Method of producing condensed seven-membered cyclic compounds or their salts

专利摘要:
Novel condensed, seven-membered ring compounds of the formula …<CHEM>… [wherein R<1> and R<2> are independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both jointly form tri- or tetramethylene; R<3> is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl; R<4> is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted cycloalkylalkyl; Y is a carboxyl group which may be esterified or amidated; m is 1 or 2] and salts thereof. …<??>These compounds and salts thereof exhibit inhibitory activity on angiotensin converting enzyme and so forth, and are of value as an agent for diagnosis, prevention and treatment of circulatory diseases (e.g. hypertension, cardiopathy, cerebral apoplexy).
公开号:SU1563593A3
申请号:SU853940048
申请日:1985-08-19
公开日:1990-05-07
发明作者:Сугихара Хиросада；Нисикава Кохей；Ито Кацуми
申请人:Такеда Кемикал Индастриз, Лтд (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new benzoxazazine derivatives, namely condensed seven-membered cyclic compounds of the general formula
2 O-h I2
VNH-CH-COOP,
g /
,
ABOUT
(D
CH2-Y
where R is hydrogen, lower Cf-C-alkyl
or benzyl;
R is lower C -C-alkyl, possibly substituted amino group, phenyl (lower) alkyl5 cyclohexyl (lower) alkyl, tetrahydropyranyl (lower) alkyl, piperidyl (lower) alkyl;
Y is a carboxyl group, or their salts, possessing valuable pharmacological properties.
The purpose of the invention is to obtain new benzoxazepine derivatives that exhibit unexpected pharmacological properties of this number of compounds,
Example I. In 10 ml of ethanol is dissolved 0.5 g of benzyl-3 (8) -amino 4-OXO-2,3 s 4,5-tetrahydro-1,5-6 en-oxazepine-5-hydrochloride acetate, the solution was introduced with triethylamine (0S49 g) and ethyl bromoacetate (0.46 g). After stirring the solution for 4 days, the solution is dried under reduced pressure. The residue is purified on a chromatographic column filled with silica gel (eluted with hexane: egylacetate in 4: 3 ratio). 0.28 g of benzyl-3 (8) -ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate is obtained as a pale yellow oil.
IR: cm-1: 3330 (NH), 1740S 1680 ().
Mass spectrum (t / e): 412 (M4). C ° d- 148 ° (, 4 in methanol). Examples 2-22 Using the procedure of Example 1, the compounds of Examples 2-9 are prepared (Table 1).
A catalytic reduction of the benzyl-1,5-benzoxase of the pin-5-acetate derivative obtained in examples 2-9 is carried out using 10% palladium-carbon in
,
P
five
„

0
50
five
as a catalyst, resulting in a derivative of 1.5 g of benzoxazepine-5-acetic acid, presented in Table. 2 (examples 10-22).
Example 23. In 200 ml of ethanol is dissolved 9.5 g of tert-butyl-3 (3) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate, to a solution - 2.34 g of acetic acid, 34.5 g of ethyl 4-cyclohexyl-2-oxobutyrate and 50 g of molecular sieves 4A are added. The mixture is stirred at room temperature for 1 hour. A solution (2.5 g) of sodium cyanoborohydrate in 50 ml of ethanol is added 3 hours. A solution of 5.1 g of sodium cyanoborohydride in 100 ml of ethanol is then added dropwise to the mixture over 2 hours, and the reaction mixture is concentrated under reduced pressure. 300 ml of water and 400 ml of ethyl acetate are added to the residue, and the mixture is stirred. Then, the insolubles were removed by filtration, the ethyl acetate layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. To the residue are added 100 ml of ethyl ether and 8 g of oxalic acid, shaken and diluted with 500 ml of petroleum ether. The mixture was left overnight. The floating layer was removed by decantation, and 300 ml of water and 400 ml of ethyl acetate were added to the residue, followed by neutralization with an excess of sodium bicarbonate. The ethyl acetate layer was dried over anhydrous MgSO4. and concentrated under reduced pressure to give the product as an oil, which is separated and purified on a chromatographic column filled with silica gel (eluted with hexane: ethyl acetate in a 5: 1 ratio). 2.3 g of tert-butyl-3 (8) (K) ethoxycarbonyl-3-cyclohexylpropyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazazepine are obtained from the first fraction. -5-acetate as a colorless oil.
Calculated,%: C, 66.37; H 8.25; N 5,73C17H4oNaOt
Found,%: C 66.57; H 8.57; N 5.48,
Mass Spectrum (t / e): 488 (M +),
bUn-112 (, 5 in methanol).
From the second fraction, 3.2 g of tert-butyl-3 (8) (3) -ethoxycarbonyl-3-cyclohexyl-spheno-amino-4-oxo2, 3,4,5-tetrahydro-1,5-benzoxazepine 5-acetate are obtained in the form colorless oil.
Calculated,%: C, 66.37; H 8.25; N 5.73.
C77H40N20
Found,%: C 66.72; H 8.72; N 5.82.
Mass spectrum (m / e): 488 (M).
CoOv-125 ° (, 4 in methanol).
Example 24. 1.5 g of tert-butyl-3 (3) -C1- (5) -ethoxycarbonyl-3-cyclohexylpropyl 3 amino-4-oxo-2,3,4,5-tetrahydro are dissolved in 10 ml of ethanol -1, 5-benzoxazepine-5-acetate, prepared in Example 23, and added dropwise 1 n. sodium hydroxide solution for 15 minutes. After stirring for 3 hours, the solution was diluted with water (200 ml) and extracted with ethyl ether (100 ml). The aqueous layer was weakly acidified with 1N. hydrochloric acid and precipitating crystals. This product is recovered by filtration and dried. 1.2 g of tert-butyl-3 (5) (3) -carboxy-3-cyclohexyl-propyl-amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5 are obtained. -acetate in the form of colorless needles, so pl. 180-183 ° C.
Calculated,%: C 65.20; H 7.88; N 6.08.
C2SH3tNtO
Found,%: C 65.18; H 7.83; N 6.14,
Co / L 1220 (, 5 in methanol).
Example 25. In 10 ml of K, I-dimethylformamide, 0.25 g of tert-butyl-3 (S) -1 (5) -k arboc Si-3-cyclohexylpropyl-amino-4-oxo-2 is dissolved. , 3,4,5-tetrahydro-1,5-benzoxazepin-5-acetate, prepared in Example 24, and benzyl bromide (0.14 g), sodium bicarbonate (0.7 g) and potassium iodide are added to the solution (0.05 g). The reaction solution is stirred at room temperature for 6 hours, diluted with water (OO ml) and extracted with ethyl acetate. The extract is washed successively with 1N. hydrochloric acid and water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The oily product is purified on a chromatographic column filled with silica gel (hexane: ethyl acetate 5: 1), the result is 0.25 g of tert-butyl-3 (8) (3) -benzyloxycarbonyl-3-cyclohexylpropyl-amino-4- oxo-2, 3,4,5-tetragl-dro-1,5-benzoxazepine-5-acetate as a colorless oil.
1R: J
Chnstau
cm-: 3330 (NH), 1740,
GM “KS”
5 1680 ().
tVJjj-1550 (, 6 in methanol). Mass spectrum (m / e): 550 (M). Examples 26-27., Q, tert-butyl-3 (B) (3) -carboxy-3-cyclohexylpropyl} -amino-4-ox-with-2,3,4,5-tetrahydro-1 is reacted , 5-benzoxazepin-5-acetate with the halide given in table. 4, similar to the reaction 5 described in Example 25, resulting in a benzoxazepine derivative as shown in Table 2. 3
Example 28. In 10mln. dissolving hydrogen chloride-ethyl acetate dissolved 0.5 g of tert-butyl-3 (3) -1 (3) -ethoxycarbonyl-3-cyclohexyl-propyl-amino-4-oxo-2,3,4,5-tetra- , hydro-1,5-benzoxazepine-5-acetate,
5 obtained in Example 23, and the solution is allowed to stand at room temperature for 4 hours. 200 ml are injected into the solution. petroleum ether and the mixture is thoroughly shaken. After removal
In the supernatant, decanting is extracted with 100 ml portions of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure.
under pressure. Ethyl ether is introduced into the viscous residual. The result is 0.37 g of 3 (S) (S) -ethoxycarbonyl-3-cyclohexylpropyl J-amino-4-oxo-2,3,4,5-tetrahydroxy 1,5Q benzoxazepin-5-acetic acid as colorless crystals, so pl. 135-139 ° C.
S-144 ° C (, 3 in methanol). This product was recrystallized 5 from ethyl acetate and petroleum ether, and 3 (8) - {(3) -ethoxycarbonyl-3-cyclohexyl - propyl 3 amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetic
0 acid in the form of colorless prisms, which is identical to the compound obtained by recrystallization in Example 23.
Examples 29-31. The benzoxazepine-5-acetic acid tert-butyl derivatives obtained in Examples 26-27 are treated with hydrogen chloride as described in Example 28, resulting in benzoxazepin-5-acetic derivatives shown in Table 2. four.
Example 32.B1 ml of ethanol dissolved 0.2 g of 3 (S) (3) -ethoxy-carbonyl-3-cyclohexylpropyl} -amino-4-oxo-2,3,3,5-tetrahydro-1,5-benz sazepin-5-acetic acid, prepared in Example 28, and 3 ml of 1N are introduced into the solution. sodium oxide nitrate solution. After stirring at room temperature for 2 hours, the solution is weakly acidified with 1N hydrochloric acid. The precipitated crystals are removed by filtration, washed with water, dried and recrystallized from ethanol. The result of 0.14 g of 3 (8) (8) -carboxy-3-cyclohexylpropyl} -amino-4-oxo-2,3, 495-tetrahydro-1,5-benzoxazepin-5-acetic acid as colorless crystals , tpl, 202-205 S.
Calculated,%: C 59.70; H 7.16; N 6.63.
Cr1Ng | NgO (
1CO
Found,%: C 59.81; H 7.03; 6.68
ЈsPs-131 ° (, 4 in methanol).
PrierZZ. B5 ml 1 n. sodium hydrate solution dissolve 0.2 g
, (S) - 0 (8) -ethoxycarbonyl-3- (3,4,5,6, - tetrahydro-2H-pyran-4-yl) propyl amino-4-oxo-2,3,4,5-tetrahydro -1,5-benzoxazepin-5-acetic acid hydrochloride prepared in Example 17 and the solution was allowed to stand at room temperature for 1 hour. The solution was neutralized with 1.5 ml of acetic acid and purified on a chromatographic column filled with Amberlite XAD-2 (elution with acetone: water 1: 1). The eluate is concentrated under reduced pressure and lyophilized, resulting in 0.16 g of 3 (S) l (3) -carboxy-3- (3,4,5,6-tetrahydro-2H-pyran-4-yl) propyl - amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine-5-acetic acid as a colorless powder.
Calculated,%: C 57.82; And 6.55; N 6.74-.
., - 1 / 21TSO
Found,%: C 57.41; H 6.01; N 6.36.
