mg of alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -2- (2-naphthyl) -5- -oxoperhydro-1,4-thiazepin-4-Sh1 acetic acid, prepared as described in Example 35, are hydrolyzed with aqueous sodium hydroxide solution according to the procedure described in Example 37, and 133 m of the title compound, which is a powdery material, are obtained.
 NMR ((CD5) SO) S, ppm: 1.7-2.1 (2H, multiplet, Ph); 2.5 - 4.8 (11H, multiplet, Ph JV CH CH -CE-N protons of the thiazepine ring, N-CH2, —CO); 7.30 (5H, singlet, phenyl protons), 7.2-8.1 (7H, multiplet, naphthyl protons).
Example 37. tert-Butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2- (3-thienyl) perhydro-1,4-thiazepin-4-sh11 acetate.
37a. 2-tert-Butoxycarbonylamino- -1- (3-thienyl) ethanol.
The semi-product (raw) of 2-amino-1- (3- -thienyl) ethanol, which is obtained by reducing 28 g of cyano-hydrile 3-thiophenecarbaldehyde with lithium-aluminum hydride, is mixed with 30 ml of triethylamine and 44 g of di-tert- butyl pyrocarbonate in methanol for 1.5 hours at room temperature. The resulting reaction mixture is further concentrated by evaporation under reduced pressure, the resulting residue is dissolved in ethylacetate and water. The resulting organic layer is separated, washed with water and dried with anhydrous magnesium sulfate, and the solvent is separated by drying. The residue obtained is chromatographed on a column filled with silica gel as eluent.
ten
0

This uses a mixture of ethyl acetate and methylene chloride with a volume ratio between these components of 1: 4. The result is a compound indicated in the title, which is a crystalline material having a mp. 103-105 C. The yield is 13.2 g. NMR (CDClpS, ppm: 1.42 (9H, singlet, tert-butyl)} 2.9-3.7 (ZN, multiplet, OH ) i 4.83 (1H, doublet of triplets, J 4.0 and 8.0 Hz, -CH-OH); 5.0 (1H, broad, NH); 6.95-g 7.12 (ZN, multiplet , protons of the thiophene ring).
37b. 2-tert-Butoxycarboxylamino -1 -1 chloro-1- (3-thienyl) ethane.
To a solution consisting of 12.2 g of 2-tert-butoxycarbonylamino-1 (3-thienyl) ethanol, obtained in stage a, in 100 ml of a6cojpoTHoro methylene chloride, 10.4 g of pentachloride; phosphorus in 200 ml of absolute methylene is added - 5 chloride, the addition is carried out at 0 - (- 5) C. After completion of the addition operation, the resulting reaction mixture is stirred for 10 minutes, and then 4N aqueous sodium hydroxide solution is added to the obtained reaction mixture, the resulting mixture is stirred for 5 minutes. The resulting methylene chloride layer is separated, washed with plenty of water and then dried with anhydrous magnesium sulfate, and the solvent is separated by evaporation. The resulting residue is chromatographed on a column filled with silica gel, using a mixture consisting of ethyl acetate and cyclohexane in a 1: 4 ratio as eluent. The yield of the product indicated in the title is 7.3 g, m.p. 63-65 0.
NMR (CDClI) S, ppm: 1.43 (9H, singlet, tert-butyl) i 3.43-3.81 (2H, multiplet, -CHj-), 4.7-5.3 (3N , multiplet, -CH-C1, NH), 7.0-7.5 (3N, multiplet, protons of the thiophene ring).
37c. Benzhydryl ester of S-2-tert-butoxycarboxylate-1- - (3-thienyl) ethyl-N-phthaloylcysteine.
 6.2 g of sodium bicarbonate was added to a solution containing 10.0 g of L-cysteine p-toluenesulfonate and 5 7.5 g of K-ethoxycarbonylphthalimide in 68 ml of dimethylformamide.
five
0
five
0
. (51
ira. The resulting reaction mixture is stirred for 3–5 h at 90–100 ° C. The reaction mixture is then cooled and poured into a mixture composed of ethyl 1, potassium etatate and potassium sulfate, in order to produce its oxidation. The resulting organic layer is separated, washed with an aqueous solution of sodium chloride JH, then dried with anhydrous magnesium sulfate. Next, 7.4 g of diphenyldiazomethane is added to the obtained reaction solution, this addition process is carried out under a nitrogen atmosphere, and the mixture is stirred for 1 hour. This solvent is removed by evaporation, and the resulting residue is dissolved in 60 ml dimethyl ™ formamide. Next, 8.0 g of 2-tert-butoxycarbonyl amino-1-chloro-1- (3-thienyl) ethane obtained in step b, and 8.6 g of sodium carbonate are added to this solution, and the addition process is carried out in nitrogen atmosphere and the resulting reaction mixture is stirred for 16 hours at 70 ° C. This reaction mixture is then poured into a mixture consisting of ethyl acetate and water. The resulting organic layer is separated and washed with an aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate, the solvent is separated by welding. The resulting residue is chromatographed on a column filled with silica gel, and a mixture consisting of ethyl acetate and diclohexane with a volume ratio between these components equal to 1: A is used as eluent. The result is compound j indicated in the title, which is a solid amorphous product, the product yield is 10.9 g.
5iMP (CDClj) S, ppm; 1.36 (9Hs singlet, tert-butyl) I 3j, 1-3.6 (4H, multiplet, CH, S, 3-S-CH,); 4.12 (1H, broad ™ triplet, J 7 Hz, S-CH-thienyl) i 4.5-5.05 (2H, multiplet, NHN-CH-CO) j 6.76 (1H, singlet, CHPh ).: 6.85-753 (13H, multiplet, CH () -, protons of thiophane ring); 7.4-7.85 (4H, multishshit, phthalo protons).
37d. 5- (2-amino-1- (3-thienyl) ethyl- - -phthaloylcysteine,
To a solution consisting of 10.9 g of S-L2l-bisydryl ester
51
46
Q - - -n 25 „
0 5
35
40
45
-tert-butoxycarbonylamio-1- (3-thienyl) these: 1 -H-phthaloylcysteine, obtained in step c, in 40 ml of anisole, 50 ml of trifluoroacetic acid are added, the resulting reaction mixture is settled for 2 hours at room temperature . The solvent is separated by extrusion and then 40 ml of ethyl acetate, 30 ml of water and 2.4 g of sodium bicarbonate are added to the residue, the process is carried out under constant stirring, the pH of the resulting reaction mixture is adjusted to 5.8 by addition of 3N. hydrochloric acid. The resulting reaction mixture is stirred while cooling with ice, and the precipitate, which is the title compound, is collected by filtration and washed with a mixture of acetone and diethyl ether in a ratio of 1: 1. As a result, 5.9 g of the title compound, having a h. Rpm of 165 ° C, is obtained.
37th. 5-Oxo-6-phthalimido-2- (3- -thienyl) perhydro-1,4-thiazepine.
To a solution consisting of 5.8 g of S-2-amino-1 -t 3-thienyl) -etxx -N-β-phthaloylcysteine, obtained in step d, in 100 ml of dimethylformamide, was added 7.7 g of diphenylphosphoryl azide and 3.1 ml of N-methylmorpholine. The resulting mixture is stirred for 15 hours at room temperature, and then 200 ml of water and 500 ml of ethyl acetate are added, the addition is carried out with stirring, and a compound is obtained which is a solid substance, the yield is 2.7 g. the organic layer of the filtrate is separated and evaporated to give an additional amount of the title compound. This compound is collected by filtration using a small amount of ethyl acetate and diethyl ether, the yield is 1.4 g. The total yield of the title compound is 4.1 g, mp. 274 C.
NMR ((Heb, 80), ppm: 2.95- 4.35 (5H, multiplet, CH-W-CHS-ing-nsh1} -CE -Y, 5.31 (1H, doublet of doublets, J 4, 5 and 8.0 Hz, N-CH-CO) V - 7s05-7j15 (1H, multiplet, proton in
A7
4-position thiophene ring), 7.4 7.5 (2H, multiplet, protons in 2- and 5-positions of thiophene ring); 7.82 (4H, singlet, phthaloyl protons); 8.02 (1H, broad, NH).
37f, tert-Butyl alpha-3-oxo-b- -phthalimido-2- (3-thienyl) -perhydro-1,4-thiazepin-4-yl acetate-.
To a suspension consisting of 4.1 g of 5-oxo-6-phthalimido-2- (3-thienyl) per-hydro-1,4-thiazepine, obtained on stage e,. in 60 ml of dimethylformamide, 2.2 g of tert-butyl bromoacetate are added dropwise, and then 593 mg (50% by weight) of sodium hydride suspension in oil are added in a stream of nitrogen, at 0 - (- 5) C. The resulting the reaction mixture is stirred for 20 minutes and then poured into a mixture of ethyl acetate and water. The resulting ethyl acetate layer is separated, washed with water and dried with anhydrous magnesium sulfate, and the solvent is separated by extracting. The semisolid residue is collected by filtration using ethyl acetate and diisopropyl ether, and 3.7 g of the title compound is obtained, having so pl. 157-160 C (with decomposition).
