前苏联专利SU1526583A3 Method of producing condensed heptacomposed cyclic compounds

专利PDF首页>>前苏联专利

专利附录

专利说明

权利要求

类似技术

同族专利

引用文献

法律状态

优先权

专利摘要:
Novel fused 7-membered ring compounds represented by the following formula (I), wherein R<1> and R<2> each represents hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy or, when taken together, they represent tri- or tetra-methylene, R<3> represents hydrogen, lower alkyl or aralkyl, R<4> represents hydrogen, alkyl or optionally substituted aralkyl or cycloalkyl, and X represents S(0)n (wherein n represents an integer of 0 to 2), Y represents an optionally esterified or amidated carboxyl group, and m represents 1 or 2, and the salts thereof. These compounds have an effect of inhibiting angiotensin-converting enzyme, and are useful for diagnosis, prophylaxis or treatment of hypertension.
公开号:SU1526583A3
申请号:SU843732828
申请日:1984-04-20
公开日:1989-11-30
发明作者:Сугихара Хиросада；Нисикава Кохеи；Ито Катсуми
申请人:Такеда Кемикал Индастриз, Лтд (Фирма)；
IPC主号:

专利说明:

This invention relates to organic chemistry, namely to a method for producing fused seven-membered cyclic compounds of the general formula.
II VNllOllCOORi CHj- COOH
where R is hydrogen, lower alkyl;
And - C4-C, alkylene,
or their salts, which exhibit an inhibitory effect on the enzyme converting angiotensin and can be used in medicine and veterinary medicine.

with
The aim of the invention is to develop a process for the preparation of a compound of formula I having valuable pharmacological properties.
Example 1 The catalytic reduction of 10 g of 3- (o-ntrophenyl) thio-2- (K) -phthalimidopropionic acid is suspended in 300 ml of methanol at normal temperature and at atmospheric pressure using 5% palladium-carbon as a catalyst. After absorbing the calculated amount of hydrogen, the catalyst is removed, methanol is evaporated under reduced pressure. The evaporation residue crystallizes from ether-petroleum ether, resulting in 8.4 H (o-aminophenyl) thio-2 (R) -phthalimidopropionic acid pale yellow crystals. To a stirred solution of 8.4 g of this product in 50 ml of N, N-dimethyl forms and 5.5 g of diethyl phosphorocyanidate are added dropwise at the temperature of the ice bath. After stirring the reaction mixture for 5 minutes, 2.28 g of triethylamine was added dropwise at the temperature of the ice bath. The mixture was stirred for 30 minutes in an ice bath and for another 1 hour at room temperature, diluted with 200 ml of water and allowed to stand overnight. The precipitated solid product is recovered by filtration and the li chromatographic column is purified, filled with silica gel (dichloromethane: ethyl acetate 2: 1), resulting in 5.4 g 3 (R) - phthalimido-2, 3-dihydro-1.5 ( 5H) -benzothiazepin-4-one in the form of colorless prismatic crystals. Melting point 202 - 205 C.
Calculated: C, 62.95; H 3.73; N 8.64.
AST, and “go, 3.
Found: N 8.49.
C 63.15; H 4.02;
oi - 164 (, 9, in methanol). Example 2 To a stirred mixture of 50 ml of N, N-dimethylformamide and 0.5 g of sodium hydride (60% in oil) are added 4 g of 3 (K) -phthalimido-2,3-dihydro-1.5 (5H) -benzothiazepin-2-one, prepared in Example 1, at the temperature of the ice bath. After 5 minutes, add 2 g of tert-butyl chloroacetate at the temperature of the ice bath. The mixture was stirred in an ice bath for 15 minutes and diluted
five
0
five
0
five
0
five
five
ice water (200 ml). Precipitated crystals are removed by filtration, dried and purified on a silica gel chromatography column (hexane: ethyl acetate 3: 1), resulting in 4 g of tert-butyl-4-oxo-3 (K) -phthalimido-2,3,4, 5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless crystals.
After recrystallization of a part of the crystals from ethyl ether, colorless prismatic crystals are obtained with a melting point of 181-184 ° C.
Calculated: C 63.01; H 5.06; N b, 39.
C2} Hj j N20sS.
Found: C, 62.95; H 5.10; N 6.34.
oi j 156 (, 9, in chloroform).
PRI me R 3. A mixture comprising 100 ml of ethanol, 4 g of tert-butyl-4-oxo-3 (K) -phthalimido-2,3,4,5-tetra-hydro-1,5-benzothiazepine. 5-acetate, obtained in example 2, and 1.4 g of hydrazine hydrate is heated under reflux for 1 h with simultaneous stirring. The reaction mixture is concentrated under reduced pressure and 300 ml of ethyl acetate and 100 ml of water are added to the residue, followed by vigorous stirring. The ethyl acetate layer was washed successively with a dilute aqueous solution of sodium hydroxide and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue of concentration crystallizes from a mixture of ethyl ether and petroleum ether, resulting in 2 p tert-butyl-3 (K) -amino-4-oxo-2, 3,4,5-tetrahydro-1,5- benzothiazepine-5-acetate as colorless prismatic crystals. Melting point 86 - 89 C.
Calculated: C 58.42; And 6.54; N 9.08.
C ..
Found: C 58.73; H 6.48;
N 9.13.
- 238 with (, in methanol).
Example4. VOOOm ethanol is dissolved with 4.5 g of sodium, 30 g of ethyl 3-cyclohexyl propionate and 29 g of diethyl oxalate are introduced into the solution, after which heating is carried out at about 70 ° C for 30 minutes. Iekokip shchy
The solvent is removed by evaporation under reduced pressure at 70 seconds for 30 minutes. After cooling, 500 ml of water, 200 ml of ether and 100 ml of petroleum ether are introduced into the brown brown residue, and the mixture is stirred vigorously. The aqueous layer was separated, weakly acidified with sulfuric acid, and extracted with 200 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulphate.

