Method of producing derivatives of thiolactam-n-acetic acid or their salts with alkali metals

专利摘要:
Compounds of the general formula: <CHEM> (wherein, R<1> and R<2> are, the same or different, hydrogen, a halogen, a lower alkyl, a cycloalkyl, a lower alkoxy, a phenylalkyloxy, or trifluoromethyl; R<3> is hydrogen or methyl; R<4> is carboxyl or an esterified carboxyl; and X is oxygen or sulfur), or a salt thereof, are novel compounds, possess aldose reductase inhibitory and platelet aggregation innibitory activities, and of use as drugs for prevention and treatment of diabetic complications such as diabetic cataract, retinophathy, nephropathy, and neuropathy.
公开号:SU1538895A3
申请号:SU874202416
申请日:1987-04-16
公开日:1990-01-23
发明作者:Мегуро Кандзи；Икеда Хитоси；Ямамото Юдзиро
申请人:Такеда Кемикал Индастриз Лтд (Фирма)；Сендзю Фармасьютикал Ко. Лтд (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new thiolacam-K-acetic acid derivatives or their salts with alkali metals, which have a high aldose reductase inhibitory and aggregation activity.
platelet and can be used in medicine.
The aim of the invention is the creation of new compounds in a series of thiolactam-M-acetic acid derivatives exhibiting increased activity.

O4
inhibition of aldose reductase and platelet aggregation
They are prepared by alkaline hydrolysis of the corresponding thiolactam ester of N-acetic acid in a solvent, such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, dioxane, tetrahydrofuran, dimethotoethane, acetonitrile or acetone at 10-60 ° C followed, if necessary, by treating the reaction mixture with a mineral or carboxylic acid to isolate the target product in free form or in the form of its | 5 diluted with water, acidified with 2N.
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35
salts with alkali metal.
Example 1. Preparation of 3, di-hydro-2-isopropyl-3 thioxo-2H-1, t-β-benzoxazin-i-y cyclic acid.
(1) To a solution of 2-isopropyl 2H-1, k-benzoxazin-3 (H) -one (19.1 g) in I, M-dimethylformamide (200 ml) was added sodium hydride (60% in oil 4 , 0 g) and stirred at room temperature for 30 minutes and a solution of methyl bromoacetic acid ester (10 ml) in NjN-dimethylformamide is added dropwise to the reaction mixture.
(200 ml) with ice cooling. After stirring under ice cooling for an hour, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and evaporated to dryness. The methyl ester of 3, - dihydro-2- -isopropyl-3 oxo 2H-1,4-benzoxazine- - t-y-cyclic acid is obtained in the form of an oil. Yield 26.0 g (98.9%).
(2) A mixture of hydro-2-isopropyl-3-oxo-2H-1,4-benzoxazin-4 acetic acid methyl ester (26.0 g), phosphorus pentasulfide (, g) and toluene (250 ml) are heated under reflux for 3 hours. After cooling, the insoluble material is filtered off and the solvent is evaporated. Isopropyl ether (200 ml) is added to the residue and the insoluble material is removed by filtration. The solvent is evaporated, hexane is added to the residue and crystals of methyl dihydro-2-isopropyl 3-thioxo-2H-194-benzoxazin-4 ™ acetic are obtained
acid.
hydrochloric acid and extract with ethyl acetate. The extract is washed with water, dried (magnesium sulphate) and the solvent is evaporated. hexane was added to the residue and 3, -dihydro-2-isopropyl-3-TIOXO-2H-1,4-benzoxazine A-acetic acid crystals were obtained.
The yield is 12.6. G (79.2%). By recrystallization from a mixture of isopropyl hexane, yellow prisms are obtained (melting point 99-100 ° C). Output 11.2 g (70.6%).
Found,%: C 58.85; H 5.69; N 5
C | 3 fl
Calculated,%: C 58.85, H 5.60 / N 5.28.
Example 2. Preparation of 6-phto 3 DIhydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in Example 1, from the starting compound 6-ft -2-isopropyl-2H-1, benzoxazin-3 (H) -one, 6-fluoro 3, -dihydro-2-isopropyl-3 α-thioxo-2H-1, -ben oxazine-α-oxus yU acid as light yellow prisms (recrystallization from isopropyl ether hexane), mp 132 133 ° C.
Total yield 60.0%.
Found,%: C 55J3J N C, 98; N4,
Cl} H14FN03S
, Calculated,%: C 55, Hj H, 98; 50 N ..
Example 3 ° Preparation of 8-chloro-35A-dihydro 2-isopropyl-3-thioxo-2H-1,4-benzoxazine-acetic acid.
40
45
Yield: 22.5 g (80 6%). By recrystallization by 55 lysis from isopropyl alcohol, yellow prisms are obtained (melting point 60-61 ° C).
Found 3: C, 59.98; H 6.18; N4.96.
C) 4HnNO S
Calculated: С6QJ9; H6.13; N 5.01.