NMR ((ppm: 1.46 (9H, singlet, tert-butyl)} 2.8-4.6 (7H, multiplet, CH —3-CHN),;); 5.60 (1H , doublet of doublets, J 3.0 and 8.0 Hz, N-CH-CO) 7.05-7.42 (MN, multiplet, thiophene ring protons) i 7.7-7.85 (4H, multiplet, phthaloyl protons).
37g. tert-Butyl alpha-b-amino-5-oxo-2- (3-thiensh1) perhydro-1,4-thiazepin-4-yl acetate.
To a solution consisting of 3.6 g of tert-butyl alpha-5-oxo-6-phthalimi- to-2- (3-thienyl) perhydro-1,4-thiazepin-4-yl acetate, obtained in the step f, in 40 ml of methylene chloride and 10 ml of methanol, 1.8 ml of methyl hydrazine is added and the reaction mixture was decanted for 16 hours at room temperature, and then concentrated by evaporation under reduced pressure and added to the resulting residue are ethylene chloride. The precipitate formed is filtered off and the filtrate is concentrated. The resulting residue is chromatographed on a column, 35351
- -
- - J

ten
20
48
a mixture of methanol, cyclohexane and ethyl acetate with a volume ratio between these compounds equal to 1: 4: 5. As a result, 2.33 g of the title compound, which is a solid material having m.p. 115-117 C.
NMR (CDCloj) S, ppm: 1.48 (9H, singlet, t-butyl); 2.10 (2H, broad singlet, Nil,}; 2.4-4.6 (8H, multiplet, protons of the thiazepine ring 15, -N-CH,) -, 6.9-7.35 (MN,
multiplet, thiophene ring protons).
37h. tert-Butyl alpha-b- (1-to-toxycarbonyl-3-phenylpropylamino) -5-oxy-2- (3-thienyl) perhydro-1,4-thiase-pin-4-Sh1 acetate.
To a solution consisting of 0.47 g of tert-butyl alpha b-amino-5-oxo-2- - (3-thienyl) -perhydro-1,4-thiazepin-4- -yl acetate, obtained in steps g, and 0.8 g of ethyl-2-bromo-4-phenylbutyrate in 7 ml of dimethylformamide, 1.0 g of sodium carbonate are added. The resulting reaction mixture was stirred for 18 hours at 70 ° C, and then dissolved in ethyl acetate and an aqueous solution of sodium chloride. The resulting ethyl acetate layer is separated, washed with water and dried with anhydrous magnesium sulfate. The solvent is evaporated off. The resulting residue is chromatographed on a column filled with silica gel, the zylation process is carried out with a mixture of ethyl acetate and methylene chloride with a volume ratio between the indicated components of 1:20, and two isomers are obtained by chromatography: and isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached). Isomer A is first eluted, which is an oily product, and its yield is 0.27 g.
25
thirty
35
40
45
50
NMR (CDC1,) S, ppm: 1.23 (1H, triplet, J 7.5 Hz,), 1.46 (9H, singlet, tert-butyl) 1.7-2.2 (2H, multiplet, Ph), 2.3-4.6 (14H, multiplet, Ph CH — CH CH — NH, protons of the thiazepine ring, N-CH, —CO,. 6.9-7.4 (ZN, multiplet, protons .tiof 14
New ring) i 7,19 (5Hr singlet, phenyl protons).
The second one is eluted from iso-4p B, which is an oily compound, its output is 0.30 g. RR NO. (CDC1) & ppm: 1.25 (3N, triplet, J 7.5 Hz, CO, CH, CH5); 1.46 (9H, singlet, tert-butyl)} 1.8 - 2.2 (2H., Multiplet, Pb.), 2.5-4.55 (14H, multiplet, Ph) j protons of the thiazepine ring, , j), 6.9- 7.35 (ZN, multiplet, protons of the thiophene ring) J 7.19 (5Nz singlet, phenyl protons) „
Example 38, Alpha-b- (Sicarbonsh1, 3-phenipropylamino) -5-oxy-2- (3-thienyl) perhydro - 1,4-thiazepine-4-yl acetic acid
300 mg of isomer B tert-butyl alpha-b- (1-ethoxycarbonyl-3-fennylproproim-1-amino) -5-oxo-2 (3-thienyl) perhydro-1,4-thiazepin-4-yl acetate prepared as indicated in Example 37b, dissolved in 1.8 ml of anisole and in 2 ml of trifluoroacetic acid. The resulting reaction mixture was kept at room temperature for 3 hours.
then it is concentrated by filtration, and the mixture is run under reduced pressure. Next, add & get to the resulting diisopropyl ether residue with stirring and as a result, a powdery residue is obtained (with a small amount of water and diisopropyl ether, resulting in 120 mg of the product indicated in the title.
NMR ((CD) SO) 8, ppm: 1,
soluble, which is collected by filter - (21, multiplet, Ph,); 2.5-4.6
radio, to obtain 258 mg of powder)
(11H, multiplet, Ph, protons of the thiazepine ring, N-CH, jCO); 7.1-7.65 (3N, multiplet; protons of the thiophene ring) i 7.27 (5H5 singlet, phenyl protons).
Next, 0.3 g of sodium bicarbonate and 10 ml of ethyl acetate are added to a suspension of this powder in 4 ml of water. The resulting mixture was stirred for 10 minutes. The pH of the reaction mixture was adjusted to 2.5 by the addition of 3N hydrochloric acid. The resulting ethyl acetate layer is separated; the aqueous layer is extracted with ethyl acetate. The resulting ethyl acetate solutions are combined and dried with anhydrous magnesium sulphate. The separator is prepared by extracting, the title compound is obtained in the form of a crystalline powder, the powder is collected by filtration and washed with a mixture,. consisting of diisopropyl ether and cyclohexane, and as a result, 205 mg of the title compound is obtained, which
50
is at a temperature of about 140 ° C, and so on. 165 ° C
NMR (CDCl 2), ppm: 1.26 (3N, triplet, J 7.5 Hz,,), 1.9 - 2.5 (2H, multiplet, Ph); 2.5-4p7 (13H, multiplet, Ph, protons of the thiazepine ring,
) 6.75-7.3 (3N, multi-, protons of the thiophene ring)
g plet
7.19 (5H, snnglet, phenyl protons),
Pr and im p 39. Alpha-b- (1-carboxy-3-phenylpropylamino) -5-oxo-2- (3-thienyl) perhydro-1,4-thiazepin-4- -yl acetic acid (compound 82).
150 mg of alpha-b- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2- (3- -thienyl) perhydro-1,4-thiazepin-4-yl-acetic / acid, obtained as
described in example 38, mixed with 2 ml of 1N aqueous hydroxide solution. sodium, the resulting mixture, stirring for 16 h, the pH of the reaction
the mixture is then adjusted to 2.0 with 1N hydrochloric acid, the resulting sweaty solid material which is the title compound,
filter by filtration and flush with a small amount of water and diisopropyl ether to obtain 120 mg of the title product.
NMR ((CD) SO) 8, ppm: 1,
(21, multiplet, Ph,); 2.5-4.6
0
five
five
(11H, multiplet, Ph, protons of the thiazepine ring, N-CH, jCO); 7.1-7.65 (3N, multiplet; protons of the thiophene ring) i 7.27 (5H5 singlet, phenyl protons).
Example 40. tert-Butyl alpha-b- (1-butoxycarbonyl-3-phenylpropylamino) -5-oxo-2- (3-thienyl) perhydro-1,4-thiazepine 4-yl acetate.
0.66 g of tert-butyl alpha b-amino-5-oxo-2- (3-thienyl) -perhydro-1,4-β-thiazepin-4-yl) acetate, synthesized as described in example 37g, is subjected to reaction N α-alkali using 0.86 g butyl-2-bromo-4 phenylbutyrate, using the procedure described in Example 37h. The resulting reaction product is chromatographed on a column filled with silica gel, using as eluent a mixture consisting of ethyl acetate and methylene chloride with a volume ratio of 51143515152
between these components, tiplet, protons of the thiophene ring)
equal to 1:20. Chromatography affords 2 isomers: isomer A and Isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached).
Isomer A is first zoned and is an oily compound, the yield is 140 mg.
NMR (CDC1,) S, ppm: 0.7-1.1 (MN, multiplet, СН from n-butyl); 1.46 (9H, singlet, tert-butyl), 1.17, 21 (5H, singlet, phenyl protons).
Example 42. tert-Butyl alfa-6} -1-ethoxycarbonyl-3-phenylIpropyl-amino-5-OXO-2- (2-thienyl) perhydro-1,4-thiazepin-4-un acetate,
42a. 2-tert-Butoxycarbonylamino- -1- (2-thienyl) ethanol.