R
5836
5V.-MeTimaueTaT (7.8 g) as a colorless powder.
IR mgs, cm-: 1770, 1730, 1720, 1680 ().
Calculated: C 62, A6; And, 46; N 6.07.
C H NjOjS- 1/2
Found: C, 62.62; H 5.14;
N 6.13.
PRI me R 6. The tert-butyl-3 (K) -phthalimido-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5- “obtained in the solution of re 5 is -methyl acetate in amount
concentrated under reduced pressure, 7.6 g is treated with hydrate
SRI. 110 MP of a 10% aqueous solution of dimethyl sulfoxide and 10 g of sodium chloride are introduced into the oily residue of concentration and the mixture is stirred at 140 ° C for 20 2.5 hours. After cooling the reaction mixture, 1 l of water is added, then extraction is carried out 500 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The brown oily residual product is distilled off under reduced pressure, resulting in 18 g of ethyl 4-cyclohexyl-2-oxo-butyrate as a pale yellow liquid.
25
thirty
hydrazine in the same manner as about sano in example 4, the result is that tert-butyl-3 (K) -aminooxo-2, 3,4,5-tetrahydro-1,5-benzothiazepin-5-o-methyl acetate ( 5.4 g) as a pale yellow oil.
, px, cm-: 1735, 1670 (С
. p - 223 ° (, 5, in methanol
Mass spectrum (ha / e): 322 ().
Example 7. In a solution of tert-3 (K) -amino-4-oxo-2,3,4,5-tet gchdro-1,5-benzothiazepine-5-acetate (3.08 g) obtained in example 3 in N, N-dimethylformamide (20 ml) in d ethyl-2-bromo-6-phthalimidohexanoate (7.36 g), potassium carbonate (2.76 g) and potassium iodide (1.66 g). Ethyl bromo-6-phthalimidohexanoate (3.68 g potassium carbonate (1.38 g) was added overnight at room temperature and the stirring continued for 3 days. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (300 ml). ml The extract is washed with water and concentrated under reduced pressure. The mild residual product is dissolved in a mixture of oxalic acid (5 g) and ethyl acetate (30 ml). The solution is diluted with petroleum ether (120 ml) and thoroughly stirred After standing, the aperture layer is removed by decanting. acidic, followed by dilution and decantation is repeated four times. The resulting product is introduced into a cm of saturated sodium bicarbonate aqueous solution (100 ml) and ethyl acetate (300 ml). The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrate under reduced pressure. Oily about
The boiling point is 105-110 ° C (1.5 mm Hg).
Example 5. In a solution of 3 (R) - phthalimido-2, 3-dihydro-1.5 (5H) -benzotiazepin-4-one (6.48 g) obtained in example 1, in N, N-dimethyl - tert-butyl -2 -2-bromopropionate (6.27 g), potassium carbonate (5.5 g) and potassium iodide (0.5 g) are injected with formamide (25 ml). The resulting mixture was stirred overnight at room temperature, diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract was washed successively with 0 K. Hydrochloric acid (200 ml) and saturated sodium bicarbonate aqueous solution (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The oily residue was concentrated by chromatography on silica gel using hexane-ethyl acetate as eluant in a ratio of from 3: 1 to 2: 1, resulting in tert-butyl-3 (R) -phthalimido-4-oxo-2 , 3.4,5-tetrahydro-1,5-benzothiazepine hydrazine in the same manner as described in Example 4, resulting in tert-butyl-3 (K) -amino4-oxo-2,3,4,5-tetrahydro-1 , 5-benzothiazepine-5-o-methyl acetate (5.4 g) as a pale yellow oil.
0
five
0
0
0
five
, px, cm-: 1735, 1670 ().
. p - 223 ° (, 5, in methanol).
Mass spectrum (ha / e): 322 ().
Example 7. In a solution of tert-butyl-3 (K) -amino-4-oxo-2,3,4,5-tetra-gchdro-1,5-benzothiazepine-5-acetate (3.08 g) obtained in Example 3 , in N, N-dimethylformamide (20 ml) ethyl 2-bromo-6-phthalimidohexanoate (7.36 g), potassium carbonate (2.76 g) and potassium iodide (1.66 g) are added. After stirring overnight at room temperature, ethyl 2-bromo-6-phthalimidohexanoate (3.68 g) and potassium carbonate (1.38 g) are added and stirring is continued for 3 days. The mixture was diluted with water (100 ml) and extracted with ethyl acetate (300 ml). The extract is rinsed with water and concentrated under reduced pressure. The oily concentration residue is dissolved in a mixture of oxalic acid (5 g) and ethyl acetate (30 ml). The solution is diluted with petroleum ether (120 ml) and thoroughly mixed. After standing, the supernatant is removed by decanting. The treatment with oxalic acid, followed by dilution and decantation, is repeated four times. The resulting product is introduced into a mixture of an aqueous solution of sodium bicarbonate (100 ml) and ethyl acetate (300 ml). The ethyl acetate layer is separated, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The oily residue was concentrated by chromatography on silica gel using hexane-acetone (4: 1) as eluant, resulting in tert-butyl-3 (R) (R) -ethoxy-carbonyl-5-phthalimidopentyl amino A-oxo-2,3, A, 5-tetrahydro-1,5-benzothiazepine-5-acetate (1.75 g) as an oil from the first fraction.
IR iTaVc. cm-: 3330 (W), 1780, 1720, 1680 ().
Mass spectrum (ha / e): 595 (M).