O. D-1280 (, 4 in methanol).
Example 34. 3 (S) (H) -ethoxy-carboyl-3- (4-piperidyl) propyl j-s
five
0
five
BUT-4-OXO-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid, prepared in Example 20, is subjected to hydrolysis as in Example 33, purified and lyophilized. The result is 3- (8) - 1- (8) -carboxy-3- (4-piperidyl) -propyl-amino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzoxazepin-5 - Acetic acid in the form of a colorless powder.
X -132 ° (, 6 in methanol).
Mass spectrum (t / e): 406 ().
PRI me R 35. 3 (8) (H) -Etoxy-carbonyl-3- (4-thianyl) propyl-amino-4-OXO-2,3,4,5-tetrahydro-1,5-benzok The sazepin-5-acetic acid hydrochloride prepared in Example 19 is hydrolyzed as in Example 34 and purified on a chromatographic column filled with Amberlite XAD-2. The eluate is concentrated under reduced pressure, and 3- (8) (3) are obtained. -carboxy-3- (4-thianyl) propyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid as crystals.
Calculated,%: C 54.53; H 6.41; N 6.36
0
five
0
five
0
five
sgvn
liPlCt
KЈ C 54.12; H 6.32;
Found N, 6.30.
Example 36. In 150 ml of acetonitrile, 5 g of benzyl-3 (8) -amy-HO-4-OXO-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-hydrochloride hydrate and 13 are dissolved. g of ethyl 2-bromo-5 phthalimidohexanoate and 3.2 g of triethylamine are introduced into the solution. After heating at 80 ° C for 4 days, the solution is concentrated under reduced pressure and diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (15 ml) and oxalic acid (3 g) are added to the residue. Petroleum ether (200 ml) is injected into the solution and the mixture is shaken. After standing, the supernatant is separated by decantation and 100 ml of water and 150 ml of ethyl acetate are added to the residue. The mixture is neutralized with sodium bicarbonate and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil is separated and purified on a chromatographic column filled with silica gel (eluted with a mixture of hexane-ethyl acetate in a ratio of 2: 1 to 3: 2), resulting in first obtaining 2.3 g of benzyl-3 (8) C1 (K ) -ethoxy-carbonyl-5-phthalimidopentyl j-aMHHo-4-oxo-2,3,4,5-tetrahydro-, 5-benzoxazepine-5-acetate as a colorless oil.
IR: K ™, cm 1: 3330 (NH), 1770, 1740, 1720, 1680 ().
oOD -104 (in methanol).
Benzyl-3 (8) -O (8) -ethoxycarbonyl-5-phthal-imidopentyl} -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5 is obtained from the next fraction. -cetate as a colorless oil.
IR:, cm-: 3330 (NH), 1760, 1710, t 1680 (OO).
Co (3d-1000 (in methanol).
Example 37. 0.15 g of benzyl-3 (8) (S) -ethoxycarbonyl-5-phthalimidopentyl J-am10 is dissolved in 20 ml of ethanol.
15
20
The mixture is diluted with 200 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Ethyl acetate (10 ml) and oxalic acid (2.8 g) were introduced into the residue, and 200 ml of petroleum ether were added to the solution. After agitation, the resulting solution is allowed to stand. The supernatant was removed by decantation, and 200 ml of ethyl acetate and 150 ml of water were introduced into the precipitate. The mixture was neutralized with sodium bicarbonate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is separated and purified on a chromatographic column filled with silica gel. 1.5 g of tert-butyl 3 (8) (K) -ethoxycarbonyl-7-phthalimi- to heptyl-amino-4-oxo-2,3,4,5-tetNO-4-OXO-2, 3 are obtained. , 4,5-tetrahydro-1,5-benz-25 ragidro-1,5-benzoxazepin-5-acetate
0
0
The mixture is diluted with 200 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Ethyl acetate (10 ml) and oxalic acid (2.8 g) were introduced into the residue, and 200 ml of petroleum ether were added to the solution. After agitation, the resulting solution is allowed to stand. The supernatant was removed by decantation, and 200 ml of ethyl acetate and 150 ml of water were introduced into the precipitate. The mixture was neutralized with sodium bicarbonate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is separated and purified on a chromatographic column filled with silica gel. 1.5 g of tert-butyl-3 (8) (K) -ethoxycarbonyl-7-phthalimi- to heptyl-amino-4-oxo-2,3,4,5-tet are obtained.
oxazepin-5-acetate, prepared in Example 36, and catalytically reduced at normal temperature and atmospheric pressure using 0.1 g of 10% palladium-carbon as a catalyst. After stopping the consumption of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The oily product is dissolved in 3 ml of ethyl ether, and 0.5 ml, 5N is added to the solution. solution of hydrogen chloride a-ethyl acetate. The result is 0.12 g of 3 (S) (8) -ethoxycarbonyl-5-phthalmicopentyl} -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetic acid hydrochloride as a colorless powder.
Calculated,%: C 56.07; H 5.61; N 7.54.
Cr4Hg, K3Ov -HC1-
Found,%: C 56.19; H 5.31; N 7.44.
ePS-104 ° (in methanol).
EXAMPLE 38. 2.8 g of tert-butyl-3 (8) -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine is dissolved in 100 ml of acetonitrile. -5-acetate and 7.6 g of ethyl-2-bromo-8-phthalimido-octanoate and 1.3 g of triethylamine are added to the solution. After heating at 80 ° C for 3 days, the reaction solution is concentrated under reduced pressure from the first fraction.
IR; l
CHIST "9 lls kS
cm 1: 3340 (NH) ,,
0
five
0
five
0
five
1770, 1740, 1710, 1670 ().
Јy D-104 ° (in methanol).
From the second fraction, 1.7 g of tert-butyl-3 (S) -Ll (8) -ethoxycarbonyl-7-phthalimidoheptyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5- benzoxazepin-5-acetate.
, cm-: 3340 (NH), 1775, 1740, 1720, 1680 ().
From "3 to-115 ° (in methanol).
Example 39. B5ml5n. a solution of hydrogen chloride - ethyl acetate is dissolved 0.12 g of tert-butyl-3 (S) -D (E.) - ethoxycarbonyl-7-phthalimide dogepyl-amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzoxazepin-5-acetate, obtained in Example 38, and the solution is allowed to stand at room temperature for 3 hours. Neutral ether (100 ml) is introduced into the solution, and the precipitated precipitate is dried under reduced pressure. The result is 0.08 g of 3 (8) (K) -ethoxycarbonyl-7-phthalimy-dogeptil-amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetic acid hydrochloride in the form of colorless powder.
OPD-1280 (in methanol).
Calculated,%: C 58.34; H 5.90; N 7.03,
Ci9H33N308 HC1-1 / 2Ngo
11156
Found,%: C 58.25; H 5.75; N 7.08.
Example 40. In 5 ml of 5 n. hydrogen chloride-ethyl acetate solution dissolve 0.11 g of tert-butyl-3 (3) -Cl (8) -ethoxycarbonyl-7-phthalimidoheptyl-amino-4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine-5-acetate, prepared in Example 38, and the solution is allowed to stand at room temperature for 3 hours. Petroleum ether (100 ml) is added to the solution, and the precipitate is dried under reduced pressure. As a result, 0.095 g of 3 (8) (3) -ethoxycarbonyl-7-phthalimy-dogeptil-amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine-5-acetic acid hydrochloride is obtained in the form colorless powder.
Calculated,%: C 58.34; H 5.90; N 7.03
C79H33N30, -HCl.l / 2HaO
Found,%: C 58.43; H 6.02; N 6.80.
W 1-p -104 ° (in methanol).
PRI me R 41. 0.7 g tert-butyl-3 (B) -D (5) -ethoxycarbonyl-7-phthalimidoheptyl} -amine-4-oxo-2,3 is dissolved in BOT ml of ethanol. , 4,5-tetrahydro-1, 5-benzoxazepine-5-acetate, prepared in Example 38, and 0.29 g of hydrazine hydrate are introduced into the solution. After standing overnight, the solution is concentrated under reduced pressure, diluted with 50 ml of water and extracted five times with 30 ml (in each extraction) of ethyl acetate. 50 ml of water and 0.7 g of sodium bicarbonate are added to the ethyl acetate layer. while the mixture was stirred, 0.38 g of di-tert-butyl dicarbonate was added dropwise. The mixture is stirred at room temperature for 30 minutes, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified on a chromatographic column filled with silica gel (eluted with hexane-ethyl acetate in a 2: 1 ratio), and 0.51 g of tert-Buty 3 (8) -C7-tert- butoxycarbonylamino-1 (3) -ethoxycarbonylheptyl C-amino-4-cc-2,3,4,5-tetrahydro-1,5-6 benzo-sazepine-5-acetate as a colorless oil.
12
0
Clean
1K: S: kg. ™ 1740, 1710,
1680
five
20
(00).
Co Jj} -122D (in methanol). Example42. In 10 ml 5 n. 1.1 g of tert-butyl-3 (5) -7-tert-butoxycarbonylamino-1 (3) -ethoxycarbonylheptyl 1-amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzoxazepine-5-acetate, prepared in Example 41, and the solution is allowed to stand at room temperature for 3 hours. Petroleum ether is introduced into the solution, and the precipitate is dried under reduced pressure. The result is 0.9 t 3 (8) - 7-amino-1 (5) -ethoxycarbonyl-heptyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid dihydrochloride in the form of a colorless powder.
spd 1080 (in methanol). Example 43. In 15 ml of 1N. sodium hydroxide solution is dissolved
25 0.5 g 3 (5) -C7-amino-1 (3) -ethoxycarbonylheptyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid dihydrochloride , obtained in example 42, and the solution stand at
30 room temperature for 30 min. Acetic acid (3.5 ml) is introduced into the solution, and the mixture is purified on a chromatographic column filled with Amberlite XAD-2 (methanol: water ratio 1: 2). The eluate is concentrated under reduced pressure and lyophilized. The result is 0.31 g of 3 (8) -7-amino-1 (3) -carboxyheptyl-amino-4-ca co-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5- acetic acid as a colorless powder. d at -159 ° (in methanol). SIMS spectrum (m / e): 394 (MH +). PRI me R 44. A mixture of tert-butyl45 3 (5) -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetate (2 g), ethyl-2 β-bromo-7-phthalimidoheptanoate (3.9 g), acetonitrile (100 ml) and triethylamine (0.9 g) are heated at
50 to 80 ° C for 3 days. After evaporation, the acetonitrile is introduced into water (150 ml), ethyl acetate (200 ml) in the evaporation residue, and the mixture is thoroughly stirred. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is dissolved in a mixture of ethyl acetate (10 ml) and oxalic acid (2 g). Received by
35
40
131
the solution is diluted with petroleum ether (200 ml) and thoroughly mixed. The supernatant is removed by decanting. Water (150 ml), ethyl acetate (200 ml) and sodium bicarbonate were added to the precipitate while stirring. The ethyl acetate layer was separated, dried over anhydrous magnesium sulphate and concentrated in vacuo. The oil precipitate was subjected to separation on a chromatographic column filled with silica gel using hexane-ethyl acetate 2: 1-1 for elution: After evaporation of the first fraction, tert-butyl-3 (5) (P) -ethoxycarbonyl-6 was obtained -phthalimidohexyl} -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) as a devil


colored oil.
, cm: 3330 (NH), 1770, 1740, 1710, 1680 ().
Scd-1100 (in methanol).