Intermediate (syfec) 2-amino-1- (2- -thienyl) ethanol, obtained by reducing 62 g of cyanohydrin 2-thiophenecarbonaldehyde with lithium10
2.3 (7H, multiplet, COjCE () CEj aluminum pzdrida, subjected to the reaction Ph, NH) i 2,3-4,, 5 (13H, multiplet, Ph CH H -CH-N, protons of the thiazepine ring, (CR)) 6.85-7.3 (8H, multiplet, phenyl protons, protons of the thiophene ring). The second isomer B is eluted, which is an oily compound, its output is 140 mg.
NMR (CDClpS, ppm: 0.8-1.1 (3N, multiplet, CH-norm-butyl) i 1.47 (9H, singlet, tert-butyl); 1.1-2.3 (7H , multiplet, (Ph, NH) i 2.4-4.5 (13H, multiplet, PhCH CH —CH-N, protons of the thiazepine ring, (CH2.) 4CH3); 6.85-7.5 (8H , multiplet, phenyl protons, protons of the thiophene ring).
Example 41. Apfa-b- (1-butyroxycarbonyl-3-phenylpropylamino) -5- -oxCo-2- (3-thienyl) perhydro-1,4-tyazepin-4-yl acetic acid, 130 mg of isomer In tert-butyl alpha-b- (1-butoxycabarbonyl-3-phenylpropyl-amino) -5-oxy-2- (3-thienyl) peptide-1, 4-thiazepin-4-ylJ acetate, prepared as indicated in Example 44, was treated with trifluoroacetic acid in accordance with the procedure described in Example 48 to remove the tert-butyl trupy, resulting in the title compound, which is a crystalline powder having m.p. 156 ° C, yield 70 mg.
NMR (CDCls) S, ppm: 0.7-1.1 (MN, multiplet, CH norm-butyl); 1.1-1.9 (4H, multiplet, c64CHi (CH2) iCHj) i 2.0-2.6 (2H, multiplet, Ph CH jCH); 2.6-4.9 (13H, multiplet, Ph CH CH -CH-N, protons of the thiazepine ring,
20
tert-butoxycarbonylization according to the procedure described in Example 37a, and 45 g of the title compound, which is a solid crystalline substance having mp. 101-102 C.
NMR (CDCl1), ppm: 1.43 (9H, singlet, tert-butyl), 3.0-3.6 (3N, 25 multiplet, OH); 5.0 (1H, doublet of doublets, J 7.0 and 7.5 Hz, CH-CH); 4.8-5.2 (1H, broad triplet, NH); 6.94 (2H, multiplet, protons at the 3- and 4-positions of the thiophene ring), 7.18 (1H, multiplet, proton at the 5-position of the thiophene ring).
thirty
42b. 2-tert-Butoxycarbonylamino--1-CHLORO-1 (2-thienyl) ethane. - Using the procedure described in Example 37b, 15 g of 2-tert-butoxycarbonylamino-1- (2-thienyl) ethanol is chlorinated with phosphorus pentachloride to give a result of 13.6 g of compound
45
NIN specified in the title, which is a crystalline prodzgkt, having so pl. 40-43 C. The resulting substance is used in the next stage without further purification, due to the fact
50
that it decomposes at
chromatography on a column filled with silica gel.
NMR (CDC1) &, ppm: 1.43 (9H, singlet, tert-butyl); 3.5-3.8 (2H, multiplet -CRj.) 4.90 (1H, broad multiplet, NH); 5.21 (1H, doublet of doublets, J 6.0 and 7.0 Hz, -CH-C1), 6.75-7.3 (3N, multiplet, 55 protons of the thiophene ring).
42c. Benzhydryl ester S- | 2-tert-butoxycarbonylamino-1 -
 .
(CH2)); 6.75-7.3 (3N, multi- (2-thiens1) ethn1-N-phthaloylcysteine.
7.21 (5H, singlet, phenyl protons).
Example 42. tert-Butyl alfa-6} -1-ethoxycarbonyl-3-phenylIpropyl-amino-5-OXO-2- (2-thienyl) perhydro-1,4-thiazepin-4-un acetate,
42a. 2-tert-Butoxycarbonylamino- -1- (2-thienyl) ethanol.
Intermediate (syfec) 2-amino-1- (2- -thienyl) ethanol, obtained by reducing 62 g of cyanohydrin 2-thiophenecarbonyl aldehyde with lithium
aluminum pzdrida, subjected to the reaction
tert-butoxycarbonylization according to the procedure described in Example 37a, and 45 g of the title compound, which is a solid crystalline substance having mp. 101-102 C.
NMR (CDCl1), ppm: 1.43 (9H, singlet, tert-butyl), 3.0-3.6 (3N, multiplet, OH); 5.0 (1H, doublet of doublets, J 7.0 and 7.5 Hz, CH-CH); 4.8-5.2 (1H, broad triplet, NH); 6.94 (2H, multiplet, protons at the 3- and 4-positions of the thiophene ring), 7.18 (1H, multiplet, proton at the 5-position of the thiophene ring).
42b. 2-tert-Butoxycarbonylamino--1-CHLORO-1 (2-thienyl) ethane. - Using the procedure described in Example 37b, 15 g of 2-tert-butoxycarbonylamino-1- (2-thienyl) ethanol is chlorinated with phosphorus pentachloride to give 13.6 g of the compound
five
NIN specified in the title, which is a crystalline prodzgkt, having so pl. 40-43 C. The resulting substance is used in the next stage without further purification, due to the fact
0
that it decomposes at
chromatography on a column filled with silica gel.
NMR (CDC1) &, ppm: 1.43 (9H, singlet, tert-butyl); 3.5-3.8 (2H, multiplet -CRj.) 4.90 (1H, broad multiplet, NH); 5.21 (1H, doublet of doublets, J 6.0 and 7.0 Hz, -CH-C1), 6.75-7.3 (3N, multiplet, 5 protons of the thiophene ring).
42c. Benzhydryl ester S- | 2-tert-butoxycarbonylamino-1 -
1-l
- (2-tiensh1) etsh1 -N-phthaloylcysteine.
531
The procedure described in Example 38c is used; β-phthaloyl-1-cysteines benzhydryl ester obtained from 10 g of L-cysteine p-toluenesulfonate, 7.5 g of N-ethoxycarbonylphthal imide, 6j2 g of sodium bicarbonate and 7e4 g of diphenyldiazomethane and 10 g of 2-tert-butoxycarbonylamino-1-chloro--1 (2-thienyl) ethane, obtained as indicated in step b, is dissolved in 60 ml of dimethylformamide. To the resulting solution was added 8.6 g of carbon

That sodium, and then the resulting mixture was stirred for 16 hours at 60 ° C in a stream of nitrogen gas. Next, the resulting reaction mixture is processed in accordance with the procedure specified in Example 38c, to obtain as a result the compound indicated in the title, which is a solid amorphous product, the yield is 7.3 g.
NMR (CDCl,) S, ppm: 1.38 (9H, singlet, tert-buty.p); 3.0-3.7 (4H5. Multiplet, CHj, S,). 4.31 (IH, broad triplet, J 7 Hz ;, S-CH-thienyl), 4.75 (W, stylic multiplet, NH); 4.92 (1H, doublet of doublets, J 6.5 and 7 "O Hz, N-CH-CO) .J 6.7-7.3 (14H, multiplet,) protons of the thiophene ring) ,. 7,: -7j85 (4H5: yltshtxIet, phthaloyl protons),
42d. 3-2 Amsho 1 - (2-tyensh1) Eshg) - -N-phthaloylcysteine,
Using the procedure described in Example 37d, 9.3 g of a benzhydryl complex fir of S-2-tert-butoxycarbonylamino-1- (2 thienyl) ethyl-N-phthaloylcysteine, obtained in Step 5, are treated with removing the protection using trifluoroacetic acid results in 1.7 g of the compound indicated in the title, which is a pale yellow powder,
42e. 5-Oxo 6-phthalim 1-2- (2-thienyl) -perhydro-1, 4-thiazepine.
Using the procedure specified in Example 37e5 1.7 g D - 2 -amino 1- (2-thienth) ethyl} D-phthalo-cystine obtained in step d, top the cyclization reaction by condensation using ml of diphenylphosphoryl azide , with the resulting compound indicated in the title, in the amount of g, having so on, pl. 183-184 S.
54
5151
NMR ((CD) SO) 8
ten
15
0
ppm: 2.953, 95 (4H, multiplet,); 4.46 (1H, doublet, doublets, J 4.0 and 8.0 Hz, S-CH-thienyl), 5.38 (1H, doublet of doublets, J 5.0 and 8.0 Hz, N-CH- CO), 6.9-7.5 (ZN, multiplet, protons of the thiophene ring) 7.87 (4H, singlet, phthaloyl throtons), 8.12 (1H, broad triplet, J 7.0 Hz, W).
42f. tert-Butyl alpha-5-oxo-6-phthalimido-2- (2-thiensh1) per hydro-1,4-thiazepin-4-Sh1 acetate.