From the second fraction, tert-butyl-3 (K) (S) -ethoxycarbonyl-5-phtapimidopentyl amino-A-oxo-2, 3, A, 5-tetrahydro-1,5-benzothiazepine-5-acetate (2.5 g) is obtained. type of oil;
IR)
Max
cm: -3330 (NH), 1770
17AO, 1720, 1680 ().
Mass spectrum (ha / e): 595 (Mj.
foi - 119 (, 3, in methanol).
Calculated: C 55, A2; H 5 FOR; N 7.18.
HC1-1 / 2.
Found: C 55.09; H 5.12; N 7.15.
11А ° (, 5, in methanol).
PRI me R 8. A mixture of tert-butyl-- 3 (R) (R) -ethoxycarbonyl-5-phthal. Dopentyl1-amino-A-oxo-2,3, A, 5-tetrahydro-1,5-benzothiazepine-5-acetate (1.6 g) obtained in Example 7, ethanol (20 ml) and 85% - Hydrazine hydrate (0.8 g) stood overnight at room temperature. This mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). An ethyl acetate layer is washed sequentially with 0.1 n. an aqueous solution of sodium hydroxide and water, resulting in a solution of tert-butyl-3 (R) -5-amino-1 (R) -ethoxycarboxy spentilj amino-A-oxo-2,3, A, 5-tetrahydro-1 , 5-benzothiazepine-5-acetate in ethyl acetate. A mixture of sodium bicarbonate (1.6 g) and water (50 ml) is added to this solution. A mixture of di-t-butyl carbonate (0.9 g) in ethyl acetate (5 ml) is added dropwise to the resulting mixture with stirring at room temperature. stirring for 30 min. The ethyl acetate layer is separated, dried under anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residual concentration product is subjected to column chromatography using A = 1 ratio of hexane-acetone as eluant, The result of which is tert-butyl-3 (R) 5-tert-butoxycarbonylamino-1 (R) -troxycarbonyl-pentilyl amino-A-oxo-2,3, A, 5-tetrahydro-1,5- benzothiazepine 5-acetate
(1, A g) in the form of a colorless oil.
, cm-H 3350 (NH), 17AO, 1710, 1680 ().
Mass spectrum (ha / e): 565 (M).
PRI me R 9. Obtained in Example 5 re 7 t-butoxy-3 (R) (S) -ethoxy-carbonyl-5-phthalimido L-amino-A-oxo-2, 3, A, 5-tetrahydro-1 , 5-benzothiazepine-5-acetate in the amount of 2.7 g is subjected to treatment with successive hydrazine hydrate and di-t-butoxy-bicarbonate in the same way as described in example 8. After chromatographic purification in a silica gel-filled column, tert-butyl-3 is obtained. (R) - 5-tert-Butoxycarbonylamino-1 (5) -ethoxycar-. bonylpentyl amino-A-oxo-2,3, A, 5-tetrahydro-T, 5-benzothiazepin-5-acetate (1.87 1) as a colorless oil.
, cm-: 3350 (NH), 17AO, 1710, 1670 ().
0
Mass spectrum (m / e): 565 (M). Wu 136 (, 8, in methanol).
An example. A mixture of tert-butyl-3 (R) - 5-tert-bytoxycarbonylamino- 1 (5) -ethoxycarbonylpentyl amino-A-oxo-2, 3, A, 5-tetrahydro-1,5-benzothiazepine-5-acetate ( 0.6 g) obtained in example 9, methanol (AO ml), 1 n. an aqueous solution of sodium hydroxide (25 ml) and water (10 ml) is stirred for 2 hours at room temperature. After evaporation of the methanol, the mixture is weakly acidified with phosphoric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulphate and concentrated under reduced pressure from the scientific research institute, resulting in a three-byH-3 (R) -5-three-by-3-carboxylamino-1 (3) -carboxypentyl | amino-A-oxo-2, 3, A, 5-tetrahydro-1,5-benzothiazepine-5-acetate (0.37 g) as
5 colorless viscous substance which is mixed with ztity acetate to form colorless crystals with a melting point of 13A - 135 C.
Calculated: N 7.82.
.
C 58.08; H 7.31;
C 58.11; H 7.22;
(NH) 1730
-and
Found: N 7.73. . R
, cm: 3350 1700, 1680 ().
Example 11. A mixture of tert-butyl 3 (K) -amino-4-oxo-2,3,4,5-tetrahydro-5-benzothiazepine-5-acetate (5 g) obtained in example 3, ethyl-2-bromophthalimidohexanoate (17.9 g), acetonitrile (200 ml) and triethylamine (2.46 g) are heated under reflux for 45 hours. After evaporation of the acetonitrile, water (200 ml) and ethyl acetate (300 ml) are evaporated off. ), after which the extraction is carried out. This acetate layer is washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The oily residue is chromatographed on silica gel using 4: 1 hexane / acetone as eluant, resulting in tert-butyl-3 (K) -G1 (K) -ethoxycarbonyl-5-phthalimium 1; about o / s
Dopentyl1-amino-4-oxo-2,3,4, e-tetra hydro-1,5-benzothiazepin-5-aietate (3.9 g) and tert-butyl-3 (K) (8) - ethoxycarbonyl-5-ft p1-imidopentyl-amino-4oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepine-4-acetate (4.1 g). Both products are obtained in the form of colorless oils, which are identical to the compounds obtained in Example 7,
PRI me R 12, A mixture of 50 ml of ethane 1.5 g of tert-butyl 3 (K) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5 -acetate obtained in Example 3, 0.3 g of acetic acid, 4.2 g of ethyl 2-oxo-4-phenylbutyrate and 8 g of 4A molecular sieve are stirred at room temperature for 30 minutes. A solution of 0.6 g of cyanobore sodium hydride in 40 ml of ethanol is added dropwise to this mixture at room temperature for 2 hours. After stirring at room temperature overnight, 2.1 g of ethyl 2-oxo-4- is introduced into the mixture. phenyl butyrate. A solution of 1.3 g of sodium cyanoborohydride in 40 ml of ethanol is added dropwise to the resulting mixture over 2 hours. The mixture is evaporated under reduced pressure, diluted
0
five
0
five