Mass spectrum (m / e): 593 (M).
After evaporation of the second fraction, tt-butyl-3 (5) -C1 (3) -ethoxycarbonyl-6-phthalimidohexyl J-amino-4-OXO-2,3,4,5-tetrahydro-1,5-benz is obtained. - oxazepin-5-acetate (0.75 g) as a colorless oil.
IR:, 3320 (NH), 1770, 1740, 1710, 1670 ().
C ° Itz-123 ° (in methanol).
Mass spectrum (m / e): 593 (M).
Example 45. A mixture of 6 n. a solution of hydrogen chloride - ethyl acetate (5 ml) and tert-butyl-3 (5) (8) -ethoxycarbonyl-6-phthalimidohexyl j-amino-4-OXO-2,3,4,5-tetrahydro-1,5 -benzoxazepine-5-acetate (0.1 g) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml) and a colorless powder is precipitated, which is recovered and dried in vacuo. The result is 3 (S) (3) -ethoxycarbonyl-6-phthalimidohexyl-amino-4-oxo-2,3, 4,5-tetrahydro-1, 5n benzoxazepin-5-acetic acid hydrochloride (0.08 g), CotJB -108 ° (in methanol).
Calculated,%: C 57.68; H 5.53; 7.21.
Gt H3iN3 VHCl l / 2HiO Found,%: C 57.65; H 5.65; 7.13,
PRI me R 46. A mixture of tert-butyl-3 (S) - U (5) -ethoxycarbonyl-6-phthalimidhexyl 3-amino-4-oxo-2,3,4,5-tetN
N
14
0
Ragidro-1,5-benzoxazepin-5-acetate (0.65 g), hydrazine hydrate (0.27 g) and ethanol (10 ml) are allowed to stand overnight at room temperature. The mixture was concentrated in vacuo, diluted with water (50 ml) and extracted with ethyl acetate (50 ml h 4). In a mixture of organic extract, water (50 ml) and sodium bicarbonate (0.65 g), di-tert-butyl dicarbonate (0.36 g) is added dropwise with simultaneous stirring at room temperature. After stirring the mixture for 30 minutes
5 The ethyl acetate layer was separated, dried over anhydrous magnesium sulphate and Ig concentrated in vacuo. The residue is concentrated in a chromatographic column.
0 A silica gel filled canister using hexane-ethyl acetate 2: 1-1: 1 for elution. The result is tert-butyl- 3 (5) -b-tert-butoxycarbonylamino5 1 (5) -ethoxycarbonylhexyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5- acetate (0.54 g) as a colorless oil.
CHIstS-I «« КС
1: 1740, 1720, 1680
()
 (in methanol). facc-spec (m / e): 563 (M). PRI me R 47, Solution of tert-butyl-3 (5) - b-tert-butoxycarbonylamino-1 (3) -ethoxycarbonylhexyl amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzo-azepine-5-acetate (0.5 g) in 5 n. a solution of hydrogen chloride - ethyl acetate (10 ml) stand for
3.5 hours at room temperature. Petroleum ether (80 ml) is introduced into the solution, and the resulting precipitate is recovered and dried under vacuum. The result is 3 (8) -C6-amino1 (3) -ethoxycarbonylhexyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dichlorohydrate (0 , 4 g) in the form of a colorless powder.
With 1D-1 18 ° (in methanol).
NASS spectrum (m / e): 407 (M +). PRI me R 48. Solution 3 (S) amino-1 (G) -ethoxycarbonylhexyl} -amy-HO-4-OXO-2,3,4,5-tetrahydro-1,5benzoxazepin-5-acetic acid di - hydrochloride (0.35 g) in 1 n. The sodium hydroxide solution (10 ml) is allowed to stand at room temperature for 30 minutes. After adding
Acetic acid (2.5 ml) was subjected to separation on a chromatographic column filled with Amberlite XAD-2, using 1: 10 methanol-water for elution. The eluate was concentrated under reduced pressure and lyophilized. The result is 3 (5) - b-amino-1 (8) -carboxyhexyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.17 g ) in the form of a colorless powder.
til About -157 ° (in methanol). SIMS spectrum (m / e): 380 (MN). PRI me R 49. A mixture of tert-butyl-3 (5) -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetate (2.1 g ethyl 2-bromo-9-phthalimidonanoate (3 g), acetonitrile (O00 ml) and triethylamine (0.96 g) are heated at 80 ° C for three days. After evaporation of the solvent, ethyl acetate (200 ml) and water (150 ml) are added to the residue. The ethyl acetate layer was separated, dried over anhydrous magnesium sulphate and evaporated in vacuo. The oily residue was subjected to chromate 25 (50 ml) and sodium bicarbonate (0.6 g), and di-tert-butyl dicarbonate (0.29 g) was added dropwise with simultaneous stirring. After stirring for 30 minutes
graphical columnization
filled with silica gel. using ethyl acetate at room temperature with ethyl acetate as the eluent of the mixture, the hexane layer is separated, dried over
anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified on a chromatographic column filled with silica gel using hexane: ethyl acetate (2: 1-1: 1) for elution. The result is tert-butyl-3 (3) -C8-tert-butoxycarbonylamino-1 (S) -ethoxycarboxy} -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5- acetate (0.48 g) as colorless
ethyl acetate (2: 1-1: 1). After evaporating the first eluate, tert-butyl-3 (5) (K.) -Estoxycarbonyl-8-phthalimido-octyl} -amino-4-oxo-2,3,3,5-tetrahydro-1, 5- is obtained. benzoxazepin-5-acetate (0.6 g) as a colorless oil.
IR: SLS 333 ° No.), J770, 1740, 1710, 1680 ().
From Zs-106 ° (in methanol).
From the second eluate, tert-butyl-3 (3) (8) -ethoxycarbonyl-8-- phthalimido-octyl} -amino-4-oxo-2,3S4,5-tetrahydro-1,5-6 enoxoxazine-5-acetase are obtained. that (0.65 g) as a colorless oil,
1670
35
40
tg. ,) clean ik VM "KC
oils.
IR: V с0, cm 1: 1 740, 1 720, 1680 45 () cm-1: 3320 (NH), 1670, Ы 1 D-l02 ° (in methanol).
1740, 1710, 1680 (). Mass spectrum (m / e): 591 (M +).
 D –110 ° (in methanol). EXAMPLE 52. Cross-tert-butyl Mass spectrum (m / e): 621 (M +)) 3 (5) - 8-tert-butoxycarbonylamino Example 50. Mixture 5 n . solution 1 (H) -ethoxycarbonyloctyl} amino-4-hydrogen chloride - ethyl acetate (5 ml)
and tert-butyl-3 (8) (H) -ethoxycarbonyl-8-phthalimido-octyl-amino-4-oxo-
2,3,4,5-tetrahydro-1,5-benzoxazepine 5-acetate (0.1 g) is set at a temperature of 3 hours at room temperature. Mixture
diluted with petroleum ether (80 ml) for 3 hours.
The mixture is diluted with petroleum ether.
(80 ml). As a result, a colorless powder is precipitated which is recovered.
oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.45 g) and 5N. a solution of hydrogen chloride - ethyl acetate (10 ml) stand for
and as a result, a colorless powder precipitated, which is recovered and dried under vacuum. As a result of the floor, 30H35N3Oe HC1 1 / 21CO
by filtration and dried under vacuum. The result is 3 (S) -Cl (S) - ethoxycarbonyl-8-phthalimido-octyl-ami-HO-4-OXO-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid (0.067 g).
oId-UO0 (in methanol). Calculated,%: C 58.97; H 6.10;
N.
WITH.
Found,%: C 59.10; H 6.26; N 6.72.
PRI me R 51. A mixture of tert-butyl 3 (S) (8) -ethoxycarbonyl-8-phthalimido octyl amino-4-oxo-2 3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetate (0.55 g), hydrazine hydrate (0.22 g) and ethanol (10 ml) are allowed to stand overnight at room temperature. After evaporation of ethanol, the residual product was dissolved in water (50 ml) and extracted with ethyl acetate (50 ml 4). Water is added to the organic extract.
(50 ml) and sodium bicarbonate (0.6 g), and di-tert-butyl dicarbonate (0.29 g) was added dropwise while stirring. After stirring for 30 minutes
oils.
IR: V с0, cm 1: 1 740, 1 720, 1680 45 () Ы 1 D-l02 ° (in methanol).
 1 (3) -ethoxycarbonyl octyl} -amino-4oxo-2, 3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.45 g) and 5N. a solution of hydrogen chloride - ethyl acetate (10 ml) stand for
and as a result, a colorless powder precipitated, which is recovered and dried under vacuum. As a result, semi17156
3 (5) -8-amino-1 (H) -ethoxycarbo-. niloctyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.37 g).
CoPv -114 ° (in methanol).
Mass spectrum (tp / e): 435 (M).
Example 53. A solution of 3 (S) -C8- amino-1 (W) -ethoxycarbonyloctyl-amino
4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid chlorhydrate (0.3 g) in 1 n. The sodium hydroxide solution (10 ml) is allowed to stand at room temperature for 30 minutes. After adding acetic acid (2.5 ml), the mixture was subjected to separation on a chromatographic column filled with Amberlite XAD-2, with elution with methanol-water (in a ratio of 1: 2). The eluate is concentrated under reduced pressure and lyophilized. The result is 3 (8) -8-amino-1 (H) -carboxyoctyl-J-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid (0.2 g ) in the form of a colorless powder.
Calculated,%: With 56.46; H 7.34; N 9.87.
CioH19N3OrHaO
Found,%: C 56.61; H 6.86;
N 9.55.
o / D-147 ° (in methanol).
SIMS spectrum (m / e): 408 (MH4).
PRI me R 54. A mixture of tert-butyl-3 (8) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (1.65 g), ETSH1-2- &amp; ROM-10-phthalimidodecanoate (2.4 g), acetonitrile (100 ml) and triethylamine (0.75 g) are heated at 80 ° C for 4 days. After evaporation of the solvent, water (100 ml) and ethyl acetate (200 ml) are added to the residual evaporation product. The ethyl acetate layer was dried over anhydrous magnesium sulphate and evaporated in vacuo. The thick residue was subjected to chromatographic separation on a column filled with silica gel, using hexane-ethyl acetate in a 2: 1 ratio as eluant. After evaporation of the first fraction, tert-butyl-3 (S) -1 is obtained (Yu-ethoxycarbonyl-9-phthalimidonyl-amino-4-oxo-2, 3, 4,5-tetrahydro-1,5-benzoxazepin-5-acetate ( 0.45 g) as a colorless oil.
1770
IR: cm 1: 3320 (NH)
on the
1740, 1710, 1680 ().
YZV-U00 (in methanol).
18
Q 5 0 5
0
50
five
0
Mass spectrum (m / e): bJb (M).
From the second fraction, tert-butyl-3 (S) (5) -ethoxycarbonyl-9-phthalimidonyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetate (0, 55 g) in the form of colorless oil.
, cm-: 3320 (NH), 1770, 1740.1710, 1680 ().
C "nD-98 ° (in methanol).
Mass spectrum (m / e): 635 (M).