Using the procedure indicated in Example 37f, 1.6 g of 5-oxo-6-phthalimi- to-2- (2-thienyl) perhydro-1,4-thiazepine, crawled in step f, are treated with tert-butybtbromoacetate, resulting in a compound {specified in the title, in the form of crystals and having so pl. 183-184 C. The yield amounted to 1.15 g,
NMR (CDClj) ,, ppm: 1.47 (9H, 25 singlet, tert-butyl), 2.9-4.9 (7H, multiplet, N-CH-SN-Stenyl-3-CH, N-CHj -CO) 5.67 (1H, doublet of doublets, J 3.0 and 10.0 Hz, N-OT-CO), 6.95-7.35 (3N, multiplet, protons of the ggiofennoy ring); 7.65-8.0 (4H, multiplet, phthaloyl protothl).
42g. tert-Butyl alpha-b-amino-5- (2-thiensh1) perhydro-1,4-thiazepin-4-sh1 | acetate.
Using the procedure described in Example 37g, 1.1 g tert-butyl alpha-5-oxo 6-phthalimido-2- (2-thiensh1) perhydro-1, 4-thiazepin-4-yl | the acetate obtained in step f is subjected to a dephthaloisation reaction with i methyl hydrazine to obtain as a result 0.52 g of the title compound, which is a crystalline powdery material, i.p. 84-86.5 C.
NMR (CDCl.j), ppm: 1.47 (9H, singlet, tert-butyl), 2.29 (2H, broad singlet, NHj), 2.6-4.7 (8H, multiplet, protons thiazepine ring, -NC% -CO) i 6.75-7.2 (3N, multiplet, protons of the thiophene ring).
42h. tert-Vutyl alpha-6 l (1-etoc-cccabaronyl-3-fenche / propanolamo) -5-oc co-2- (2-thienyl) perhydro-1,4-thiazepin-4-yl acetate D compound 119).
Using the procedure described in Example 37h, g tert-butyl alpha-b amiko-5-oxo-2- (2-thienyl) per 30
35
40
45
50
55
551A3515156
hydro-1,4-thiazepin-4-yl acetate, gives 83 mg. The product obtained in step g is subjected to N-alkylation reaction using 0.64 g of ethyl 2-bromo-4-phenylbutyrate. The resulting product is chromatographed on a column filled with silica gel, a mixture consisting of ethyl acetate and methylene chloride, with semi-, N-CHj CO, COjiCH CH) is used as the solvent; 7.0-7.6 (ЗН,
has a softening temperature of about 135 ° C, and so forth. 168 ° C.
NMR ((CD,), SO) 5, ppm: 1.26 (3N, triplet, J 7.3 Hz, CO.CH, CH,)
1.9-2.3 (2H, multiplet, Ph CH, CA); 2.5-5.1 (13H, multiplet, Ph, protons of the thiazepine ring
This is due to the presence of two isomers: isomer A and isomer B (due to the presence of the asyl polymer of the carbon to which the phenethyl group is attached).
From the fraction eluted first, 0.21 g of isomer A is obtained, which is an oily substance.
NMR (CDCl 3) ppm: 1.24 (3N, triplet, J 7.5 Hz,) 1.48 (9H, singlet, tert-butyl); 1.7-2.3 (2H, multiplet, Ph); 2.4-4.8 (14H, multiplet, Ph CH CH CH multiplet, protons of the thiophene ring); 7.30 (5H, singlet, phenyl protons)
Example 44 Alpha- 6- (1-carb-5 hydroxy-3-phenylpropylamino) -5-oxo-2- - (2-thiensh1) perhydro-1,4-thiazepin-4- -yl acetic acid.
Apply the procedure specified in Example 39, 70 mg of alpha-6- (1-etoxy-cicarbonyl-3-phenylpropshtamino) -5-oxy-2- (2-thienyl) perhydro-1,4-thiazepin-4- mf of acetic acid, prepared as indicated in Example 43, is subjected to a hydrolysis reaction using hydro-
20
thirty
header, which is a powdered material.
NMR ((CDj), jSO), ppm: 1.7-2.05 (2H, multiplet, Ph); 2.5-4.8 (11H, multiplet, Ph-CH-N, protons of the thiazepine ring); 7.0-7.55 (3N, multiplet. Protons of the thiophene ring), 7, 28 (5H, singlet, phenyl protons). 35 Example 45. tert-Butyl alpha-b- (1-butoxycarbonyl-3-phenylpropylamino) -5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-yl 3 acetate.
Apply the procedure specified in example 37h, 0.40 g of tert-butyl al40
-SL-NH, protons of the thiazepine ring, 25 sodium rooxide. The result is-,) -; 6.85-7.35 (GH, 52 mg of the compound indicated in 1 multiplet, protons of the thiophene ring); 7.20 (5H, singlet, phenyl protons).
From the fraction that is eluted by the second, 0.30 g of isomer B is obtained, which is an oily substance.
NMR (CDC1,) S, ppm: 1.26 (3N, triplet, J 7.5 Hz,,) 1.48 (9H, singlet, tert-butyl); 2.25 (2H, multiplet, Ph), 2.55-4.8 (12H, multiplet, Ph —CH-NH, protons of the thiazepine ring,), 4.15 (2H, quartet, J 7.5 Hz, CO ) 6.85-7.35
(MN, multiplet, protons thiophene (amino-5-oxo-2- (2-thienyl) pepper) J 7.20 (5H, singlet, phenyl-hydro-1,4-thiazepin-4-yl acetate, - ny protons). radiated as described in example 42g,
Example 43. Alpha-6- (1-etho-) is subjected to N-alkylation reaction with sicarbonip-3-phenylpropylamino) -5-about-using 0.52 g of butyl-2-bromo-4-phenylbutyrate. The resulting product is chromatographed on a column filled with silica gel, the elution process is carried out with a mixture consisting of ethnacetate and methylene chloride with a volume ratio between the indicated components of 1:20. As a result of chromatography, the mixture is divided into
bottling with trifluoroaceticus-55 two isomers: isomer A and isomer B (nano-acid. The result is the asymmetry-based compound in the form of a crystalline carbon atom to which the lytic powder is, and the yield is co-connected. and a group).
co-2- (2-thienyl) perhydro-1,4-thiasepin-4-yl2 acetic acid.
Using the procedure described in Example 38, 0.3 g of isomer B tert-butyl alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -5-oxo-2- (2-thienyl) perhydro-1, 4-thiazepine -4-ylSaccharide, prepared as indicated in Example 42h, is subjected to the reaction 50
 puts 83 mg. The resulting product d N-CHj CO, COjiCH CH); 7.0-7.6 (ЗН,
has a softening temperature of about 135 ° C, and so forth. 168 ° C.
NMR ((CD,), SO) 5, ppm: 1.26 (3N, triplet, J 7.3 Hz, CO.CH, CH,),
1.9-2.3 (2H, multiplet, Ph CH, CA); 2.5-5.1 (13H, multiplet, Ph, protons of the thiazepine ring
multiplet, thiophene ring protons); 7.30 (5H, singlet, phenyl protons)
Example 44 Alpha- 6- (1-carb-5 hydroxy-3-phenylpropylamino) -5-oxo-2- - (2-thiensh1) perhydro-1,4-thiazepin-4- -yl acetic acid.
Apply the procedure specified in Example 39, 70 mg of alpha-6- (1-etoxy-cicarbonyl-3-phenylpropshtamino) -5-oxy-2- (2-thienyl) perhydro-1,4-thiazepin-4- mf of acetic acid, prepared as indicated in Example 43, is subjected to a hydrolysis reaction using hydro-
0
thirty
header, which is a powdered material.
NMR ((CDj), jSO), ppm: 1.7-2.05 (2H, multiplet, Ph); 2.5-4.8 (11H, multiplet, Ph-CH-N, protons of the thiazepine ring); 7.0-7.55 (3N, multiplet. Protons of the thiophene ring), 7, 28 (5H, singlet, phenyl protons). 35 Example 45. tert-Butyl alpha-b- (1-butoxycarbonyl-3-phenylpropylamino) -5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-yl 3 acetate.
Apply the procedure specified in example 37h, 0.40 g of tert-butyl al40
25 Sodium rooxia. As a result, 52 mg of the compound indicated in
(amino-5-oxo-2- (2-thienyl) perhydro-1, 4-thiazepin-4-yl acetate, prepared as described in example 42g,
50
57
From the fraction that is eluted; first, 125 mg of isomer A, which is an oily substance, are obtained.
: NMR (CDCl,), ppm: 0.7-1J 1 (3N, multiplet, CH, n-butyl),
1.46 (9H, singlet, tert-butyl) 1.1-2.3 (6H, multislet, (CE) CH, Ph CHjCH), 2.3-4.7 (UH, multiplet, Ph CHj-QH OT-NH , photons of the thiaz-epin ring,, CO, CH (CH ,,) CH,); 6.85-7.35 (ZN, multiplet, protons of the thiophene ring) 7 ,, 18 (ZN, multiplet, phenyl protons).