(3) To a solution of methyl ester of 3, -dihydro-2-isopropyl-3-thioxo-2H-1, -benzoxazine-acetic acid (16.7 g) in methanol-dioxane (2: 3, 150 ml) 2 n is added dropwise. sodium hydroxide (60 ml) for 10 minutes with stirring. After completing the addition, stirring is continued for another 15 minutes, then the mixture
0
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hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried (magnesium sulphate) and the solvent is evaporated. Hexane was added to the residue to give 3, -dihydro-2-isopropyl-3-TIOXO-2H-1,4-benzoxazine A-acetic acid crystals.
The yield is 12.6. G (79.2%). The recrystallization of isopropyl ether-hexane from the mixture yields yellow prisms (melting point 99-100 ° C). The yield of 11.2 g (70.6%).
Found,%: C 58.85; H 5.69; N 5.30.
C | 3 fl
Calculated,%: C 58.85, H 5.60 / N 5.28.
Example 2. Preparation of 6-fluoro-3 DIhydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in Example 1, from the starting compound 6-fluoro-2-isopropyl-2H-1, -benzoxazin-3 (H) -one, 6-fluoro 3, -dihydro- is obtained. ro-2-isopropyl-3-thioxo-2H-1, -benzoxazin-α-axus UY acid as light yellow prisms (recrystallization from isopropyl ether-hexane), melting point 132-133 ° C.
Total yield 60.0%.
Found,%: C 55J3J N C, 98; N4.95.
Cl} H14FN03S
, Calculated,%: C 55, Hj H, 98; 0 N ..
Example 3 ° Preparation of 8-chloro-35A-dihydro 2-isopropyl-3-thioxo-2H-1,4-benzoxazine-acetic acid.
In the same manner as in Example 1, from the starting compound 8-chloro | -Zr yyhydro-2-isopropyl-2H-1, -benzoxazin 3 (H) -one gives 8-chloro
five
-3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid as light yellow prisms (recrystallization from isopropyl ether-hexane), melt temperature 15
Leni 144-145 ° C, Found: C
N
C ,, H, 4ClNOj Calculated,: 4.67. Example
Total yield 69.5. 52.40; H 4.6 {N 4.6
C 52.09 {H 4.71,
4. Preparation of 8-fluoro-3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in Example 1, 8-fluoro-3,4-dihydro-2- is obtained from the starting compound 8-fluoro-2- -isopropyl-2H-1,4-benzoxazin-3 (4H)--one -isopropyl-3-thioxo-2H-1, 4-benzox-31 -4-acetic acid as light yellow prisms (recrystallized from isopropyl ether-hexane), melting point 125-127 ° C. Total yield 70.7%.
Found: C 55.36; H 5.05; N4.96
C hUFNO S
Calculated; C 55.11, H 4.98; N 4.94.
Example 5. Preparation of 3,4-di-hydro-2-isopropyl-8-methoxy-3 thiox-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in example 1, from the starting compound 2-isopropyl-8-methoxy-2H-1,4-benzoxazin-3 (4H) -one, 3 4-dihydro-2-isopropyl-8 -methoxy-3-thioxo-2H-1,4-benzoxazin-4-acetic acid as light yellow prisms (recrystallized from isopropyl ether), melting point 159-1 ° C. Overall yield 69.9%.
Found: C, 56.99; H 5.83; N4,73
Sc
Calculated: C 56.93; H 5.80; N 4.74.
Example. 6. Preparation of 3,4-di-hydro-2-yopropyl-8-methyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in Example 1, 3,4-dihydro-2-isopropyl is obtained from the starting compound 2-isopropyl-8-methyl-2H-1,4-benzoxazin-3 (4H) - -one -8-methyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid as yellow needles (by recrystallization from isopropyl ether-hexane), temperature 538895
63,
ten
- e - - about 20
Melting point 148-149 ° С 71.7%.
Found: C
C (4 H p N0.3 Calculated, N 5.01.
Example
Common and exit
bo, zo; n 6.18; N5.01, C 60.19 / n, 6.13;
7. Preparation of 3,4-di-hydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid.
In the same manner as in Example 1, 3,4-dihydro-2,8-diiso-15 propyl is obtained from the starting compound 2,8-diisopropyl-2H-1,4-benzoxazin-3 (4H) -one. -3 thioxo-2H-1,4-benzoxazine-4-acetic acid as yellow prisms (recrystallized from isopropyl ether-hexane), melting point 128-129 ° C. Total yield 68.2.
Found: C 57.11; H 5.98, N4.71.
five
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С14Н „Н048 Calculated: С N 4.74.
56.93; H 5.80,
Example 8. Obtaining 3,4-β-dihydro-2-isopropyl-3 thioxo-2H-1,4-β-benzthiazine-4-acetic acid.