PRI me R 55. A mixture of tert-butyl-3 (S) -Cl (5) -ethoxycarbonyl-9-phthalimononyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine-5-acetate (0.08 g) and 5 n. a solution of hydrogen chloride-ethyl acetate (5 ml) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml), and a colorless powder is precipitated, which is removed and dried under reduced pressure. 3 (S) -D (S) -ethoxycarbonyl-9-phthalimidonyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride (0.066 g) is obtained.
 -101 ° (in methanol).
%: C 58.56; H 6.28;
N
Calculated 6.72. C3lH3, N3Og
l / 2H70 C 59.29; H 6.48;
Found, N 6.51.
PRI me R 56. A mixture of tert-butyl-3 (S) -U (3) -ethoxycarbonyl-9-phthalimidonyl} -amino-A-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-4-acetate (0.46 g), hydrazine hydrate (0.18 g) and ethanol (10 ml) are allowed to stand overnight at room temperature. The mixture is concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (50). Water is added to the organic extract.
(50 ml) and sodium bicarbonate (0.5 g), and di-tert-butyl dicarbonate (0.24 g) was added dropwise with simultaneous stirring. After stirring for 30 minutes at room temperature, the ethyl acetate layer is dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue was purified on a chromatographic column filled with silica gel, using hexane: ethyl acetate in a 2: 1 ratio as eluant. The result is tert-butyl-3 (S) - 9-tert-butoxycar19
bonylamino-1 (H) -ethoxycarbonylnonyl amino-4-oxo-2, 3.4E 5-tetrahydro-1,5 benzoxazepine-5-acetate (0.35 g) as a colorless mesl „
IR: iC "ir 1740.4710, 168 ().
Mass spectrum (m / e): 605 (M).
oOts -116 ° (in methanol).
EXAMPLE 57 A mixture of tert-butyl- 3 (8) -C9-tert-butoxycarbonylamino (3) -ethoxycarbonylnonyl-amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzox- azepin-5-acetate (0.33 g) and 5 n, ras

hydrogen chloride thief - acylacetate - is evaporated in vacuo. To residual
that (8 ml) stand for 2.5 hours at room temperature. The mixture is diluted with petroleum ether (80 ml), and a colorless powder is precipitated, which is recovered and dried under reduced pressure. The result is 3 (5) -C9-amino-1 (S) ethoxycarbonylnon-amino-4-oxo - 2,3,4,5-tetrahydro ™ 1,5-benzoxazepine-5-acetic acid dihydrochloride (0.25 g).
Calculated,%: C 515 AND; H 7326;
Water (50 ml) and ethyl acetate (200 ml) are added to the evaporation product, and the mixture is thoroughly stirred. The ethyl acetate layer is dried over anhydrous.
Magnesium sulfate and evaporated in vacuo to give an oily residue containing 3- (1-ethoxycarbonyl-3-cyclohexylpropyl) - amino-2,3,4,5-tetrahydro-1,5-benzoc25 sazepin-4 -he. A mixture of oil, potassium carbonate (4 g), tert-butyl chloroacetate (3 g), potassium iodide (0.2 g) and NjN-di methylformamide (20 ml) is stirred overnight at room temperature.
N
7577. C-, F, KN, 0,
13 of s1N ei t 2CH1 Found,%: C 51.17; H 7.57; K 7.34.
cPc-U0 (in methanol) o Makeup 58, Solution 3 (S) amino-1 (3) -ethoxycarbonylnonyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5benzoxazepin-5- Acetic acid dichloro hydrate (0.2 g) in 1 N, sodium hydroxide solution (6 ml) is allowed to stand for 30 min at room temperature. Acetic acid was added (1.5 ml) and the resulting mixture was subjected to separation on a chromatographic column filled with Amberlite XAD-26 using methanol-water 1: 2 as the solvent. The eluent is concentrated in vacuo and lyophilized. The result is 3 (8) 9-amino-1 (S) carboxinonyl-amino 4-oxo-2,3,4,525 sazepin-4-one. A mixture of oil, potassium carbonate (4 g), tert-butyl chloroacetate (3 g), potassium iodide (0.2 g) and NjN-dimethylformamide (20 ml) is stirred overnight at room temperature and then diluted with water (300 ml) and ethyl acetate (200 ml). The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. As a result, an oil is obtained, which is purified on a chromatographic column filled with silica gel using hexane-ethyl acetate ( in the ratio of 4: 1) as eluent. A tert-bu-40-thyl-3- (1-ethoxycarbonyl-3-cyclohexylpropyl) -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine-5-acetate (1 g) is obtained. as colorless oil.
45
ti. .msta 1K V «« ks 1680 ().
cm 1: 3330 (NH), 1730,
Example 60 A mixture of benzyl-3 (3) -amino-4 oxo-2,3,4,5-tetrahydro-1,3-benzoxazepine-5-acetate hydrochloride
tetrahydro-1,5-benzoxazepino-5-vinegar-50 g of ethanol (oO ml), sodium acetate
Ny acid (0.15 g) as a colorless powder i
: Calculated,%: C 57.39; H 7.57; N 9.56Сг1Н „Н504 НгО
Found,%: C 57.42; H 7.27; N 9.58,
Sp-1420 (in methanol).
SIMS spectrum (m / e): 422 (MH +).
(0.57 g), acetic acid (0.4 g), ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) -2-oxovalerate (2.5 g) and molecular sieve behind (10 g) are stirred for 10 min at room temperature. A solution of sodium cyanoborohydrite (O54 g) in ethanol (50 ml) is added dropwise to the stirred mixture over 2 hours. After standing overnight
20
Example 59. A mixture of 3 (5) -amino-2,3,4s5-tetrahydro-1,5-benzoxazepine-4one hydrochloride (2 g), ethanol (100 ml), sodium acetate (0.8 g), acetic acid ( 0.6 g), 4A molecular sieve (5 g) and ethyl 4-cyclohexyl-2-oxo-butyrate (5 g) are catalytically hydrogenated over the catalyst — Rene nickel at room temperature at atmospheric pressure. After the consumption of hydrogen ceases, the catalyst is removed by filtration, and the filtrate
Water (50 ml) and ethyl acetate (200 ml) are added to the evaporation product, and the mixture is thoroughly stirred. The ethyl acetate layer is dried over anhydrous magnesium sulphate and evaporated in vacuo to give an oily residue containing 3- (1-ethoxycarbonyl-3-cyclohexylpropyl) - amino-2,3,4,5-tetrahydro-1.5 -benzoxazepin-4-one. A mixture of oil, potassium carbonate (4 g), tert-butyl chloroacetate (3 g), potassium iodide (0.2 g) and NjN-dimethylformamide (20 ml) is stirred overnight at room temperature and then diluted with a mixture of water ( 300 ml) and ethyl acetate (200 ml). The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. An oil is obtained which is purified on a chromatographic column filled with silica gel using a mixture of hexane-ethyl acetate (in relation to 4: 1) as eluent. The tert-butyl-3- (1-ethoxycarbonyl-3-cyclohexylpropyl) -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine-5-acetate (1 g) is obtained colorless oil.
ti. .msta 1K V «« ks 1680 ().
cm 1: 3330 (NH), 1730,
Example 60 A mixture of benzyl-3 (3) - amino-4 oxo-2,3,4,5-tetrahydro-1,3-benzoxazepine-5-acetate hydrochloride
 g of ethanol (oO ml), sodium acetate
(0.57 g), acetic acid (0.4 g), ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) -2-oxovalerate (2.5 g) and molecular sieve behind (10 g) are mixed in for 10 min at room temperature. A solution of sodium cyanoborohydrite (O54 g) in ethanol (50 ml) is added dropwise to the stirred mixture over 2 hours. After standing overnight
at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (300 ml) and ethyl acetate (300 ml). The resulting mixture is thoroughly mixed and filtered. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate (.20 m with oxalic acid (2 g). This solution was diluted with petroleum ether (300 ml), and the supernatant was removed by decanting. Water (100 ml) and ethyl acetate ( 200 ml) and excess sodium bicarbonate. The ethyl acetate layer is separated, dried over anhydrous magnesium sulphate and evaporated in vacuo. The oily residue is separated on a chromatographic column filled with silica gel using hexane / ethyl acetate as eluent. 2: 1. After evaporation of the first fraction, benzyl-3 (S) -L4- (l-benzyloxycarbonyl-4-piperidyl) -1 (R) ethoxycarbonyl-amino-4-oxo-2,3,4,5 tetrahydro- 1,5-benzoxazepin-5-acetates (0.65 g) as a colorless oil.
IR: max. 332 ° (NH), - 1740 1690, 1680 ().
Mass spectrum (m / e): 671 (M +).
From the second fraction, benzyl 3 (8) -C4- (1-benzyloxycarbonyl-4-pyperidyl) - (3) -ethoxycarbonylbutyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5- benzoxazepin-5-acetate (0.75 g) as a colorless oil.
 , cm: 3320 u), 1740 1690, 1680 ().
Mass spectrum (m / e): 671 (M).
Example 61. A solution of benzyl- 3 (8) -C4- (1-benzyloxycarbonyl-4-pipedyl) - (K) -ethoxycarbonylbutyl} - amino-4-oxo-2,3,4,5-tetrahydro-, 5- Benzoxazepin-5-acetate (0.65 g) in ethanol (50 ml) is subjected to catalytic hydrogenolysis over 10% palladium-carbon (1 g, 50% moisture) at room temperature at atmospheric pressure. After stopping the consumption of hydrogen, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residual product was triturated four times with ethyl ether (100 ml) and then dissolved in ethanol (5 ml). To this solution is added 5 N, solution







P ° shka
hydrogen chloride - ethyl acetate (1 ml) and the mixture was diluted with ether. As a result, 3 (S) (K) -ethoxycarbonyl-4- (4-piperidyl) butyl-amino-4-oxo2,3,4, 5-tetrahydro-1,5-benzoxazepin-5- acetic acid dichlorohydrate (0.12 g) as colorless; 0
five
P ° shka
Q
0
Calculated,%: C 49.64; H 7.06; N 7.55
C 3KMN304 2HS1-2H20
Found,%: C 49.17; H 6.99; 5 N 7.52
lr-121 ° (in methanol).
PRI me R 62. A solution of benzyl- 3 (5) -4- (benzyloxycarbonyl-4-piperidyl) 1 (8) -ethoxycarbonylbutyl / -amino-4-oxo-2,3,4,5-tetrahydro -1,5-benzoxazepine-5-acetate (0.75 g) in ethanol is subjected to catalytic hydrogenolysis over 10% palladium-carbon (1 g, 50% moisture) at normal temperature and under pressure until hydrogen consumption does not stop. After removing the catalyst by filtration, the filtrate is concentrated and diluted with ethyl ether (30 ml), and a colorless powder is precipitated, which is recovered by filtration. 3 (S) -D (8) -ethoxy-carbonyl-4- (4-piperidyl) butyl-amino-4-oxo-2,3,4,4-tetrahydro-1,5-benzoxazepin-5- acetic acid dichlorohydrate (0.45 g).
Calculated,%: 49,64; H 7.06; N 7.55.
C73H3JN304-2HC1-2H O
Found,%: C 49.83; H 7.07; N 7.29.
 (in methanol).