From the fraction that is zlirovana second, get 120 mg of isomer B, which is an oily substance,
NMR (CDC1) & ,, h, 0.7-1.1 (3N, multiplet, CH norm-butyl)
1.47 (9H, singlet tert-butyl) -, Ijl- 2,3 (bN, multiplet, (), SI .. Ph CHjCH); 2.3-4.8 (14H ,, multiplet, Ph CH CH j CH-NH, protons of the typosine ring, k-CH, g.CO, CO, jCH, (CH),) 6.85-7.35 (MN, multiplet,, protons of a thiophenosis ring), 7.18 (MN, singlet, phenyl protons).
PRI me R 46. Alpha-6- (oxycarbonyl-3-phenylpropylamino) -5- -oxo-2- (2-thienyl) perhydro 1,4-thiase - pin-4-yl acetic acid,
Using methodology 5: as described in Example 42, 120 mg of isomer B tert-butyl alpha-b- (1-butoxycarbonyl- -: 3-feiylpropylamino) -5-oxo-2 - (- 2-tc-enyl) perg1-adro The -1,4-tnazepin-4-yl acetate, prepared as described in Example 45, is subjected to a detraptaining reaction using trifluoroacetic acid, resulting in 75 mg of the title compound, in the form of a powdered product.
NMR (CDCl 3) ppm: 0.7-1.1 (3N, multiplet, CHj n-butyl.), 1.1-1.9 (4H, multiplet, COiCH (CH,) CK j) i 1.9-2.5 (2H, multiplet, Ph) 2.5-4.9 (13H, multiplet, Ph CHjCEftCH Nj protons of the thiazepine ring, N-GH-CO, CO, CH 2. (CH2): Hp , i 6.8-7.35 (3N, multiplet, thiophenic ring ducts) 5 7.20 (5H, singlet, phenyl protoc.).
Example 47. tert-Butyl alpha-b- (1-ethoxycarbonyl-3-phenylpropyl,,;
4351515B
amino) -2- (2-furyl) -5-oxoperhydro-1, 4-thiazepin-4-Sh1 acetate.
47a. 2-tert-Butoxycarbonylamino- -1- (2-furyl) e-tanol,
Using the procedure described in Example 37a, the intermediate (raw) 2-amino-1- (2-furyl-ethanol, obtained by reducing 63 g of cyanohydrin furfural with lithium-aluminum hydride, is subjected to a tert-butoxycarbonylation reaction, to give the resultant specified
ten
in the title, in the form of crystals, having so pl. 89-90 ° C. The yield is 36.7 g.
NMR (CDCl1), ppm: 1.43 (9H, singlet, tert-butyl) 3.3-3.65 (3N, multiplet, OH); 4.74 (1H,. Doublet of triplets, J 5 and 6 ,, CH-OH); 5.07 (broad, triplet, J 5 Hz, NH) 6.28 (2H, multiplet, protons at 3 and 4 positions of the furan ring) i 7.33 (1H, multiplet, protons at 5 position of the furan ring).
47b. 2-tert-Butoxycarboxylamino-1-chloro-1- (2-furyl) ethane.
Using the procedure described in Example 37b, 14 g of 2-tert-butoxycarbonylamino-1- (2-furyl) ethanol obtained in step a are processed with phosphorus pentachloride to give 15 g of the title compound in the form of crystals, having so pl. 75-77 ° C. This material is used in the subsequent stage without additional purification, due to the fact that when chromatographed on a column filled with silica gel, this material is separated.
NMR (CDCl 2), ppm: 1.43 (9H, singlet, tert-butyl); 3.55-3.85 (2H, multiplet,) ,, 5.00 (1H, wide, W) I 5.05 (1H, doublet of doublets, J 5.5 and 6.5 Hz, -CH- C1) 6.33 (2H, multiplet, protons at the 3- and 4-positions of the furan ring) 7.39 (1H, multiplet, protons at the 5-position of the furan ring),
47c. 5- 2-tert-butoxycarbonylamino-1- (2- -furyl) ethyl-K-phthaloylcysteine beeshydril ester.
Using the technique described in
example 37c, benzhydryl complex
ether H; -taloyl-1, -cysteine, obtained
15 g of L-cysteind p-toluenesulfonate, 11.3 g of N-ethoxycarbonylphthalimide.
591
9.3 g of sodium bicarbonate and 11 g of diphenyldiazomethane, and 15 g of 2-tert-butyoxycarbonylamino-1-chloro-1- (2-furyl) ethane, obtained in stage b, are dissolved in 90 ml of dimethylformamide To this solution, 12.9 g of sodium carbonate was further added, and the mixture was stirred for 16 hours at 60 ° C in a stream of gaseous nitrogen. Next, the reaction mixture was treated in accordance with the procedure of Example 37c, to obtain the title compound, which is a solid amorphous substance. The yield was 7.6 g.
NMR (CDCl1) S, ppm: 1.39 (9H, singlet, tert-butyl) J 3.2-3.7 (4H, multiplet ,, 8,, N) 4.13 (1H, wide triplet, J 7.5 Hz, -3-CH-furyl); 4.7-5.1 (2H, multiplet, NH, N-CH-CO) -, 6.22 (2H, multiplet, protons at the 3- and 4-positions of the furan ring); 6.84 (1H, singlet, SNSSbNU)), - 7.20, 7.27 (together with UN, each singlet,)), approximately 7.25 (1H, multiplet, proto in the 5-position of the furan ring), 7.55-7.95 (4H, multiplet, phthaloic protons).
47d. 2- (2-furyl) -5-oxo-6-phthalimy doperhydro-1,4-thiazepine.
To a solution consisting of 7.6 g of benzhydryl ester-tert-butoxycarbonylamino-1- (2-furyl) eth-H-phthalo-cysteine obtained in step c, 30 ml of anisole is added 30 ml of trifluoroacetic acid, and This process is carried out under ice cooling. As a result, the resulting mixture instantly changes its color to brown and then the mixture is stirred for 1.5 hours at room temperature. The resulting reaction solution is concentrated by evaporation under reduced pressure. The resulting residue is dissolved in ethyl acetate, and then 2 g of sodium bicarbonate and water are added to the resulting solution, and the mixture is further stirred. The aqueous layer, characterized by a pH value of 7; separated from the ethyl acetate layer having a brown color. The pH of the aqueous layer is adjusted to a value of 5.5, by the addition of 3 N hydrochloric acid, and the resulting solution is evaporated to the mixture.
51
60
Q g
o 5 o

0
five
dry material. The residue thus obtained, containing - 2-amino-1- (2-furyl) ethyl-N-phthaloylcysteine, is suspended in 60 ml of dimethylformamide. To the suspension thus obtained, 21 methyl morpholine and 5 g of diphenylphosphoryl azide are added. The resulting mixture was stirred for 24 hours at room temperature, and then to this: water and ethyl acetate were added. The resulting ethyl acetate layer is separated and dried with anhydrous magnesium sulfate, and the solvent is separated by drying. The result is the desired product in the form of a crystalline powder. The product thus obtained is collected by filtration using a small amount of ethyl acetate and diethyl ether, to give the title compound, having mp, 135 ° C., the yield is 1.18 g,
NMR ((CD,) 2SO) S, h, ppm: 3.26 (2H, broad doublet, J 6 Hz, N-CH, - C) i 3.5-4.35 (ZN, multiplet, 8 -CH (furSh1), N-CH-CH-S), 5.33 (1H, triplet, J 6 Hz, N-CH-CO) -, 6.33 (2H, multiplet, protons at 3- and 4 positions of the furan ring); 7.50 (1H, multiplet, proton in the 5-position of the furan ring); 7.78 (4H, singlet, phthaloyl protoxy 1),
47e, tert-Butyl alpha-2- (2-fural) -5-oxo-6-phthalimidoperhydro-1,4-β-thiazepin-4-yl | acetate,
Using the procedure described in Example 37f, 1.15 g of 2- (2-furyl) -ox-6-phthalimidoperhydro-1-thiacycloheptane obtained in step d is treated with tert-butyl bromoacetate to give 0.86 as a result. g of the title compound is in the form of crystals and has a melting point; 158-1b1 ° C. ,
NMR (CDCl1) ppm: 1.44 (9H, singlet, tert-butyl); 2.9-4.6 (7H, multiplet, K-CH, - CH (furyl) -8-Sh5 ,, N-CHi-CO); 5.58- (1H, doublet, duplicate - TT J 4.5 and 8.0 Hz, -N-CH-CO); 6.33 (2H, multiplet, protons and at the 3- and 4-positions of the furan ring) i 7.37 (1H, multiplet, a proton in the 5-position of the furan ring), 7.58-7.95 (4H, multiplet , phthaloyl protons),
.61U
47f. tert-butyl alpha-b-amino; 2- (2.-FURIL). Operhydro-1 ,, 4--: azepin-4-yl acetate. : Use the procedure described in Example I of STgsOjSS of tert-butyl alpha-i-2- (2-4-1) 5-oxo-6-phthalimidopa Ihydro-1 4-thiazepn-4-yl 1-acetate, obtained in step c, is subjected to dephthaloization reaction by image
MethylhydrazinoMe preparations result in a semi-product, which is then purified by chromatography on a column filled with silica gapem. A fraction of 1: 1: 85 from 0 to 45 g of the crystalline compound of the title compound, having a melting point of 90-92, is obtained from the fraction that is used as a mixture of methanol, cyclohexane and ethyl acetate with a volume ratio between the components equal to 1: 1: 85. WITH.