100 ml of water are added and 200 ml of ethylacetate are extracted. The insoluble matter is removed by filtration, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After adding 50 ml of ethyl ether and 2 g of oxalic acid to the residue, the mixture is thoroughly shaken and diluted with 300 ml of petroleum ether. The resulting mixture was allowed to stand overnight. The surface layer was removed by decantation, and 50 ml of water, 300 ml of ethyl acetate were added to the precipitated product, followed by neutralization with excess sodium bicarbonate. The ethyl acetate layer is dried over anhydrous magnesium sulphate and concentrated under reduced pressure, resulting in an oily residual product p which is separated and purified in a chromatographic column filled with silica gel (hexane-ethyl acetate in an RHI ratio of 5: 1 to 10: 3), resulting in syachala, 0.55 g of tert-butyl-3 (R) -1 (R) -ethoxycarboni.n-3-phenylpropyl 1-amino-4-oxo-2,3,4,5 -tetrahydro-1,5-benzothiazepine-5-acetate in the form of - oil.
Example 13. A mixture of 5 ml of 5 n. a solution of hydrogen chloride - ethyl acetate And 0.5 g of tert-butyl-3 (K) (R) - 5 ethoikarbonyl-3-phenylpropyl amino-4-OXO-2,3,4,5-tetrahydro-1,5- The benzothiazepine-5-acetate prepared in Example 12 is allowed to stand at room temperature overnight. 20 ml of ether and 100 ml of petroleum ether are introduced into this mixture, which results in the precipitation of a colorless powder, which is recovered by filtration, and as a result, 0.42 g of 3 (K) (R) -ethoxycarbonyl-3-phenylpropol is obtained. amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-be1 {zothiazepine-5-acetic acid.
Calculated: C 57.68; H 5.68;
0
five
0
N 5.85.
five
HC1.
N
Found: C 57.53; H 5.76; 5.70.
“1 - 173 ° (s 1, in methanol).
Example 14. A solution of 1 g of tert-butyl-3 (R) (3) -ethoxycarbonyl-3-phenylpropyl amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzothiaze1In-5-ace
II
Tata prepared in Example 12 in 100 ml of methylene chloride was added to 0.51 meta-chlorobenzoic acid. After stirring for 30 minutes, 0.15 g of m-chlorobenzoic acid is added and stirring is continued for another 30 minutes. 50 ml of 1 and are added to the mixture. an aqueous solution of sodium hydroxide and a layer of methylene chloride are separated, washed with water and concentrated under reduced pressure to give 1-oxide-tert-butyl-3 (K) (5) -ethoxycarbonyl-3-phenylpropyl 1-amino-A-oxo -2, 3, 4,5-tetrahydro-1,5-benzothiazvpin-5-acetate as a mixture of two stereoisomers. After separation on a chromatographic column filled with silica gel, 0.3 g of one isomer and 0.5 g of the other isomer are obtained. Both substances are obtained in the form of a colorless oil. The mass spectrum of each isomer shows a peak in accordance with the molecular weight (514).
Example 15. A mixture of 6 ml of ethanol, 0.8 g of pef-butyl-3 (R) (S) - ethoxycarbonyl-3-phenylpropyl amine-4-1Oxo-2,3,4,5-tetrahydro-1,5-ben - zothiazepine-5-acetate, obtained in example 12, and 3 ml of 1N. an aqueous solution of sodium hydroxide is stirred at room temperature for 2 hours. The mixture is diluted with 200 ml of water and extracted with 100 ml of ethyl ether. The aqueous layer is weakly acidified with 1N. hydrochloric acid to precipitate 0.5 g of tert-butyl 3- (a) (5) -carboxy-3-phenylpropyl amino-4-oxo-2,3,4,5-tetrahydro-1 , 5-benzothiazepine-5-acetate in the form of colorless crystals with a melting point of 165 - 167 C.
ci.p - 101 ° (in methanol).
Calculated: C 63.81; H 6.43; N 5.95.
CjjHjoN G S.
Found: C 63.69; H 6.38; N 5.87.
PRI me R 16. A mixture of 10 ml of N, N-dimethylformamide, 0.3 g of tert-butyl-3 (R) -1 (S) -carboxy-3-phenylpropyl - amino-4-hydroxy-2,3 , The 4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 15, 0.5 g of sodium bicarbonate and 0.15 g of benzyl bromide are stirred at room temperature overnight. The mixture is diluted with water (100 ml) and extracted with ethyl 15
ten
15
20
35 e
25
658312
acetate (200 ml). The extract is washed sequentially with 0.1N. hydrochloric acid and water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure, resulting in 0.35 g of tert-butyl-3 (K) -l (5) -benzpoxycarbonyl-3-phenylpropyl amino-4- oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
i 3330 (NH), 1740 (ester), 1680 (amide).
Mass spectrum (m / e): 560 (M).
PRI me R 17. In the same manner as described in example 13, tert-butyl-3- (R)-p (5) -benzyloxycarbonyl-3-phenylpropyl amino-4-oxo-2,3,4, 5-tetrahydro-1,5-benzothiazepine-5-acetate (0.35 g) is treated with hydrogen chloride, resulting in 0.25 g of hydrochloride 3 (R) -p (3) -benzyloxycarbonyl-3-phenylproxy drank amino-4-oxo-2,3,4,5-tetrahydro-1,5-beisothiazepine-5-acetic acid as an unsaturated powder.
Calculated: C 62,16; H 5.40; N 5.18.
CjgHjgN OjS. HC1.
Found: C, 61.77; H 5.44; N 4.96.
oi. - 82 ° (in methanol).
Mass spectrum (t / e): 504 ().
Example 18. In a solution of 2 g of tert-butyl-3 (R) -amino-4-occo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, obtained in Example 3, in 20 ml of ethanol are added with 1.6 g of ethyl bromoacetate and 1 g of triethylamine. After v: staining at room temperature overnight, the mixture was concentrated to dryness under reduced pressure and the residue was purified on a chromatographic column (hexane: ethyl acetate 2: 1) filled with silica gel, resulting in 1.8 g of tert-butyl-3 ( TO)-. ethoxycarbonylmethylamino-4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
3330 (NH), 1740 (ester), 1670 (amide).
Mass spectrum (m / e): 394 (M).
PRI me R 19. A mixture of 15 ml of 5 n. a solution of hydrogen chloride ethyl acetate and 1.8 g of tert-butyl-3 (K) -ethoxycarbonylmethylamino-4-oxo-2,3,4, 5-tetrahydro-1,5-benzothiazepin-5-acetam is standing at room temperature30
40
45
50
for 3 hours. 50 ml of ethyl ether are introduced into this mixture, resulting in the precipitation of 1.6 g of 3 (R) -ethoxycarbonylmethylamino-4-oxo-2,3,4,5-tetrahydro-1 hydrochloride , 5-benzothiazepine-5-acetic acid in the form of colorless prismatic crystals.