Example 63. A solution of 3 (S) (S) - 5 ethoxycarbonyl-4- (4-piperidyl) butyl-amino4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid d- hydrochloride (0.35 g) in 1 n. The sodium hydroxide solution (8 ml) is allowed to stand for 30 minutes at room temperature. After the addition of acetic acid (1.5 ml), the mixture was subjected to separation on a chromatographic column filled with MC1 gel (CHP 20P 150-300 microns, Mitsubishi Chemical), using water-methanol in a 2: 1 ratio as eluant. The eluate is concentrated in vacuo and lyophilized. As a result
five
23156359
3 (S) (5) -carboxy-4- (4 piperidyl) butyl} -amino 4 oxo-2,3,4, 5-tetrahydro-1,5-benzoxazepine 5-acetic acid (0.2 g ) in the form of a colorless powder.
Calculated,%: C 56,49; H 7.22; N 9.41.
C11H, 9N306 3/2HiO
Found,%: C 56.86; H 7
N 9.41.
cll-fr- 33 ° (in methanol).
SIMS spectrum (m / e): 420 (MH +).
PRI me R 64. A mixture of benzyl-3 (8) amino-4-exo-2,3,4,5 tetrahydro 1,5-benzoxazepine-5-acetate hydrochloride (3.4 g), ethanol ( 30 ml), sodium acetate (0.77 g), acetic acid (0.56 g), ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate (4.4 g) and molecular FOR screens (10 g) are stirred for 10 minutes at room temperature. A solution of sodium cyanoborohydride (0.6 g in ethanol (50 ml) is added dropwise to the stirred mixture over 3 hours. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (100 ml) and ethyl acetate (200 ml). The resulting mixture was thoroughly mixed and filtered, the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (20 ml) and oxalic acid (3 d). This solution is diluted with petroleum (100 ml), and the surface layer is removed by decantation. Water (50 ml), ethyl acetate 200 ml and excess sodium bicarbonate are added to the precipitated product. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo .
The oily residual product is evaporated on a chromatographic column filled with silica gel, using hexane-ethyl acetate in a ratio of 2: 1 as an eluent. After evaporation of the first fraction, benzyl-3 (S) -t is obtained. 5- (1-benzyloxycarbonyl-4-piperidyl) - (I) -ethoxycarbonylpentyl} -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetate (0 , 35 g in the form of a colorless oil.
0
five
20 25 30 ,, Q 45
50 55
24
IR: VM "K 332 ° NH) 173 °
1680 ().
Mass spectrum (m / e): 685 (M).
From the second fraction, benzyl-3 (S) -C5- (1-benzyloxycarbonyl-4-piperidyl) - (S) -ethoxycarbonylpentyl-amino-4-oxo-2,3,4,5-tetrahydro -1,5-benzoxazepine-5-acetate (0.65 g) as a colorless oil.
IR: V ™ c, 3330 (NH), 1730, 1680 ().
Mass spectrum (m / e): 685 (M +).
II p and meper 65. A solution of benzyl- 3 (S) (1-benzyloxycarbonyl-4-piperidyl) - (K) -ethoxycarbonylpentyl-amino-4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepine-5-acetate (0.35 g) in ethanol (20 ml) is subjected to catalytic hydrogenolysis over 10% palladium-carbon (0.5 g, 50% moisture at room temperature and at elevated pressure until until the consumption of hydrogen ceases. After removing the catalyst by filtration, the filtrate is concentrated. To the residue concentration is added a 5N solution of hydrogen chloride - ethyl acetate (1 ml), and the mixture was diluted with ethyl ether (50 ml), and 3 (S) (I) -ethoxycarbonyl-5- (4-piperidyl) pentyl-amino-4-oxo-2,3,4,5 was precipitated tetrahydro-1,5-benzoxazepine-5-acetic acid dichlorohydrate (0.25 g) as a colorless precipitate. This acid is dissolved in 1N sodium hydroxide solution (10 ml) and the resulting solution stand for 30 minutes at room temperature. After adding acetic acid (2 ml), the mixture is subjected to separation on a chromatographic column filled with MC1 gel using water-methanol (2: 1) in as eluent. The eluate is concentrated in vacuo and lyophilized. The result is 3 (S) -Јl (U-carboxy-4- (4-piperidyl) pentyl-amino-4-oxo-2, 3,4 s 5-tetrahydro-1,5-benzoxazepine-5-acetic acid ( 0.15 g) as a colorless powder.
Calculated,%: C 57.38; H 7.44; N 9.13.
C7lH31N306-3 / 2H70 Found: C, 57.39; H 7.62; N 9.06.
S at -149 ° (in water). SIMS Spectrum (m / e): 434 (MH).
25
PRI me R 66. A solution of benzyl- 3 (S) (1-benzyloxycarbonyl-4-pyperidyl) - (S) is ethoxycarbonylpentyl amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine-5-acetate (0.65 g) in ethanol (40 ml) is subjected to catalytic hydrogenolysis over 10% palladium-carbon (1 g, 50% moisture) at room temperature and at elevated pressure until hydrogen consumption does not stop. After removal of the catalyst by a pu-TLM filtration, the filtrate is concentrated. 5N is added to the residue. a solution of hydrogen chloride - ethyl acetate (2 ml and the resulting mixture was diluted with ethyl ether (50 ml). As a result, 3 (S) (SO-ethoxycarbonyl-5- (4-piperidyl) pentyl-amino-4-oxo- 2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid dichlorohydrate (0.45 g) as a colorless precipitate. This acid is dissolved in 1N sodium hydroxide solution (15 ml) and the resulting solution is allowed to stand for 30 minutes at room temperature. After adding acetic acid (3 ml), the mixture is separated on a chromatographic column, filled with using silica gel, using a water-methanol mixture of 2: 1 as eluant. The eluate is concentrated in vacuo and lyophilized to give 3 (5) (3) -carbroxy-5- (4-piperidyl) pentyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.3 g) as a colorless powder.
Calculated,%: C 57.38; H 7.44; N 9.13.
CaaH3, N306-3 / 2H10
Found,%: C 57, H 7.76; N 9.00.
Ub-118 ° (in water).
SIMS Spectrum (m / e): 434 (MH).
PRI me R 67. A mixture of tert-butyl-3 (S) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.4 g), ethanol (30 ml), acetic acid (0.5 g), ethyl 7- (1-benzyloxycarbonyl-4-piperidyl) -2-oxoheptanoate (3.2 g) and molecular sieve (10 g) are stirred within 10 min. A solution of sodium cyanoborohydride (0.51 g) in ethanol (50 ml) is added dropwise to the stirred mixture.
1563593
26
five
0
for 3 h at room temperature. After standing overnight at room temperature, the mixture was concentrated in vacuo and diluted with a mixture of water (50 ml) and ethyl acetate (200 ml). The resulting mixture was mixed thoroughly and filtered. The ethyl acetate layer is washed successively with 0.1N. hydrochloric acid, 0.1 n. With a solution of sodium hydroxide and water, the hell is dried with anhydrous magnesium sulfate and concentrated in vacuo. The oily residual product of the concentration is subjected to chromatographic separation on a column filled with silica gel, using hexane-ethyl acetate as an eluant with respect to
0 2: 1. After evaporation of the first fraction, tert-butyl-3 (3) (1-benzyloxycarbonyl-4-piperidyl) -1 (R) - ethoxycarbonylhexyl-amino-4-oxo-2,3,4,5-tetrahydro-1 is obtained, 5-benzoxazepine
5 5-acetate (0.35 g) as a colorless oil.
five
0
five
0
tr. clean J-K- V “„ KC
 3320 (NH), 1730,
1680 ().
From the second fraction, t-o-butyl-3 (5) (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylhexyl-amino-4-oxo-2,3,4,5-tetrahydro-1, is obtained. 5-benzoxazepin-5-acetate (0.5 g) as a colorless oil.
1K: milsach, 3320 (NH), J730, 1680 ().
Example 68. To a solution of tert-butyl-3 (8) (1-benzyloxycarbonyl-4-piperidyl) -1 (K) -ethoxycarbonylhexyl-amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5-acetate (0.35 g) in acetic acid (1 ml) was added a 30% solution of hydrogen bromide - acetic acid (2 ml). The resulting mixture was allowed to stand at room temperature for 1 hour and then diluted with ethyl ether (100 ml). The surface layer was removed by decantation and the precipitating solution was dissolved in 1N. sodium hydroxide solution (10 ml). The solution is allowed to stand for 60 minutes at room temperature. After the addition of acetic acid (1 ml), the mixture was subjected to division on a chromatographic column filled with MC1 gel, using water-methanol 1: 2 as eluent. The eluate is concentrated in vacuo and lyophilisugst,
the result is 3 (S) - (K) -carb-hydroxy-6- (4-piperidyl) hexyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5 α-acetic acid (0.13 g) as a colorless powder. ° PV-139 ° (in water). SIMS spectrum (m / e): (448 MH4). Example 69. In a solution of tert-butyl-3 (S) (1-benzyloxycarbonyl-4 - piperidyl) - (5) -ethoxycarbonylhexyl - amino-4-oxo-2,3,4,5-tetrahydro-1,5 - 6-benzoxazepine-5-acetate (0.5 g) in acetic acid (1 ml), a 30% solution of hydrogen bromide — acetic acid (2 ml) is added. The mixture was allowed to stand at room temperature for 1 hour and then diluted with ethyl ether (100 ml). The surface layer was removed by decantation, and the precipitate was dissolved in 1N. sodium hydroxide solution (20 ml). The solution is allowed to stand at room temperature for 30 minutes. After the introduction of acetic acid (4 ml), the mixture is subjected to chromatographic separation on a column filled with MC1, using water-methanol in a 1: 2 ratio as eluent. The eluate is concentrated in vacuo and lyophilized. whereby 3 (S) (3) -carboxy-b- (4-piperidyl) hexyl-amino-4-oxo-2,3,4,5-tetrahydro-G, 5-benzoxazepin-5-acetic acid (0.23 g) as a colorless powder.
U B-133 ° (in water). SIMS spectrum (m / e): 448 (MH +). EXAMPLE 70 According to the procedure of Example 1, an oily residue is obtained, which is subjected to chromatographic separation on a column filled with silica gel, using hexane / ethyl acetate in the ratio 5: 2-2: 1 as eluent. After evaporation of the first fraction, tert-butyl-3 (8) -Ј7- (1-benzyloxy-carbonyl-4-piperidyl) -1- (H) -eth-hydroxycarbonylheptyl-amino-4-oxo-2,3 4.5 is obtained. -tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.

,
 M (X COP,
m «ks, cm-1: 3320 (NH), 1740, 1680 (). the second fraction get tert-butyl-3 (8) -C7- (1-benzyloxycarbonyl-4-piperidyl) -1- (8) -ethoxycarbonyl heptyl-amino-4-oxo-2,3,4,5-tetra
five
0
five
0
five
0
five
0
five
hydro-1, 5-benz-Oxazepine-5-acetate (0.35 g) as a colorless oil.
1KHM “SKTSVYa, 332 ° (NH) 17AO 1690, 1680 ().