NMR (CDC1,) S, hours / million; - | ,, 48 (9H., Singlet, tert-butyl) 2.20 (2H5 broad singlet NHj) i 2.81 (2H, doublet, J 6, Hz, N-CH, C) -, 3, (bN multiplet ,, -N-CH-CH2.-S-CH- furyl, N-CHa -CO); 6J 18-6.35 (2H5 multiplet protons in the 3- and 4-positions of the furan ring) 7.35 (1H, m3 lijplet, 5 proton in the 5-position of the furan b-ohl "yes)
47ge tert-Butl-l alpha-5- (1-ethoxycarbonyl-3-fennl; phylamino) 2 (2- -fursh1) -5-oxoperhydrO 1,4 tiazep-4-yl acetate.
 Using the procedure described in Example 37h, xananzto, 0.40 g of tert-butyl alpha ™ b-amino-2- (2-furyl) -3-oxopergic ro-1,4-thiazepin-4-yl acetate in step f, is subjected to N-alkylation using 0.68 g ethyl -2-bromo 4-phenylbutyrate. The resulting product is chromatographed on a column filled with silica gel, and the zylation process is carried out with a skewer consisting of ethyl acetate and meth. Penchloride with a volume ratio between these components equal to 1:20. As a result, the resulting product is divided into two isomers; isomer A and isomer B (due to the presence of an asymmetric carbon atom to which the phenyl group is attached),
From the fraction that is first eluirozan, 0.30 g of isomer A is obtained, which is an oily substance.
62
0
NMR (CDCl 3) 5 ppm: 1.22 (3H, triplet, J 7.5 Hz, COjCH j CH,); 1.46 (9Hp singlet, t-butyl); 1.7 - 2.2 (2H, multiplet, Ph) 2.4 - 455 (4H, multiplet, Ph CH CH CH CH-NH-, protons of the thiazepine ring,,) - 6.05-6.3 (2H, multiplet, protons in the 3- and 4-positions of the furan ring); 7.13 (5H, singlet, phenyl protons), 7.25 (IH, multiplet, proton at the 5-position of the furan ring).
From the fraction that is zoned
5 second, 0.30 g of isomer B, which is an oily 1 substance, is obtained.
NMR (CDCl) ,, ppm: 1.75-2.3 (2H, multiplet) 2.5-4.5
Q (UH, multiplet, PhCHj CHjCHNH,. Protons of the thiazepine ring,,); 6.1–6.35 (2H, multiplet, protons in the 3- and 4-position of the furan ring) j 1.26 (3N, triplet, J
5 Hz,); 1.48 (9H, singlet, tert-butyl), 7.15 (5H, singlet, phenyl protons) J 7.27 (1H, multiplet, proton in the 5-position of the furan ring),
Example 48. Alpha-b- (1-ethoxycarbonyl-3-fenschropylamino) -2- (2- -furyl) -5-oxoperhydro-1,4-thiazepine-4-yl-Z-acetic acid.
Using the procedure outlined in gfimer 38, 270 mg of isomer B tert-butyl alpha b- (1-ethoxycarboxy-1-3-phenylpropylamino) -2- (2-furyl) -5-ctg co-1,4-thiazepin-4- Sh1 acetate, prepared as described in Example 47g, is subjected to a detritularization reaction with trifluoroacetic acid, resulting in 140 mg of the title compound, which is poroF
NMR ((CI),) SO) S; 5 ppm: 1.26 (ZN, triplet, J 7.5 Hz, C02. CH2CH; 1.9-2.3 (2H, multiplet, Ph CHgQH,), 2.5-4.9 (13H , multiplet, Ph СБ.2 CH CH-N-, protons of the thiazepine ring,, COjCH CH j); 6.48 (2H, multiplet, protons in the 3- and 5-folds of the furan ring), 7.30 ( 5H, singlet phenyl protons), 7,, 67 (1H, multiplet, proton in 5-positions of the furan ring),
Example 49 .. Alpha-b- (1-carboxy-3-phenylpropylamino) 2- (2-buffet1) 0
0
0
-5-oxoperhydro-1,4-thiazepin-d-yl - acetic acid.
Using the procedure described in Example 43, 130 mg of alpha-6- (1-ethoxycarbonyl-3-phenylpropylamino) -3- (2- -furyl) -5-oxoperhydro-1,4-thiaz epin-4-Sh1 Acetic acid, prepared as described in Example 48, is hydrolyzed with sodium hydroxide. 87 mg of the title compound are obtained as a powder.
NMR ((CDj) 2SO) S, ppm: 1.7-2.05 (2H, multiplet, Ph,); 2.5-4.7 (11H, multiplet, Ph, protons of the thiazepine ring,); 6.42 (2H, multiplet, with 3- and 4-positions of the furan ring); 7.27 (5H, singlet, phenyl protons); 7.66 (1H, multiplet, proton in the 5-position of the furan ring).
Example 50. tert-Butyl alpha-Sb- (1-ethoxycarbonyl-3-phenylpro (pilamino) -2- (2-furyl) -5-oxoperhydro-1, 4-thiazepin-4-yl acetate.
Using the procedure described in Example 37h, 0.30 g of 6-butyl alpha: - b-amino-2- (2-furyl) -2-oxoperhydro-1,4-thiazepin-a-yl acetate, As described in Example 47f, the reaction is N-alkylated using 0.50 g of butyl 2-bromo-4-phenylbutyrate. The product obtained is chromatographed on a column filled with sipicagel, and a mixture consisting of ethyl acetate and methylene chloride is used as eluent with a volume ratio of 1:40. Chromatography gives two isomers: isomer A and isomer B (due to the presence of an asymmetric carbon atom to which the phenethyl group is attached).
From the fraction eluted first, 0.5 g of isomer A is obtained, which is an oily substance.
NMR (0001) 5 ppm: 0.7-1.1 (3N, multiplet, n-butyl CH) 1.47 (3N, singlet, tert-butyl) J 1.1-2.3 (6H , multiplet, СОгСН (СН2) СН, Ph CH, CH) j 2.3-4.5 (14H, multiplet, Ph CH CH CH-NH, protons, thiazepine 25
thirty
35
40
7.14 (5H, singlet, Feng's protons); 7.25 (1H, multiplet, proton
in the 5-position of the furan ring).
From the fraction that is eluted second, 0.15 g of isomer B, which is an oily substance, is obtained.
NMR (CDC1,), ppm: 0.7-1.1
TO (RFP, multiplet, CH nor-butyl); 1.46 (9H, singlet, tert-butyl); 1.1-2.3 (6H, multiplet, CO, g.CH (CH) CH3; Ph); 2.3-4.5 (14H, multiplet, Ph CH CHCHCH-NH, —protons of the thiazepine ring 15, CO.CH (CH) .CH3) 6.05-6.03 (2H, multiplet, protons in 3- and 4 positions of the furan ring)
7.15 (5H, singlet, phencl protons); 7.25 (1H, multiplet, proton in
20 5-position furan ring).
Example 51. Alpha- 6- (1-by-oxy-parabons I-3-phenyl-propylamino) -2- - (2-pyryl) -5-oxy-prophydro-1, 4-thiazepin-4-yl acetic acid.
Using the procedure given in Example 38, 0.15 g of the isomer B tert-butyl alpha-6- (1-butoxyprobonyl-3-phenylpropyl amino) -2- (2-furyl) -5- -oxopergide. Pro-1,4 -thiase epin-4-yl acetate, prepared as described in Example 50, is subjected to a de-tolumentation reaction using trifluoro-acetic acid, to give 95 mg of the title compound as a powder.
NMR (CDCl 2), ppm: 0.7-1.1 (3N, multiplet, CHj n-butyl); 1.1-2.3 (6H, multiplet CO, CH (CH, j) CH, Ph CHjCH,); 2.4-4.6 (13H, multiplet,, protons of the thiazepine ring,, CO, CH JCH),., CH,); 6.05-6.3 (1H, multiplet, protons at the 3- and 4-positions of the furan ring);
7.16 (5H, singlet, phenyl protons); 7.25 (1H, multiplet, proton in the 5-position of furan).
Example 52 Alpha-1 6- (R) - - I (G) -ethoxycarbonyl-3-phenylpropyl-amino-5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-yl-acetic acid .
The procedure outlined in Example 38 is repeated, except that
50
The starting material used is tert-butyl alpha- | 6- (R) - (5) -toxycarbonyut-3-phenylpropylamino ring,,, (CH) ,; CH,), but -5-oxo-2- (2-thienyl) perhydro-1 4- 6.05-6.3 (2H, multiplet, protons in -thiazepin-4-yl acetate, in the amount of 3- and 4 positions of the furan ring). 2.81 g. As a result, 2.3 g are obtained.
five
0
five
0
7.14 (5H, singlet, Feng's protons); 7.25 (1H, multiplet, proton
in the 5-position of the furan ring).