Melting point 223 - 225 C (with decomposition).
Calculated from 48.06; And 5.11; N 7.47.
C, 5H ,,. S,
HC1. c 47.99;
N
H 5.11; (in methanol).
Found: 7.25.
Wp- 193
Mass spectrum (m / e): 338 (M).
Example 20 B2 ml of methanol was dissolved in 0.1 g of 3 (R) - Pl (8) -ethoxycarbonyl-3-cyclohexyl-1 hydrochloride.
propyl amino-4-oxo-2,3,4,5-tetra-hydro-1,5-benzothiazepine-5-acetic acid and 1.5 ml of 1N. aqueous raster of sodium hydroxide. The solution is 25-colorless crystals,
PRI me R 26. A mixture of hydrade 3 (R) - 5-amino-1 (5) -etoxic neiiTiinJ amino-4-oxo-2,3,4, 5-t ro-1, 5-benzothiazepine- 5-acetic lots (0.2 g) obtained in paragraph 25, and 1 n. aqueous solution of sodium oxide (4 ml), stirring at room temperature. After a weak acidified acid (1 ml), the mixture was chromatographed using Amberlite and eluted with methane in a ratio of 3: 7. The eluate is concentrated under reduced pressure; it is filizable; as a result, 3 (R) -5-amino-1 (3) -spentyl amino-4-oxo-2, 3, 4, 5 hydro-1,5-benzothiazepine-5 is obtained. α-acetic acid (0.1 g) as a colorless powder.
concentrated at room temperature for 2 hours, concentrated to a residual volume of about 1 ml at a temperature not higher than 40 ° C under reduced pressure, and slightly acidified with 1N. hydrochloric acid, resulting in 0.067 g of 3 (R) (S) -carboxy-3-cyclohexylpropyl amino-4-OXO-2,3,4,5-tetra-trans-1,5-benzothiazepine-5-acetic acids in the form of colorless prismatic crystals with a melting point of 207 - 210 C.
H 6.89;
N
H 6.91;
N
PRI me R 21. Tert-butyl-3 (K) - amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-o-methyl acetate obtained in example 6 ( 2.5 g), is reacted with 4-cyclohexyl-2-oxobutyrate. The product obtained is purified by passing it through a chromatographic column filled with silica gel, using a hexane: ethyl acetate mixture in the ratio 4: 1. whereby 3 (R) - 1 (R) -ethoxycarbonyl-3-cyclohexylpropyl amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzothiazepine-5-o6-methyl acetate is obtained in the form of an oil from the first fraction.
0
five
0
Mass spectrum (m / e): 518 (M).
From the second fraction, tert-butyl-3 (K) -l (8) -ethoxycarbonyl-3-cyclohexyl-propyl-Jamo-4-oxo-2,3, 4,5-tetrahydro-1,5-benzothiazepine-5- (-methyl acetate (0.28 g) as a colorless oil.
1kG; G s, cm-: 1740, 1670 ().
(X, - 222 ° (, 4, in methanol).
Mass spectrum (m / e): 518 (M).
Examples 22 and 23. The derivatives of tert-butyl-1,5-benzothiazepine-5-, -methyl acetate, obtained in example 21, are treated with hydrogen chloride in the same manner as described in example 13, resulting in the formation of are shown in table.1.
Examples 24 and 25. Benzothiazepine derivatives, prepared in Examples 8 and 9, are treated with x.porous hydrogen in the same manner as described in Example 13, resulting in the compounds shown in Table 2.
5 kind of colorless crystals
0
five
0
five
0 5
PRI me R 26. A mixture of hydrochloride 3 (R) - 5-amino-1 (5) -ethoxycarbonylneiiTiinJ amino-4-oxo-2,3,4, 5-tetrahydro-1, 5-benzothiazepin-5 α-acetic acid (0.2 g) obtained in Example 25 and 1N. an aqueous solution of sodium oxide padrat (4 ml) was stirred at room temperature for 1.5 hours. After a weak acidification with acetic acid (1 ml), the mixture is subjected to column chromatography using Amberlite XAD-2, eluting with methanol-water in a ratio of 3: 7. The eluate is concentrated under reduced pressure and lyophilized, resulting in 3 (R) -5-amino-1 (3) -carboxypentyl amino-4-oxo-2, 3, 4, 5-tetrahydro-1 , 5-benzothiazepine-5-acetic acid (0.1 g) as a colorless powder.
Calculated: C 51.12; H 6.31; N 10.52.
C ,, 0, S
Hjo.
C 50.87; H
5.83;
(, 3 in 1 n. Sol. Found: N 10.34.
WP - 1A9 acid).
Spectrum (ha / e): 382 (MP); addition of potassium iodide 420 (M + K).
Example 27. Tert-butyl-3 (R) - 5-tert-butoxycarbonylamino-1 (S) -carboxypentyl amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-vinegar151526
The amount of 0.3 g obtained in Example 10 in an amount of 0.3 g is treated with chloro-risky hydrogen in the same manner as described in Example 13, as a result of which 3 (R) –5-amino-1 (5) -carboxypentyl amino dichlorohydrate is obtained -4-oxo-2, 3, A, 5-tetrahydro-1,5-benzothiae-5-acetic acid (0.26 g) as colorless crystals.
Calculated: C, 46.49; 11 6.13; N 7.75.
Civ aiNjOpS. ZHCl.CHjCOOCjHg.
Found: C, 46.12; H 6.16; N 7.52.
This product is dissolved in 2 ml of water. After entering 1 n. an aqueous solution of sodium hydroxide (0.5 ml) and acetic acid (0.5 ml), the solution is processed in a chromatographic column using Amberlite XAD-2 in the same manner as described in Example 26, resulting in colorless powder (0.096 g), which is identical to the compound obtained in example 26.
PRI me R s 28 - 30. The reaction of tert-butyl-3 (K) -amino-4-OXO-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate with the bromo-substituted ester, similarly to that of Nfy, as described in Example 11, the benzothiazepine derivatives shown in Table 3 are obtained.
PRI me R s 31 - 33. Benzodiazepine derivatives obtained in Examples 28-30, in the same way as described in Example 8, react with hydrazine hydrate followed by reaction with di-tert-butyl dicarbonate in
resulting in compounds
given in table.4.
Examples 34-36. The benzothiazepine derivatives obtained in Examples 31-33 are treated with hydrogen chloride in the same manner as described in Example 13, resulting in the compounds shown in Table 5.
X Example 37. To the mixed sms of dichlorohydrate 3 (K) -1 7-amino-1 is. Sicarbonylheptyl amino-4-oxo-2,3,4, 5-tetrahydro-1,5-benzothiazepine-5-acetic acid, obtained in example 36 (0.7 g), triethylamino (0.5 g) and ethyl acetate (10 ml) di-tert-butyl dicarbonate (0.45 g) is added at room temperature. After nepewe- | shivaniya for 4 h the mixture was diluted