Example71. In a solution of tert-butyl-3 (8) -C 7- (1-benzyloxycarbonyl-4-piperidyl) -1 (K) -ethoxycarbonylheptyl-amino-5-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepin-5-acetate (0.35 g) in acetic acid (1.5 ml) was added a 30% hydrogen bromide-acetic acid solution (1.5 ml). The resulting mixture was allowed to stand at room temperature for 30 minutes and then diluted with ethyl ether (100 ml). The surface layer was removed by decanting and the precipitate was dissolved in 1N. sodium hydroxide solution (10 ml). The solution is allowed to stand for 30 minutes at room temperature. After the introduction of acetic acid (2 ml), the mixture is subjected to chromatographic separation on a column filled with Amberlite XAD-2, using water-methanol 1: 1 as eluent. It is then concentrated in vacuo and lyophilized. The result is 3 (8) - C1- (S) -carboxy-7- (3,4-piperidyl) hexyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5 α-acetic acid (0.1 g) as a colorless powder.
Cot D-119 ° (in water).
SIMS spectrum (m / e): 462 (W).
Example 72. In a solution of tert-butyl-3 (3) (1-benzyloxycarbonyl-4-piperidyl) - (5) -ethoxycarbonylheptyl-amino-4-oxo-2,3,4,5-tetrahydro-1 , 5-benzoxazepin-5-acetate (0.35 g) in acetic acid (1.5 ml) is administered a 30% hydrogen bromide - acetic acid solution (1.5 ml). The resulting mixture was allowed to stand at room temperature for 30 minutes and then diluted with ethyl ether (100 ml). The surface layer was removed by decantation and the precipitate was dissolved in 1N. sodium hydroxide solution (10 ml). The solution is allowed to stand for 30 minutes at room temperature. After the addition of acetic acid (2 ml), the mixture was subjected to chromatographic separation on a column filled with MC1 gel, using water: methanol in a 1: 1 ratio as eluant. The eluate is concentrated in vacuo and lyophilized. The result is 3 (8) P (5) -carboxy-7- (4-piperidyl) heptyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5 α-acetic acid (0.15 g) as a colorless powder.
cilv -108 ° (in water).
SIMS spectrum (m / e): 462 (MH4).
EXAMPLE 73: 2 g of benzyl-3 (3) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate is dissolved in 30 ml of ethanol. hydrochloride, 0.45 g of sodium acetate, 0.35 g of acetic acid, 0.45 g of ethyl 2 oxo-4-phenylbutyrate and 10 g of 4A molecular sieve are added to the solution. After the mixture is stirred at room temperature for 30 minutes, the mixture is added dropwise a solution of 0.34 g of sodium cyanoborohydride in 30 ml of ethanol for 3 hours. After the solution is added to the mixture with 1 g of sodium cyanoborohydride in 30 ml of ethanol for 1 hour, the reaction mixture is concentrated under reduced pressure activities. 100 ml of water and 200 ml of ethyl acetate are added to the residue and the mixture is stirred. After removing the insoluble material by filtration, the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After adding 50 ml of ethyl ether and 1 g of oxalic acid to the residue, the mixture is agitated and diluted with 300 ml of petroleum ether. The resulting mixture stand overnight. The supernatant was removed by decantation, and 50 ml of water and 300 ml of ethyl acetate were added to the sediment, followed by neutralization with excess sodium bicarbonate. The ethyl acetate layer was dried over anhydrous magnesium sulphate and concentrated under reduced pressure, and an oil was obtained which was separated and purified on a chromatographic column filled with silica gel (eluted with hexane-ethyl acetate in the ratio of 5: 1 to 2: 1). Tertbutyl-3 (8) -0 (K) -ethoxycarbonyl-3-phenylpropyl} -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepin-5 is initially obtained -acetate in the form of oil. This product is dissolved in a mixture of 100 ml of petroleum ether and 20 ml of ether (diethyl), and 1 ml of solution is introduced into the solution.
hydrogen chloride-ethyl acetate (5N). 0.9 g of the hydrochloride salt of this product is obtained as a colorless powder.
%: C 65, 15; H 6.01;
N
N
Calculated
5.07.
C30H37N OЈ Found,%
4.94.
HC1: C 64.65; H 6.17;
 "(, 5 in methanol), subsequent excreted fraction -86, 9
Of
0
0
five
0
N
5 N
Benzyl-3 (3) -U (3) -ethoxycarbonyl-3-phenylpropyl} -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetateate is obtained in the form of no color oil. This product is converted to the hydrochloride salt as a colorless powder (yield 1.3 g) in the same manner as described above.
Calculated,%: C 65.15; H 6.01; 5.07.
SvNNe1I70 -NS1
Found,%: C 64.97; H 6.18; 4.99.
C d4-62,4 ° (, 5 in methanol).
PRI me R 74. In 100 ml of ethanol, 0.7 g of benzyl-3 (5) C1- (R) - ethoxycarbonyl-3-phenylpropyl-amino-4-oxo-2,3,4,5- is dissolved. tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride prepared in Example 73, and catalytic reduction at normal temperature and at atmospheric pressure using 0.5 g of 10% palladium-carbon (50% moisture) as a catalyst, when the absorption of hydrogen is stopped, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. Petroleum ether is added to the residue. The result is 0.53 g of 3 (5) (E) -ethoxycarbonyl-3-5 phenylpropyl} -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid. hydrochloric acid as a colorless powder.
0
five
Calculated N 5.83. WITH
%: C 57.44; H 6.08;
 73
nl ° HCl-H O
Found,%: C 57.39; H 5.97; N 5.74,
Example 75. 1.1 g of benzyl-3 (S) -tl (5) -ethoxycarbonyl-3-phenylpropyl-amino-4-oxo-2,3,4,5-tetrahydro-1.5 are catalytically reduced. -benzoxazepin-5-acetate hydrochloride, obtained in example 31
1563593
pe 73, in the same manner as described in Example 74. B, 0.8 g of 3 (S) (3) -ethoxycarbonyl-3-phenylpropyl 7-amino-4-oxo-2,3,4,5-tetrahydro is obtained -1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder.
Calculated,%: C 58.54; H 5.98; N 5.94.
C2E ° 2 "Mg °: -HS1-1 / 2H20 Found: C 58.45; H 6.08; N 5.71.
, 9 (, 6 in methanol). 10 ml of water was added to this product, and the solution was extracted three times with ethyl acetate each time in 50 ml portions. The extract is dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Ethyl ether was added to the oily concentration residue and the mixture was allowed to stand. The precipitated crystals are filtered, the filtrate is treated with a solution of hydrogen chloride - ethyl acetate, resulting in precipitated powder, which is removed by filtration. 3 (8) (3) -ethoxycarbonyl-3-phenylpropyl -} - amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride is obtained. has a higher optical purity.
oOv –Y3 ° (, 5 in methanol). Example 76. In a mixture of 1 ml of ethanol and 4 ml of a solution (1N) of sodium hydroxide solution, 0.15 g of 3 (8) -1.1- (K) -ethoxycarbonyl-3 phenylpropyl D-amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid of the borohydride prepared in Example 64, and the resulting mixture is allowed to stand for 2 hours and slightly acidified with 1N. hydrochloric acid. The precipitated powder is recovered by filtration, dried, dissolved and the filtrate is dried under reduced pressure, yielding 0.03 g of 3 (S) 1 (K) -carb-hydroxy-3-phenylpropyl} -amino- 4-oxo-2, 3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid as a colorless powder.
Calculated,%: C 59.29; H 5.92; N 6.59.
C7, HnN1Ot-3 / 2H10 Found: C 59.63; H 5.64; N 6.73,
C “Oj, -112e (, 3 in methanol).
five
32
Example. Hydrolysis of 0.16 g of 3 (8) - 0 (8) -ethoxycarbonyl-3-phenylpropyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid The hydrochloride acids prepared in Example 75 are carried out in the same manner as described in Example 76. The crystals obtained are recrystallized from ethanol. As a result, 0.1 g of 3 (8) (3) -carboxy-3-phenylpropyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid in as colorless prisms with 127-130 s.
Calculated,%: C 60.57; H 5.81; N 6.73.
Ci, H2lN4CV
nr
C, 60.44; H
N
5.69;
Found, 6.68 cD-86, 50 (, 4 in methanol). Example 78. 1.5 g of benzyl-3 (8) -amino-4-OXO-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride is dissolved in 30 ml of ethanol and added to the solution 0.34 g of sodium acetate, 0.3 g of acetic acid, 2.63 g of eth-4-cyclohexyl-2-oxobutyrate, and 8 g of molecular sieves 4A. The mixture is then stirred at room temperature for 1.5 hours, a solution of 0.26 g of sodium cyano-borohydride in 30 ml of ethanol is added dropwise to the mixture over 2 hours, the reaction mixture is concentrated under reduced pressure, 50 ml are added to the residue. ml of water and 150 ml of acetate and the mixture is stirred. The insoluble material was removed by filtration, the ethyl acetate layer was dried.
over anhydrous magnesium sulphate and concentrate under reduced pressure. Then 20 ml of ethyl ether and 1.2 g of oxalic acid are added to the residue, the mixture is shaken and diluted with 200 ml of petroleum ether. The mixture was left overnight. The upper floating layer is removed by decanting, 50 ml of water and 200 ml of ethyl acetate are added to the precipitate, neutralized with an excess of sodium bicarbonate. The ethyl acetate layer is dried over anhydrous MgSO4, concentrated under reduced pressure, and a product is obtained which is purified on a chromatographic column filled with silica gel (using hexane-ethyl acetate in the ratio of 5: 1 to 4: 1 as eluant). From the first fraction, 0.4 g of benzyl-3 (H) -Ј (E) -ethoxy is obtained.
carbonyl-3-cyclohexylpropyl-J-amino-4-hydroxy-2,3,4,5-tetrahydro-, 5-benzo azazine-5-acetate as a colorless mixture.
Calculated,%: C 68.94; H 7.38; N 5.36,
C30H3, M20
Found,%: C 69.03; H 7.27; N 5.57.
 (in methanol).
The second fraction gives 0.4 g of benzyl-3 (5) - C (5) -ethoxycarbonyl-3-cyclohexylpropyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5- benzoxazepine-5-acetate as a colorless oil.
Calculated,%: C 68.94; H 7.33; N 5.36.
SE.NE, M204
Found,%: C 69.08; H 7.35; N 5.60.
EXAMPLE 79: Benzyl-3 (S) -C (K) -ethoxycarbonyl-3-cyclohexylpropyl} -amino-4-oxo-2,3,4,5-tetrahydro -1,5-benzoxazepin-5-acetate (0.35 g) obtained in Example 79 and using 10% palladium carbon as a catalyst in the same manner as described in Example 74. The oily product is dissolved in ether, and 0.5 ml of a solution (5N) of hydrogen chloride — ethyl acetate is added dropwise to the solution. The result of 0.18 g of 3 (S) (R) - ethoxycarbonyl-3-cyclohexylpropyl - amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride in the form colorless powder.
Calculated,%: C 58.91; H 7.09; N 5.97.
Ca3H31N7Ot. HC1
Found,%: C 58.89; H 7.23; N5.82,
SALЈM34 ° (, 5 in methanol).