From the fraction that is eluted second, 0.15 g of isomer B, which is an oily substance, is obtained.
NMR (CDC1,), ppm: 0.7-1.1
O (ZP, multiplet, CH nor-butyl); 1.46 (9H, singlet, tert-butyl); 1.1-2.3 (6H, multiplet, CO, g.CH (CH) CH3; Ph); 2.3-4.5 (14H, multiplet, Ph CH CHCHCH-NH, —protons of the thiazepine ring,, CO.CH (CH) .CH3); 6.05-6.03 (2H, multiplet, protons in the 3- and 4-positions of the furan ring),
7.15 (5H, singlet, phencl protons); 7.25 (1H, multiplet, proton in
0 5-position furan ring).
Example 51. Alpha- 6- (1-by-oxy-parabons I-3-phenyl-propylamino) -2- - (2-pyryl) -5-oxy-prophydro-1, 4-thiazepin-4-yl acetic acid.
Using the procedure given in Example 38, 0.15 g of the isomer B tert-butyl alpha-6- (1-butoxyprobonyl-3-phenylpropyl amino) -2- (2-furyl) -5- -oxopergide. Pro-1,4 -thiase epin-4-yl acetate, prepared as described in Example 50, is subjected to a de-tolumentation reaction using trifluoro-acetic acid, to give 95 mg of the title compound as a powder.
NMR (CDCl 2), ppm: 0.7-1.1 (3N, multiplet, CHj n-butyl); 1.1-2.3 (6H, multiplet CO, CH (CH, j) CH, Ph CHjCH,); 2.4-4.6 (13H, multiplet,, protons of the thiazepine ring,, CO, CH JCH),., CH,); 6.05-6.3 (1H, multiplet, protons at the 3- and 4-positions of the furan ring);
7.16 (5H, singlet, phenyl protons); 7.25 (1H, multiplet, proton in the 5-position of furan).
Example 52 Alpha-1 6- (R) - - I (G) -ethoxycarbonyl-3-phenylpropyl-amino-5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-yl-acetic acid .
The procedure outlined in Example 38 is repeated, except that
50
the title compound is in powder form.
; 40 ° (with 1.1, dimethylformamide),
The nuclear magnetic resonance spectrum of this product is identical to the spectrum of nuclear magnetic resonance I of the product obtained in Example 43.
Example 53. Alpha-b (R) (8) -ethoxycarbonyl-3-phenylpropyl-amino 1 -5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-yl acetic acid
; hydrochloride (hydrochloride of the compound- I 78).
70 g of alpha-b (K) (5) -ethoxycarbonesh-3-phenylpropylamino-1 -5-oxo-2- - (2-thiensh1) perhydro-1,4-thiazepine-4-1-1-acetic acid, obtained as described in Example 52 is dissolved in 20 ml of ethtacetate. Next, add 0.7 ml of 4N hydrochloric acid in dioxane, and stir the mixture. The mixture is then condensed by compressing under reduced pressure, the resulting residue is dissolved in a small amount of ethyl acetate. Further, dithyl ether is added dropwise in order to crystallize the product. The resulting crystals are collected by filtration to give 0.62 g of the title compound, having a mp, 179-.
/ si / 4-45 ° (s - 1.27, dimethylformamide).
Example 54. Alpha-b (R) (S) -carboxy-3-phenylpropylamine-J - -5-OXO-2- (2-thieni.p) perhydro ™ 1,4-α-thiazepin-4-yl acetic acid.
Using the procedure described in (Example 38, but with the exception that alpha-6 (R) -1 (5) -ethoxy) is used as the starting material.
15
as obtained in Example 44.
Example 55. Alpha-6 (R) -I (8) -ethoxycarbonyl-3-phenylpropsh-amino | -5-OXO-2- (3-thienyl) perhydro-1, 4-thiazepin-4-yl-acetic acid.
3.74 g of tert-butyl alpha-b (R) -1 (3) -toxycarbonyl-3-phenylpropyl-amino-5-OXO-2- (3-thienyl) perhydro-1,4-thiazepin-4-yl-1-acetate I process as described in Example 38,
thus obtaining the title compound, 3.24 g, in the form of a powder.
 43 ° (with 1.43, dimethylformamide),
The spectrum of nuclear magnetic resonance of the obtained product is identical to the spectrum of nuclear magnetic resonance of the product obtained as indicated in example 38.
Example 56. Alpha-- 5 (K) (G) -ethoxycarbonyl-3-phenylpropyl-25 amino-5-OXO-2- (3-thienyl) perhydro-1, 4-thiazepin-4-pcs acetic acid hydrochloride / hydrochloride.
0.8 g alpha {b- (K) (5) -ethoxy-carbonyl-3-phenylpropylamino-5-oxo-.-2g (3-thienyl) perhydro-1,4-thiazepin-4-yl 1 acetic acid , obtained as described in example 55, is converted into the hydrochloride salt of this acetic acid in accordance with the procedure described in example 53. The result is a compound indicated in the title, in the amount of 0.68 g, and have 178-180 ° C.
20
thirty
35
40
soup t.pl.
/, ci. 47 ° (with 1.3, dimethyl form amide).
Example 57. Alpha-1 6 (R) - LI () -carboxy-3-phenylpropylamine - -5-oxo-2- (3-thienyl) perhydro-1,4-thiazepin-4-yl | acetic acid.
70 mg Alfa -. {6 (R) (W) - ethoxycar
carbonyl-3-phenylpropylamino 5-oxononyl-3-phenylpropylamino-5-oxo- (2-2- (2-tyenyl) perhydro-1,4-thiazepine-acetic acid, in an amount of 80 ml, obtained as described in example 52. After hydrolysis of this starting material with sodium hydroxide, 65 mg of the title compound are obtained.
5 In the form of (p. 1.27, digethyl form-thienyl) perhydro-, 1,4-thiazepin-4-yl J-acetic acid, prepared as indicated in Example 56, it is hydrolyzed with an aqueous solution of sodium hydroxide, as described in example 39. As a result, 60 mg of the title compound and the presently powdered material are obtained.
/ oi / V 61.6 ° (c 1.2, dimethylformamide).
amide).
The nuclear magnetic resonance spectrum of this compound is identical to that of nuclear magnetic resonance
five
as obtained in Example 44.
Example 55. Alpha-6 (R) -I (8) -ethoxycarbonyl-3-phenylpropsh-amino | -5-OXO-2- (3-thienyl) perhydro-1, 4-thiazepin-4-yl-acetic acid.
3.74 g of tert-butyl alpha-b (R) -1 (3) -toxycarbonyl-3-phenylpropyl-amino-5-OXO-2- (3-thienyl) perhydro-1,4-thiazepin-4-yl-1-acetate processed as indicated in example 38,
resulting in a compound of the title, in the amount of 3.24 g, in the form of a powder.
 43 ° (with 1.43, dimethylformamide),
The spectrum of nuclear magnetic resonance of the obtained product is identical to the spectrum of nuclear magnetic resonance of the product obtained as indicated in example 38.
Example 56. Alpha-- 5 (K) (G) -ethoxycarbonyl-3-phenylpropyl-5 amino-5-OXO-2- (3-thienyl) perhydro-1, 4-thiazepin-4-pieces acetic acid hydrochloride / hydrochloride.
0.8 g alpha {b- (K) (5) -ethoxy-carbonyl-3-phenylpropylamino-5-oxo-.-2g (3-thienyl) perhydro-1,4-thiazepin-4-yl 1 acetic acid , obtained as described in example 55, is converted into the hydrochloride salt of this acetic acid in accordance with the procedure described in example 53. The result is a compound indicated in the title, in the amount of 0.68 g, and have 178-180 ° C.
0
0
five
0
soup t.pl.
/, ci. 47 ° (with 1.3, dimethylformamide).
Example 57. Alpha-1 6 (R) - LI () -carboxy-3-phenylpropylamine - -5-oxo-2- (3-thienyl) perhydro-1,4-thiazepin-4-yl | acetic acid.
70 mg Alfa-. {6 (R) (H) -ethoxycarbonyl-3-phenylpropylamino-5-oxo- (2-carbonyl-3-phenylpropylamino-5-oxo- (2-thienyl) perhydro-, 1,4-thiazepin-4 -yl-J-acetic acid, prepared as indicated in Example 56, is hydrolyzed with an aqueous solution of sodium hydroxide, as described in Example 39. The result is 60 mg of the title compound, which is a powdered material
/ oi / V 61.6 ° (c 1.2, dimethylformamide).
The nuclear magnetic resonance spectrum of this compound is identical to the spectrum of nuclear magnetic resonance
one
The results obtained as indicated in Example 39.