five
,, about 5
35
40

50 55
0
ethyl acetate (100 ml) and washed with water (5 ml). The ethyl acetate layer is dried over anhydrous magnesium sulphate and the colorless oily residue is evaporated, which is chromatographed using a silica gel column and eluted with a hexane: acetone acetic acid mixture in a 70: 30: 1 ratio as zlyant.
The first fraction gives 3 (R) -f7-tert-butoxycarbonylamino-1 (S) -ethoxycarbonylheptyl amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-acetic acid in the form of colorless oil. The second fraction gives 3 (K) tert-butoxycarbonylamino-1 (R) -ethoxycarbonylheptyl amino-4-oxo-2,3,4, 5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless oils.
A solution of 3 (K) - 7-tert-butoxycarbonylamino-1 (8) -ethoxycarbonylheptyl amino-4-oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepine-5-acetic acid obtained from the first fraction, in solution, hydrogen chloride - ethyl acetate (5N, 5 ml) stand for 1 hour at room temperature. A mixture of ethyl ether and petroleum ether (2: 1; 50 ml) is added to this solution, and the mixture is thoroughly mixed. The supernatant was removed by decantation, and the precipitate was recovered and dried under reduced pressure, yielding 3 (K) -7-amino-1 (5) -ethoxycarbonylheptyl1 amino-4-OXO-2,3,4,5 dichlorohydrate -tetrahydro-1,5-benzothiazepine-5-acetic acid (0.2 g) as a colorless powder.
O. - 122 ° (, 2 in methanol).
A solution of 3 (K) - 7-tert-butoxycarbonylamino-1 (R) -ethoxycarbonylhepamino-4-oxo-2, 3,4,5-tetrahydro ro-1,5-benzothiazepine-5-acetic acid, obtained from the second fraction, in solution, hydrogen chloride - ethyl acetate (5N, 5 ml) stand for 1 hour at room temperature.
A mixture of ethyl ether and petroleum ether (2: 1; 50 ml) is added to this solution and the resulting mixture is thoroughly mixed. The supernatant is removed by decantation and the precipitated precipitate is recovered and dried under reduced pressure.
17
whereby dichlorohydrate 3 (R) is obtained | 7-amino-1 (K) -ethoxy-carbonylheptyl amino-4-oxo-2.3.4.5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.18 g) as a colorless powder.
oi JJ- 136 ° (, 6, in methanol).
PRI me R 38. A solution of 3 (K) -7-amino-1 (8) -ethoxy-carbonylheptyl amino-4-oxo-2, 3, A, 5-tetrahydro-1,5-benzothiazepine dichlorohydrate -5-acetic acid (0.16 g) obtained in Example 37 and 1N. sodium hydroxide (4 ml) lasts 30 minutes at room temperature. After adding acetic acid (2 ml) and water (5 ml), the mixture is subjected to chromatographic column treatment using Amberli te XAD-2, eluting with methanol-water (1: 1). The eluate is concentrated under reduced pressure and lyo it is lysed, resulting in 3 (R) -7-amino-1 (3) -carboxy-heptyl amino-4-oxo-2,3,4,5-tetrahyd ro-1,5-benzothiazepine-5-acetic acid (0.11 g) as a colorless powder.
U-1 to 1A8 (, 6, in methanol).
Example 39. A solution of tert-butyl-3 (R) -1 10-tert-butoxycarbonyl but-1 (5) -ethoxycarbonyldecyl-amino-4-OXO-2,3,4,5-tetrahydro-1,5-ben - zothiazepine-5-acetate (0.3 g) in a solution of hydrogen chloride - ethyl acetate (5 and 10 ml) is held for 3 hours at room temperature, and then a mixture of ether and petroleum ether is added. After thorough mixing, the supernatant is decanted. The precipitate formed is dried under reduced pressure to give 3 (R) amino-1 (S) -ethoxycarbonyldecyl amino 4-OXO-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride (0 , 23 g) in the form of a colorless powder.
ot3j) 116 (, 1, in methanol).
Example 40. A solution of 3 (R) amino-1 (5) -ethoxycarboxyld ethyl amine-NO-4-OXO-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.28 g ), obtained in example 39, in 1 n. Sodium hydroxide (7 ml) is incubated for 1 hour at room temperature. After adding acetic acid (2 ml) and water (5 ml), the mixture is subjected to chromatography in
ten