EXAMPLE 80 Catalytic reduction of benzyl-3 (S) (G) ethoxycarbonyl-3-cyclohexylpropyl-amino-4-oxo-2,3,4,5-tetrahydro-1.5 is carried out. -benzoxazepine-5-acetate (0.35 g) obtained in Example 78, as in Example 74. To the oily product, add 0.31 g of 3 (S) (S) ethoxycarbanyl-3-cyclohexylpropyl} -mino-4- oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid in the form of colorless prisms, so pl. 135-139 ° C.
five
0
0
5 0 5 0
five

Calculated,%: C 62.57; H 7.53; N 6.34.
C7EN32Mg04 1 / 2N20
Found,%: C 62.7; H 7.38; N 6.30.
& / -128 ° (, 5 in methanol).
This product is recrystallized twice from a mixture of ethyl acetate and petroleum ether. The result is 3 (S) (3) -ethoxycarbonyl-3-cyclohexylpropyl-amino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzoxazepin-5-acetic acid in the form of colorless prisms having more high optical purity with so pl. 146-J48 ° C.
Calculated,%: C 63.87; K 7.46; N 6.48.
C23H32N7Ot
Found,%: C 64.07; H 7.64; N 6.45. I CcU ° (, 6 in methanol).
PRI me R 81. 0.3 ml of 3 (8) -1 (3) -ethoxycarbonyl-3-phenylpropyl J-amino-4-oxo-2,3 is dissolved in 10 ml of M, K-dimethylformamide. , 4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid chlorhydrate, prepared in Example 75, and tert-butylphenylalaninate (0.3 g) are introduced into the solution. 0.13 g) diethylphosphorocyanidate in H, M-dimethylformamide (dropwise) at an ice-bath temperature. After stirring the resulting mixture for 10 minutes, a solution (0.14 g) of triethylamine in M, K-dimethylformamide was added dropwise at an ice-bath temperature, and the mixture was stirred for 30 minutes. 200 ml of ethyl acetate are introduced into the reaction mixture, and the mixture is washed successively with 50 ml of water, 50 ml of 0.1N. hydrochloric acid (twice), 50 ml 0.1 n. sodium hydroxide solution and 50 ml of water. The ethyl acetate layer is dried over anhydrous magnesium sulphate and concentrated under reduced pressure. 0.4 g of tert-butyl-3 (S) (S) -ethoxycarbonyl-3-phenylpropyl} -amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzoxazepine- are obtained. 5-yl-M-acetyl- (/ -phenylalaninate.
IR: O, cm -1: 3350 (NH), 1730 (ester), 1680, 1690 (amide).
Example 821 100 ml 5 n. a solution of hydrogen chloride - ethyl acetate is dissolved 0.4 g of tert-butyl-3 (C) -C1 (3) -ethoxycarbonyl-3-phenylpropyl-amino-2,3,4,5-tetrahydro-1,5-benzoxeepin-5 the yl-K-acetyl-o-phenylalanine obtained in Example 81 and the solution are allowed to stand for 4 hours. The recovery solution is concentrated under pressure, 50 ml of growth ether are added to the residue concentration solution. The resulting mixture is an extra "- agitated twice with a saturated solution of sodium icarbonate (70 ml each). extraction, and the aqueous layer is extract-. 50 ml of ether. The aqueous layer was neutralized with 1N hydrochloric acid and extracted with 300 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The acidic product is dissolved in 10 ml of ether and 0.5 ml of 5N is added to the solution. a solution of hydrogen chloride - ethyl acetate. 0.2 g of 3 (S) -D (3) -ethoxycarbonyl-3-phenylpropyl} -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine- 5 is obtained. -yl-K-acetyl-o-phenylalanine hydrochloride as a colorless powder, Br0-53.5 ° (, 5 in methanol).
N
Calculated 6.89.
C31H35N307C 63.00; H 5.95;
/about
HC1
: C, 62.75;
H 5.93;
N
Found 6.84.
PRI me R 83, A mixture of 2.4 g of tert-butyl-3 (8) amino-4 oxo-2,3 S4,5-tetrahydro-1,5-benzoxazepine-5-acetate and 1.5 g ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyl oxyhexanoate is kept at 9QaC for 1 day. After cooling, 300 ml of ethyl acetate are added to the mixture and the resulting solution is washed with 5% phosphoric acid solution (2 portions of 30 ml) and 20 ml in the indicated order. The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oil-like residue, which is purified by chromatography on a column of silica gel (hexane: ethyl acetate in a ratio of 2: 1). As a result, 0.75 g of tert-butyl 3 (5) -. 5- (1-benzyloxycarbonyl-4-piperidyl) -1 (I) -ethoxyxyrbonyl-pentyl-amino-4-oxo- 2,3, 4,5-tetrahydro-1,5-benzoxazepin-5-acetate. From the subsequent fraction as a colorless oil, 0.7 g of tert-butyl-3 (S) are obtained.
five
0
five
5- (1 benzyloxycarbonyl-4-piperidyl) -1 (8) -ethoxycarbonylpentyl-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate.
II p and me R 84. In a solution of 1.5 g of tert-butyl-3 (S) - 1-benzyloxycarbonyl-4-piperidyl) -1 (B) -ethoxycarbonyl-pentyl-amino-4-oxo-2 , 3,4,5-t of tetrahydro-1,5-benzoxazepin-5-acetate in 5 ml of acetic acid is added 5 ml of a 30% aqueous solution of hydrogen bromide in acetic acid. The resulting mixture is allowed to stand for 1 hour at room temperature, and then it is diluted with 100 ml of ethyl ether. The upper layer was removed by decantation, and the precipitate was dissolved in 20 ml of 1N. sodium hydroxide solution. The solution is allowed to stand for 30 minutes at room temperature. After adding 4 ml of acetic acid, the mixture is subjected to chromatography on an MC1 gel using a mixture of water and methanol in a ratio of 1: D as eluent. The eluent is concentrated in vacuo and lyophilized to give 0.71 g of 3 (S) (8) -carboxy-5- (4-pyridyridyl) -pentyl-amino-4-oxo-2, 3 as a colorless powder. , 4,5-tetrahydro-1e 5-benzoxazepin-4,5-acetic acid.
An experiment on the inhibition of the enzyme angiotensin 1 conversion (ACE) by the proposed compounds.
The experiment is conducted according to a modification of the method described by Gushman et al. (Biochemical pharmacology, 1971, Vol. 20, p. 1637). When using guppuryl-oЈ-histidyl-o (-leucine (HHoi) as the basis, the inhibitory activity of ACE is determined, expressed as a percentage of inhibition per amount of hippuric acid formed by ACE, when the proposed compound is administered. The proposed compound dissolved in a buffer solution of 0.02-0.5% dimethyl sulfoxide — 100 mmol borate — HC1 (, 3, with 50 content of 300 mmol sodium chloride) is added to 100 ml of ACE (protein concentration 20 mg / ml), and 100 µl NNO ((1.25 mmol). In this experiment, a buffer p is used as a control target borate-HC1 containing DMSO concentration equal to the concentration of the test solution. After heating at 37 C for 1 h the solution was vvo0
five
CHENT 150 MCL 1 N. SALTIC ACID FOR
complete the reaction. After adding 0.8 ml of ethyl acetate, the solution is centrifuged at a rate of 11,500 rpm for 2 minutes. A 0.5 ml aliquot is separated from the ethyl acetate layer and dried at a temperature below 40 ° C in a stream of nitrogen gas. The residual product is thoroughly mixed with 4.5 ml of distilled water, and the mixture is subjected to a colorimetric effect at a wavelength of 228 nm.
The test results obtained for the proposed compounds are given in table. five.
The effect of the compounds on the ability of angiotensin I to increase blood pressure.
Male rats (Sprague Dawleg) weighing 250-350 g, having free access to food and water, are used as experimental animals. These rats are anesthetized by intraperitoneal administration of penta-abarbital sodium (50 mg / kg) one day prior to the test. A polyethylene tube for measuring blood pressure is inserted into the femoral artery, and a tube for the injection of angiotensin I and II is inserted into the femoral vein. The tubes are fixed in place.
On the test day, the average blood pressure in the control phase is measured by an electric hemodinamometer (MPU-0.5-290-0-111 models manufactured by NEC-Sanei Japan) and recorded by a polygraph (NEC-Sanei, type 365, or Nippon Kohden type RM-45), and then angiotensin I is administered through the femoral vein 300 ng / mg and then angiotensin II with a dose of 100 ng / kg to measure the hypertonic effect. Then, the proposed compound is administered through the mouth with a dose of 10 mg / kg in the form of an aqueous solution or aqueous suspension of gum arabic, and 20, 60 and 120 minutes after such administration, angiotensin I and angiotensin II are reintroduced in order to follow the hypertonic reactions. When calculating the percent inhibition of the hypertonic effect of angiotensin I, the magnitude of the percent inhibition is corrected for the change over time of the hypertonic reaction caused by angiotensin II.
The test results obtained for the proposed compounds} are given in table. 6
The effect of the proposed compounds on the hypertonic effect of angiotensin I.
Male rats (Sprague-Dawley) weighing 300-400 g, which have free access to food and water, are used as experimental animals. Rats are anesthetized by intraperitoneal administration of pentobarbital sodium (50 mg / kg) the day before the test. A polyethylene tube for measuring blood pressure is inserted into the femoral artery. The same angiotensin I and II tube is inserted into the arterial artery. The tubes are fixed in place.
On the test day, the mean blood pressure in the control phase is measured by an electric hemodinamometer (MP models 0.5-290-0-W, manufactured by NEC-Sanei Japan), and recorded using a polygraph (NEC-Sanei type 365 or Nippon Koh, den type RM-45), and then angiotensin I is injected, and then angiotensin II is administered through the femoral vein with a dose of 300 ng / mg and 100 mg / kg, respectively, to measure the hypertonic effect. Then, by intravenous injection, a dose of 300 ng / kg of the proposed compound is administered in the form of a saline solution, and 5, 10, 30, 60, 90 and 120 minutes after this administration, angiotensin I and II are administered repeatedly to determine the hypertonic reactions. When calculating the percentage of inhibition of the hypertonic activity of angiotensin I, the value of the percentage of inhibition is adjusted for the change over time of the hypertonic reaction due to angiotensin II.
The test results obtained for the proposed compounds are given in table. 7
The compounds listed in Table 8 were subjected to an inhibition test for the angiotensin converting enzyme (ACE) according to the described experimental procedure.
The proposed compounds were subjected to oral toxicity for 5 mice at doses of 300 ng / kg. Mice were examined one week after administration (Table 9).
PhCH2OOC
-to-
Tabli
y-tt-sn-coos2n5
, 4 | J ° -E
Cllgneek2
SNSK7CH2- SR CKjCH
426
510
3330, 1740, 1680
3330, 1730, 1680
- A mixture of diastereoisomers.
one
LENOOS
| H-Shg-CH-SOOS2N5
 t
ten
eleven
CH3CHjCH, CH3CHA

SS, R 50,335,807,34
NSY / 2K20 (50.11) (5.72) (7.32)
SR 356.01
HC1-1 / 2H20 (56.64) (7.34) (5.97)
table 2
CH I
t
336
420
A mixture of diastereoisomers.x
The free base is used for measurement.