One of the known causes of hypertension is the content in the blood plasma of a polypeptide known as angiotensin II. As it has been established, a decrease in the content of angiotensin II in blood plasma leads to a decrease in the degree of hypertension. The first step in the synthesis of angiotensin II in a mammal is the conversion of blood protein by the enzyme renin into a polypeptide, known as angiotensin 1. Then this angiotensin (hereinafter referred to as ACE) is converted into angiotensin II. It is obvious that the described synthesis provides several opportunities for reducing plasma angiotensin II, for example, by inhibiting renin activity or ACE.
The compounds prepared according to the inventive method have the ability to inhibit the activity of ACE, an enzyme that converts angiotensin I to angiotensin II and, moreover, deactivates bradykinin. The physiological activity of the proposed compounds can be studied by determining the concentration of the test compound necessary to inhibit ACE activity by 50% under actual conditions (IC), using the method of D. Cushman. ACE solutions extracted from rabbit lungs and, as a substrate, gipurylgistidylleucine. to which the test compound with different concentrations was added, a borate solution containing sodium chloride was added to the buffer, and then the pH was adjusted to 8.3. The enzyme reaction was carried out at 37 ° C for 30 minutes, after which the reaction was carried out through the addition of 1N aqueous hydrochloric acid solution. Hippuric acid, which is formed as a result of this reaction, was extracted with ethyl acetate, and then the solvent was distilled off from the extract. The remaining β-hydrochloric acid was dissolved in water. The amount of hippuric acid in the resulting aqueous solution was determined by ultraviolet absorption in the range of
0
one
„
5 5 5
0
0
51f S
229 nm. Further, these values were plotted so as to obtain a curve that would indicate the ratio between the amount of hippuric acid formed by the reaction and the concentration of the compound tested. The IC can be obtained by removing the concentration of the test compound, which reduces the amount of hippuric acid produced by the reaction, by half relative to the amount of hippuric acid that is formed when the test compound is not removed from the curve obtained. present. The 1C ™ values obtained for the various proposed compounds as a result of this procedure are given below. The following compounds were used in the tests:
A: oi - {b (K) - l (W) -carboxy-3-phenylpropylamino-5-oxo-3 (K) phenylperhydro-1,4-thiazepin-4-yl acetic acid (product from example five);
B: ot- | 6 (R) (S) -carbox-3-phenyl-propylamino-3 (R) -isopropyl-5-ciKco-perhydro-1,4-thiazepin-4-yl-acetic acid (product from Example 24) ;
 C: oi - {6-p-carboxy-3-phenylpropyl aminoZ-5-oxo-2-phenylperhydro-1, 4-
-thiazepin-4-yl-acetic acid (product from example 12);
D: o, (1-carboxy-3-phenylpropano-imino) -5-oxy-2- (3-thienyl) pegy-po-1, 4-thiazepin-4-yl-acetic acid, (product from Example 39) ;
E: oi (1-carboxy-3-phenylpropsh-1-amino) -5-OXO-2- (2-thienyl) perhydro-1, 4-thiazepine-4-sh1 acetic acid (product from Example 44);
F: oi (1-carboxy-3-phenylpropyl-amino) -2- (2-fursht) -5-oxoperhydro-1,4-thiazepin-4-yl acetic acid (product from Example 49) J.
G: oi (R) (8) -carboxy-3-phenylpropylamino -5-oKco-3 (S) - (2-thienyl) J
perhydro-1,4-thiazepin-4-yl; acetic acid (product from example 17),
H: si - b- (1-el-hydroxycarbonyl-3-phenylpropylamino) -2- (1-naphthyl) -5-oxopero-hydro-1,4-thiazepin-4-yl3 acetic acid (product from Example 32 );
I: oi, (1-carboxy-3-phenylpropsh-1-amino) -2- (2-naphthyl) -5-oxoperg1adro-1,4-thiazepin-4-ylTracetic acid (product of Example 36) ",
15
J: oi - {6 (R) - l (5) -carboxy 3-phenyl-ropylamino-3 (K) -methyl-5-oxoperhyd-o-1,4-thiazepin-4-yl acetic acid (product from example 27);
K: (S) -benzyl-6 (R) (S) -carb-hydroxy-3-phenylpropylamino} 5 oxopropyro-19 thiazepin-4-yl acetic acid (product of example 30). tried and tested connections
A1.1. YU
AT
WITH
D
E
F
G
H
I
J
TO
As can be seen from the data, the compounds j obtained by the proposed method inhibit the activity of ACE in very low concentrations and, thus, can be used as diagnostic, preventive and therapeutic agents for use in patients suffering from hypertension, similarly, with the same activity. Salk of these compounds possess.
Comparative trials
Technique
Wistar Imamichi rats weighing 250–350 g were anesthetized with sodium pentobarbital in a quantity of 20
25
thirty
35
40
30 mg / kg, which was administered intra-. In particular, compounds can be administered parenterally, to the left femoral ap in the form of appropriate compositions and
The procedure and the vein were injected with a cannula for recording arterial blood pressure and administering medication, respectively. The other end of the cannula was attached to the neck,
The day after the operation, the arterial cannula was connected to pressure sensors to measure blood pressure while consciously co. standing rats. The intravenous administration of angiotension I in an amount of 0.3 µg / kg was repeated until a constant vasoconstrictor was achieved.
50
55
for injections in which the proposed compound is dissolved or suspended in an injection medium containing pyrogen. The dosage depends on the type and severity of the disease, as well as on the age and condition of the patient, on the patient's body weight. In an example, when treating an adult patient, the dosage at each use in the preferred embodiment varies in the range of 0.5-1000 mg, more preferably, in the area of 5-100 mg in case of stomatological application. After that, through a stomach tube administered through the nose , the test compound was administered in the amount of IjO mg / kg, without ceasing to periodically administer intravenously angiotension,
Percentage inhibition of test compound vasoconstrictor effect by augiotension was calculated by the formula
1 (A1 vasoconstrictor action after drug administration)
the vasoconstrictor effect of A1 before drug administration
X
100
Test compounds are listed in .tabLo 1.
0 The results are shown in Table 2,
The compounds of examples 53 and 56 have
LDyg 5 g / kg and more peros in mice
or rats. Coed Ineenie
example 54 has LD
five
0
five
0
50 1.5 g / kg. The rest of the proposed
the compounds are of low toxicity. For practical; for the therapeutic use of the inventive compound, the compound E is preferably formulated in combination with acceptable pharmaceutical carriers, diluents or diluents. The compounds can be applied by an oral method or by some other method (for example, parenterally, by intravenous or intramuscular injection) and the type of composition is defined. made by the chosen method of application. In the case of dental administration, the compounds can, for example, be used in the form of powders, zero, tablets, capsules, syrups or elixirs. With parenteral administration. These compounds can be used in the form of appropriate compositions.
50
55
for injections in which the proposed compound is dissolved or suspended in an injection medium that does not contain pyrogen. The dosage depends on the type and severity of the disease, as well as on the age and condition of the patient, on the patient's body weight. For example, when treating an adult patient, the dose at each use in the preferred embodiment varies in the range of 0.5-1000 mg, more preferably in the area of 5-100 mg in the case of dental use 143515
Research institutes, while for intravenous injections, the preferred dose for each use varies in the range of 0.3-100 mg, in a more preferred embodiment, 0.5-10 mg. One or more of these doses, in a preferred embodiment of 1-3, can be applied daily.
ten

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining perhydrothiazepine derivatives of the general formula
SOEDZ CH2CII-NH-LjL
SNG
soon
Where
R - hydrogen, phenyl, naphthyl, tieshsh, furyl
: R, i is hydrogen, C -C-alklShf phenyl, benzyl, thienyl, provided that both R and R cannot be hydrogen; R is hydrogen, C-C-alk1, or their acid-addition, pharmaceutically acceptable salts, characterized in that the perhydrothiazepine derivative of the general formula
15
72
NHjV 2 O I
where R, and Rjj, have the indicated meanings, R,
Where
R, X is a tert-butyl carboxy-10 shield group,
condense with the compound of the formula COORg
SNG-SNG-SN-X
C-C-alkyl, halogen,
in the medium of an organic solvent in the presence of a base when heated by a scientific research institute with the subsequent cleavage of a tert-butyl carboxy-protecting group, de-esterification in the case when R is hydrogen, and in isolation of the target compound in the form
5 acid additive pharmaceutically acceptable salts.
Priority featured:
04/10/84. R, is hydrogen, phenyl, naphthyl, R, is hydrogen, C-C-alkyl, phenyl, benzyl, thienyl, provided that R and R cannot be hydrogen, RJ is hydrogen, C-C-alkyl
12.26.84 with R, - thienyl, fzfip.
g kil.
hydrogen.
R5 hydrogen, s, -C-table 1
HC1 salt
73
1435151

R.
3-thienyl
H
7A Continued table. one
 Note (
HC1 salt is active
Optically active compound

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法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

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JP59071353A|JPH0559909B2|1984-04-10|1984-04-10|

---

JP27345184|1984-12-26|

---