-jr -jQ 25

55 658318
On Amberlite XAD-2 (methanol: in-). The eluate is concentrated under reduced pressure. The precipitated crystals are collected by filtration and dried to give 3 (R) -10-amino-1 (S) -carboxidecyl amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid. acids (0.12 g). , 1 ° ЕЕ 151 (, 1 in methanol - water (1: 1)).
Example41. VUOum acetonitrile dissolved 2.0 g of tert-butyl-3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-acetate and 3.0 g ethyl 2-bromo-9-phthalimidononoate. 0.85 g of triethylamine is added to the solution. The mixture is heated at 90 ° C for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The resulting oily substance is separated and purified by chromatography on a column of silica gel (hexin: ethyl acetate 3: 1–2: 1), which gives from the first fraction 0.9 g of tert-butyl-3 (R) (R) -ethoxycarbynyl- 8-phthalimidodoctyl amino-4-oxo-2,3,4,5-tetra-hydro-1,5-benzothiazepine-5-acetate in
a form of colorless oil.
/ max -
1740, 1710, 1680 ().
oi-jp-111 (in methanol).
Mass spectrum (m / e): 637 (M).
From the second fraction, 1.1 g of tert-butyl-3 (R) (8) -ethoxycarbonyl-8-phthalimido-octyl amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzotazepin-5- Acetate is obtained as a colorless oil.
. cm-: 3330 (NH), 1770, 1735, 1710, 1665 ().
117 (in methanol).
Mass spectrum (m / e): 637 (M).
Example 42. 5 np 5 n. a solution of hydrogen chloride in ethyl acetate is dissolved 0.12 g of tert-butyl-3 (R) -1 (S) -ethoxycarbonyl- (3-phthalimidooctyl amino-4-oxo-2,3,4,5-tet - rahidro-1,5-benzothiazepin-5-acetate and the solution is left to stand at room temperature for 3 hours. Petroleum ether (70 ml) is added to the solution, the precipitated is dried under reduced pressure, which gives 0.10 g of hydrochloride 3 (R) (W) -ethoxycarbonyl-8-phthalimido-octi .: amiko30
. 3340 (NH), 1775,
40
45
4-OXO-2,3,4,5-tetrahydro-1 5-benzothiazepine-5-acetic acid as a colorless powder.
oi J .J.J.- 108 ° (in methanol). C 58.29; H 5,
Calculated: N 6,8Q.
Found: N 6.60.
Example
HC1. C, 57.98;
, 87;
H 5.90;
43. In 10 ml of 5 N. solution of hydrogen chloride in ethyl acetate, dissolve 0.72 g of tert-butyl-3 (R) -GB-tert-butoxycarbonylamino-1 (S) -ethoxycarbonyl octylJamino-4-oxo-2,3 , 4,5-tetrahydro-1,5-benzothiazepine-5-acetate and the mixture is left to stand at room temperature. 3.5 To the solution is added 10 ml of ether and the precipitated precipitate is dried under reduced pressure, which gives 0 , 50 g of dihydrochloride 3 (K) - 8-amino-1 (5) -ethis of sicarbonyl octyl amino-4-oxo-2,3,4,5 tetrahydro-1,5-benzothiazepine-5-acetic acid in as colorless powder.
about..r- 125 (in methanol).
Mass spectrum (ha / e): 451 ().
N
N 7.73.
EXAMPLE 44. In a 10% solution of sodium hydroxide, 0.35 g of 3 (R) -8-amino-1 (5) -ethoxycarbonyloctyl 3-amino-4-oxo-2,3,4,5 dihydrochloride is dissolved. -tetrahydro-1,5-benzothiazepine-5-acetic acid and the solution allowed to stand at room temperature for 30 minutes. Acetic acid (2.5 ml) is added to the solution and the mixture is purified by chromatography on a Lgberite XAD-2 column (methanol: water 1: 2). The eluate is concentrated under reduced pressure and lyophilized to give 0.24 g of 3 (K) -B-amino-1 (8) -carboxy-octyl amino-4-oxo-2,3,4,5-tetrahydro-1 , 5-benzothiazepine-5-acetic acid as a colorless powder.
o6.d- 141 ° (in methanol).
SIMS spectrum (m / e): 424 (MN).
Experimental Example 1
The experiment is carried out according to a modification of the method described by Cushraun et al. (Biocheraicde ThurmacoRY, T. 20, p. 1637, 1971.). Using as a nutrient medium
0 5
0
five
0
five
0
five
hippuryl-b-histidyl-b-leucine (HHB), determine the inhibitory activity of ACE in percent inhibition on the amount of hippuric acid obtained by ACE upon administration of the proposed compound. The proposed compound, dissolved in a buffer solution of 0.02-0.5% dimethyl sulfoxide-100 mmol borate-HC1 (pH 8.3, containing 300 mmol sodium chloride), is introduced into 100 µl of ACE (concentration, protein qi 200 mg / ml) and 100 μl of NN h (1.25 mmol).
In this experiment, a borate-I1C1 buffer solution containing 1 dimethyl sulfoxide of the same concentration as the test solution is used as a control. After the solution was boiled at 37 ° C for 1 h, 150 µl of 1N hydrochloric acid was introduced into it to complete the reaction. After the introduction of O, 8 ml of ethyl acetate, the solution is centrifuged at a rotational speed of the centrifuge of 11,500 rpm for 2 minutes. Aliquot 0.5 ml is separated from the ethyl acetate layer and dried at a temperature below 40 ° C in a stream of nitrogen. The residue is thoroughly mixed with 4.5 ml of distilled water, the mixture is subjected to a colorimetric effect at a wavelength of 228 nm.
The test results are presented in Table 6.
Experimental example 2.
The effect of the proposed compounds on the hypertonic activity of angiotensin I is tested on male rats (SpraRuc - Dawley) weighing 300-400 g, which are not limited in drinking water and in food. Rats are anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg / kg) on the eve of the test, a polyethylene tube is inserted into the femoral artery to measure blood pressure and into the femoral vein for injection of angiotensin I and II. These tubes are fixed.
On the test day, the mean blood pressure in the control phase is measured by an electric modometer (MPU model 0.5-290-0-III, manufactured by NEC-TV Sanei, Japan) and recorded by a polygraph (NEC-Sanes type 365 or Hohden type RM-45), then angiotenes are inserted into the femoral vein
21152
ZIN I and angiotensin II with a dose of 300 ng / kg and 100 ng / kg, respectively, to measure the hypertonic effect. 300 ng / kg of the proposed compound are administered intravenously in the form of a saline solution and after 5, 10, 30, 60, 90 and 120 minutes angiotensin I and angiotensin II are re-administered to detect hypertonic reactions. When calculating, the percentage of inhibition of the hypertonic activity of angiotensin I is adjusted for the change over time of the hypertonic reaction under the influence of angiotensin II.
The test results are shown in Table 7.
The anti-hypoinvial effect of the compounds of formula I is caused by the inhibition of the enzyme that converts angiotensin I, while the effect of the known drug methyldopa is determined by the inhibition of the cathelamine biosynthesis or caused by the hypotensive effect of alpha methylnorepinephrine synthesized from methyldone in the central nervous system.
To check the toxicity, the compound of Example 38 was administered orally to 5 doses of 300 mg / kg. After 1 week after administration, all experimental mice were alive, no significant changes were observed.
Thus, the compounds proposed, namely the fused cyclic compounds of the formula (I) and their salts, have an inhibitory effect on the angiotensin converting enzyme, bradykinin, decomposition enzyme (kiminase), etc. in animals, particularly mammals, can be used, for example, to diagnose, prevent disease or treat hypertension and hypertension of the circulatory diseases (
Xi
NHCHCOOC2H5
I
CHjCHj
- HOCB
0
five
0
583
22
example, heart disease, brain apoplexy). The proposed compounds have low toxicity, are well digested, are extremely stable and long lasting effective.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining condensed seven-membered cyclic compounds of general formula A MP
g A-NH.
V-NHCHCOOR, L) SNg-COOH
hydrogen, lower alkyl;
2
and
where R a about t l and
, alkylene, or their salts, in that
Neither formula is performed
interaction of 30
where Y is lower alkoxycarbonyl, with a compound of the general formula
RC Rd
X
/
N-A-CHCOORi Br
where R and A have the indicated meanings; Rg and RJ form a phthalimido group with the adjacent nitrogen atom,; subsequent removal of the phthalimide-1 CYTIC group, hydrolysis of the obtained compound and isolation of the target product in the free form or transfer it to the corresponding salt.
Table
HC1
23
1526583 2
Tabli
noos
-3 NSHSOOC2H5 Y
S 1 kj
(fir Do-in / soon about
I
h) coax Y
about
in @ G: 1 .- (СН,) 4СНСОО (СН,) ЗСНз (сн,), с „,. -... и.о ,, 7.о .., lo ..
ABOUT
about
BP
29
H
are AND- (CH -,) 2CCHOOSgH5CjHj2 RS RS 3320. p Wo, i74o, pi. i670
Oh oh
Vg
30 (g (- (CH2) 6CHCOOCjHgС
ovg
Dream of dynastereomers
Spreadsheets
(W;
.. S l 1 g
LO U °°
) CEPC L1..b
(CH2) jCH3
,
Cjhj
4 R RS 3350,1730,
1710.1670
2 R RS 3400,1740,
1710.1670
6 R RS 3350,1730,
1710.1670
A mixture of diastereoisomers. dg
24 Table2
Table3
1675 1670
6 R RS 3320, 1770, 1730, 1710, 1670
Table4
noos
152658326
Table3
5-h i g
V-NHv COOR N 0. . 2HC1
(CHzln H,
A mixture of diastereomers
26, 27 26, 27 38 38 4А j40
300 300 300 300
100
100
93
100
Table
82 98 96 100 98 98
Table7
99 98 99 99
95 79 90 97
81 70 79 88
61
44 80 77