(СН3) 3 SOOS
°
V-NH-CH-COOR
J CH2CH2-N
26BrCHjCOOC H
27Vg (CH7) 3CH3
- (СНа) 3СН3
Table 3
45
1563593
46 Table 4
47
1563593
Connection example
Dose, mcg / kg (intravenously)
Inhibition of hypertensive reaction caused by angiotensin (1.0%), after, min
g
ten
thirty
60
90
120

300 300 300 300 300 300 300 300 300 300
100
100
99
100
100
100
100
99
100
100
98
100
100
100
100
100
100
100
100
100
Tables
,
Compound Concentration- ACE inhibition - according to the example of qi, Torna activity,%
8410 799
48Y-193
4310 798
5310 799
581СГ799
Table 9
Compound Example 84
The number of survivors All mice remained individuals without significant
physiological changes
Compiled by I. Fedoseeva Editor N. Gunko Tehred M. DidykKorrektor A.Obruchar
Order 1069 Circulation 317 Subscription
VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 1 13035, Moscow, Zh-35, 4/5 Raushsk nab.
Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
48 Table 7
thirty
60
90
120
74
93
86
99
100
99
100
86
99
93
52
82
75
85
100
96
100
75
85
82
26
65
65
71
100
78
100
65
71
65

权利要求:
Claims (1)
[1]
Claim
1 ..- Method for preparing fused seven-membered cyclic compounds of general formula I
where B _{ is hydrogen, lower C ^ -C ^ -alkyl or benzyl;
E - lower C _{ -C ₈ -alkyl, possibly substituted by an amino group, phenyl (lower C, -C ₊ ) alkyl, cyclohexyl (lower) alkyl, tetrahydropyranyl (lower) alkyl, piperidyl (lower) alkyl,
Υ is a carboxyl group, or their salts, characterized in that the compound of general formula II
° "Ύ-νη ₂ οη ₂ -ϊ
where Ύ is lower alkoxycarbonyl or benzyloxycarbonyl,
subject to interaction with ’a compound of general formula III
CGCH-SOOK.!
5 I
V.
where 1C and K ₂ have the indicated values,
And is a halogen or a group E ^ -O3 ^ -O10 where Eo is lower alkyl,
and the resulting compound, where B, the lower C ^ -C ^ -alkyl and / or Y is lower alkoxycarbonyl, is hydrolyzed to give compound (I), where
15 B, is hydrogen and / or Υ is a carboxy group, or a compound of formula (I), where E ^ is benzyl and / or is benzyloxycarbonyl, is subjected to a catalytic reduction to give compound (I), where B ^ is hydrogen and / or - carboxypropyl, or the compound (I), where E ₁ is hydrogen, is subjected to esterification, followed, if necessary, by the translation of the target products into salts.
25 2. Method according to π. 1, characterized in that the target compounds (I) are prepared, where K ₂ ~ C ₁ —C ₆ is alkyl or (4-piperidyl) butyl.
Priority for priz30 | N and to and m
27.04.84 when E _g - lower C, -C ₈ ~ alkyl, substituted by amino group, piperidyl (lower) alkyl, tetrahydropyranyl (lower) alkyl;
35 12.08.83 with Ed-cyclohexyl (lower) alkyl, phenyl (lower) C ₁ -C ₆ alkyl;
13.07.84 with Ed-piperidyl (lower) alkyl.
Table 1
NN ~ SN "SOOS ₂ H5
* <
РСНН ₂ ООС
Example TO Configuration*12 - Massspektr M ⁺ (m / z) Spectrum ΙΕ. Clean I _, Ί m "ks> ^cm one 2 3 four five
one sn, - 8Е8 ** 426 3330,1680 1740, 2 Sn _e sk ₂ ssk ₂ sk ₂ - Ze 510 3330, 1730, sk ₃ dn ₇ ^x1680
41
1563593
42
Continuation of table 1
one ί 3 ---,four· five sn ₃ sn ₂ sks ₂ sk _{g g} sn _e sk ₇ ^x58 510. 3330, 1740, 1670 3 ¢ 2) ^- CH ₂ CH ₂ - 5K 536 3320, 1730, 1670 .four O-ch ₂ en ₂ - 58 536 3330, 1740, 1670 five^ch 5 ~ @ - ^CH 2 ^CH 2 -8K 530 3330, 1740, 1680 - OH3 "" CH ₂ CH ₂"55 530 3330, 1740,1680 6 ίθ CH ₂ CH ₂ - 8K 524 3330, 1740,1680 o2Usn ₂ CH ₂ - 88 524 3330, 1940,1680 7 ^) - CH2CH ₂ - 8K '540 3330, 1740,1680 θ-sn ₂ ch ₂85 540 3330, 1740,1680 eight and <^ Л-сНгОС — V ^{th 2} 9 ^H 2 5K 657 3330, 1740, 1690, 1680 0 ^ y2sn ₂ wasps - ^ (2X * H ^{H2 5K} ' ⁵ * sn ₂657 3330, 1740, 1690, 1680 9 CH ₃ (CH ₂ ) ₇ - P8 *, 5 524. 3330, 1740,1680
5 Table 2
The mixture of diastereoisomers
.ABOUT
*12
o- ΝΗ-ΟΗ-ΟΟΟΟ ₂ Η ₅ - N
Noros
- - - ————— When- to Confngu measures walkie talkie *12
ten
sn.
SNEC
Sn ₃ Sn ₂
sns ₄ sk _g 8K
58, K *
Elemental analysis: Calculated (found)% Mass spectrum M ⁺ (t / e) Formula 1 ^sone. " 1 ^Ν С _1е Н _1с Н _г О ₆ х »НС1-1 / 2К ₁ 0 50.33(50.11) 5.80(5.72) 7.34(7.32) 336 С ₁₂ Н ₃₇ К _г 0 ₄ НС1 · 1 / 2Н ₂ О 56.70(56.64) 7.35(7.34) 6.01(5.97) 420
eleven
43 1563593 44
Continuation of table 2
Example TO .Configuration*12 --------— __ ------------ Elemental analysis: Calculated (found),% Russ spectrum M ⁺ (m / e) Formula | " one N 12 Sn ₇ Sn _g ^x CHCH / .H * CH ₃ CH _g ^x55 C 2, n XХКС1-1 / 21ЦО 56.70(56.81) 7.35(7.28) 6.01(6.00) 420 13 O-SNiCH ₂ - 5Р Ο ^ Ιι ^ Ν ^ Ρς χ ЖНС1 1 / 2Н _g Р 58,59(58.43) 7.38(7.40) 5.69(5.60) . 446 14 CH ₂ CH ₂ -, 55 chg'zla * 58,59 7.38 5.69 446 "NSG 1 / 2H ₂ P (58.29) (7.41) (5.58) 15 CH3- ^ 2 ^ “ ^CH 2 ^CH 2 ' 55 with _gz n ₁₈ m _g with ₄ x HC1 - 1 / 2H _g P 59.32(59.39) 6.22(6.35) 5.76(5.72) 440 sixteen Oh ^ ch ₂ ch ₂ ~ 5K С ₇ * Н ₃ „К * Р ₇ к» НС1- 1 / 2Н * 0 55.06(55.11) 6.72(6.78) 5.84(5.38) 434 17 about ^ ~~ dunn * dh _g - 35 with _g * n _r n _3o about ₇ * * HC1 · 1 / 2E _g of 55.06(54.73) 6.72(6.66) 5.84(5.71) 434 18 -θ-ΟΗ ₂ 6Η ₂ - 5K C _hey N ₃₀ Y _g R ₆ χ 53.27 . 6.50 5.65 450 xHC1-1 / 2H * 0 (53,32) (6.47) (5.59) nineteen θ-0Η ₂ 0Η ₂ - 55 With and ^to ^ ^ 1 ^ <* 53.27 6.50 5.65 450 "HC1 · 1 / ζΗ ₂ 0 (53.15) (6.20) (5.77) 20 H ^ 2) -CH ₂ CH2- 55 · С ₂₁ Н ₃ , Ν ₃ О ₆ χ х2НС1-Н * О 50.39(50.36) 6.73(6.68) 8.01(7.56) 433 · ** 21 sn _e (sn _g ) ₇ - 5K, 5 * С η _Ч Н Н ^ 06 * 57.55 7.56 5.84 434 xHC1 · 1 / 2H * P (57.60) (7.50) (5.93) 22 n five - (56.47) (5.62) (8.28) 322
*
"*
A mixture of diastereoisomers.
The free base is used for measurement.
Table 3
12
"" Ηνη-sn-juice ( I
V
(sn ₃ ) ₃ coaxial
Sn ₂ Sn ₂
Example Used halogenated compound TO ----------- ₁ Configuration 0 * 3 i(in methanol), hail *one TO:
26 VGCH _g SOOS _g N _£-CH COOC ₄ H _{7 g}five five -145(c = 0.7) 27 Br (CH _a ) _e CH _e- (CH _g ) _H sn ₃five five -200
(c = 0.5)
45
1563593
46
Table 4
*12
INSOOSI I
3 CH ₂ CH ₂
oo.1 <
noos
When- Έ Configuration ινη measures (in methano- ___________ * le), hail
-CH ₂ COOC 30 s _{5 g}
31 - (CH ₂ ) _E CH _E
3 3 -115
(c = 0.5)
3 5 -114
<c = 0.6, '
3 5 -106
(c = 0.4)
Table5
Compound Concentrate Inhibiting by example portable radio, mm- schaya active ness ACE,% 77 0.1 91 32 one 99 32 0.1 95 one 100 33 0.1 93 34 0.1 95 one 99 35 0.1 93 43 one 100 63 0.1 95 66 0.1 99 69 0.1 99 72 0.1 99 t a b and c a 6 Connecting Dose, Inhibition of hypertonic of on mg / kg reaction caused by for example (through angiotensin, a, after, mouth) min 20 | 60 | 120 75 ten 82 58 60 80 ten 97 89 86 31 ten 98 96 86 29 ten 87 78 82 12 ten 93 73 63
47
48
1563593
Table 7
Compound byfor example oneDose,mcg / kg(intravenously) Inhibition of hypertensive reaction caused by angiotensin (1.0%), after, min five ten thirty 60 90 120 34 300 100 98 97 74 52 26 42 300 100 100 '97 93 82 65 43 300 99 100 93 86 75 65 53 300 100 100 100 99 85 71 66 300 100 100 100 100 100 100 69 300 100 100 100 99 96 78 84 300 100 100 100 100 100 100 43 300 99 100 93 86 75 65 53 300 100 100 100 99 85 71 42 300 100 100 97 93 82 65 HC1
Table 8
Connection example Concentration, M ACE inhibitory activity,% 84 10 " ⁷99 48 10 ~ ⁷93 43 10 ~ ⁷98 53 ^Yu-7 99 58 10 ~ ⁷99
Table 9 Example Compound 84 The number of surviving individuals All mice remained alive without significant physiological changes.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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PCT/JP1983/000264|WO1985000810A1|1983-08-12|1983-08-12|Fused 7-membered ring compounds and process for their preparation|

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PCT/JP1984/000221|WO1985005104A1|1984-04-27|1984-04-27|Fused 7-membered ring compounds and process for their preparation|

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PCT/JP1984/000362|WO1986000617A1|1984-07-13|1984-07-13|Condensed 7-membered ring compounds and process for their preparation|

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