类似技术:

公开号 | 公开日 | 专利标题

FI68405B|1985-05-31|FRAMEWORK FOR THE PREPARATION OF THERAPEUTIC EQUIPMENT

KR880001326B1|1988-07-25|Substituted acyl derivatives of 1,2,3,4-tetrahydro isoquinoline-3-carboxylic acids

FI73698C|1987-11-09|Process for the preparation of novel pharmaceutically active N-indanylg lycin derivatives.

EP0198898B1|1988-08-24|Dipeptide compounds having pharmaceutical activity and compositions containing them

US4668797A|1987-05-26|Bicyclic aminoacids as intermediates and processes for their preparation

KR850000303B1|1985-03-18|Process for preparing octahydro-1h-indole-2-carboxylic acid derivatives

US4584294A|1986-04-22|Fused tricyclic lactams as angiotensin converting enzyme inhibitors and as antihypertensive agents

DE2753824A1|1978-06-08|MERCAPTOACYLAMINO ACID DERIVATIVES AND THEIR SALTS, PROCESS FOR THEIR PRODUCTION AND USE IN THE COMBINATION OF ANGIOTENSIN CONDITIONED HIGH PRESSURE

EP0046291B1|1985-12-27|Substituted caprolactam derivatives as antihypertensives, process for preparing them, pharmaceutical composition containing them, and intermediates

KR100694528B1|2007-03-13|A process for the preparation of perindopril, and salts thereof using 2,5-dioxo-oxazolidine intermediate compounds

US4154937A|1979-05-15|Hydroxycarbamoylalkylacylpipecolic acid compounds

KR940009528B1|1994-10-14|Process for preparing heterocyclic compound

CH645092A5|1984-09-14|MERCAPTOACYL PEPTIDES AND MEDICINAL PRODUCTS CONTAINING THEM.

SU1526583A3|1989-11-30|Method of producing condensed heptacomposed cyclic compounds

US4296033A|1981-10-20|4-Azido-1-mercaptoacyl proline

DE69634955T2|2006-05-24|Tripeptidylpeptidase INHIBITORS

EP0046289B1|1985-11-27|Substituted enantholactam derivatives as antihypertensives, a process for preparing and a pharmaceutical composition containing them, and intermediates

EP0110224A2|1984-06-13|Benzoylthio compounds, their manufacture and use as medicines

US4629787A|1986-12-16|Substituted caprolactam derivatives as antihypertensives

EP0065301A1|1982-11-24|Isoquinoline carboxylic acid derivates, process for preparing and pharmaceutical composition containing the same

CA1187870A|1985-05-28|Tripeptide inhibitors of angiotensin-convertingenzyme

JPH09500113A|1997-01-07|Antihypertensive tricyclic azepine derivatives useful as enkephalinase and ACE inhibitors

EP0059966B1|1986-08-13|Substituted thiazolidine carboxylic acid analogs and derivatives as antihypertensives

EP0080283A1|1983-06-01|N-carboxyalkylproline-containing tripeptides

DE3222779C2|1991-01-03|

同族专利:

公开号 | 公开日

WO1984004306A1|1984-11-08|

AR244217A1|1993-10-29|

DK196884D0|1984-04-17|

ZA842926B|1984-12-24|

JPH0564144B2|1993-09-14|

JPS59205372A|1984-11-20|

DK196884A|1984-10-23|

引用文献:

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US4460579A|1983-02-28|1984-07-17|E. R. Squibb & Sons, Inc.|Thiazine and thiazepine containing compounds|JPS608283A|1983-06-29|1985-01-17|Mitsui Toatsu Chem Inc|Benzothiazepine derivative and its preparation|

US4692522A|1985-04-01|1987-09-08|Merck & Co., Inc.|Benzofused lactams useful as cholecystokinin antagonists|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

PCT/JP1983/000127|WO1984004306A1|1983-04-22|1983-04-22|Fused 7-membered ring compounds and process for their preparation|

[返回顶部]