(1) A solution of 2-isopropyl-2H-1,4-benzthiazin-3 (4H) -one (62.1 g) in
QM, N-dimethylformamide (150 ml) was added dropwise to a stirred suspension of sodium hydride (60 in oil, 12.0 g) in S, M-dimethylformamide (180 ml). The mixture is stirred for 30 minutes and a solution of bromoacetic acid methyl ester (30 ml) in S, N-dimethylformamide (60 ml) is added dropwise to it under ice cooling. The mixture is stirred for one more hour under ice cooling, poured into 1 liter of ice water and extracted with ethyl acetate. The ethyl acetate layer is washed, dried (MgSCb) and concentrated. The residue is crystallized from hexane and 3-4-dihydro-2-isopropyl-3-OXO-2H-1,4-benzthiazine-4-acetic acid methyl ester is obtained in the form of crystals. The yield was 60.3 (72.0). By recrystallization from 2-propanol-hexane mixture, colorless prisms are obtained, melting point 81-82 ° C.
Found: C 60.30, H 6.13, p N 5.04.
CHH17N ° iS
Calculated: C 60.19, H 6.13, N 5.01.
(2) A mixture of methyl ester of 3,4-di-hydro-2-isopropyl-3-oxo-2H-1,4-benzothiazon-4-acetic acid (50 g), toluene (450 ml) and pentasulfide phos5
7153889
Handicap (79.5 g) is heated under reflux for 5.5 hours with stirring. After cooling, the insoluble matter was removed by filtration, and the solvent was evaporated. Isopropyl ether (300 ml) is added to the residue and the insoluble material is removed by filtration. The filtrate is concentrated, and the residue is crystallized from 2-propanol, yielding 3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzthiazine-A-acetic acid methyl ester as crystals. Yield 27.0 g (51.0%). Recrystallization from 2-propanol yields yellow prisms, melting point 9 9-100 C.
Found: - / ;: C 57.05 / H 5.87 N 4.73,
SKN NO ± S
Calculated: C 56.92; H 5.80 N 4.74.
(3) Methyl ester 354-dihydro-2-isopropyl-3-thioxo-2H-I, 4-benzothiazine-4-acetic acid is dissolved in a methanol dioxane mixture (in a ratio of 1: 2 by volume, 210 ml) and 2N was added dropwise to the solution. sodium hydroxide (70 ml) with stirring. The mixture was stirred at room temperature for another 2 hours, diluted with water and acidified with hydrochloric acid. The crystalline precipitate is collected by filtration, recrystallized from 2-propanol-water and 3,4-dihydro-2-isopropyl-3 ty- OKCO-2H-I, 4-benzthiazine-4-acetic acid is obtained in the form of yellow prisms. Yield: 18.0 g (91.5), melting point: 175 ° C.
Found,% -. C 55.63, H 5.43; N 4.9
C, bH, 5NO "S05
Calculated,%: C 55.45; H 5.37; N 4.98.
Example 9. Obtaining 8-chloro-3,4-dihydro-2-isopropyl-3 thioxo-2H-1,4-benzthiazine-4-acetic acid
In the same manner as in Example 8, from the starting compound 8-chloro-2-isopropyl-2H-1,4-benzthiazine-3 (4H) -one, 8-chloro 3,4-dihydro-2-isopropyl is obtained. 3-thioxo-2H-1,4-benzthiaine-4-acetic acid as yellow prisms (recrystallization from ethanol-water mixture). Total yield 63.5%.
Found: C 49.50; H 4.75; N 494
C., Hrt ClNO.S
Calculated: C 49, H 4.47 N 4.43.

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Example 10. Preparation of 3,4-dihydro-2- (1-methylpropyl) -3-thioxo-2H-1,4-benzthiazine-4-acetic acid.
In the same way as in example 8, from the starting compound 2- (1- -methylpropyl) -2H-1,4-benzthiazine-3 (4H) -one (a mixture of diastereomers in the ratio 1: 1, 3, - Dihydro-2- (1- -methylpropyl) -3 thioxo-2H-1,4-benzthiazine-A-acetic acid (diastereomer mixture, 1: 1) as yellow prisms (by recrystallization from isopropyl ether-hexane ), melting point 137 1380 C. Total yield 43.9%.
Found: C 57.08; H 5.99, N4.70.
C (4Ht7NCX, S,
Calculated,%; C 56.92; H 5.80; N 4.7.
Example 11 Preparation of 8-ethoxy-3,4-dihydro-2-isopropyl-3-thioxo-2H-1,4-benzoxaine-4-acetic acid.
In the same manner as in Example 1, from the starting compound 8-ethoxy-2-isopropyl-2H-1,4-benzoxazin-3 (4n) -one, 8-ethoxy-3,4-di-hydro -2-Isopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid as yellow prisms (recrystallization from isopropyl ether-hexane). Melting point 138-139 ° C.
Overall yield 72.4%.
Found: C, 58.45; H 6.23, N4.59.
C, 5H19N04S
Calculated,% C 58.23; H 6.19, N 4.53.
Example 12. Preparation of 8-ethyl-3,4-dihydro-2-isopropyl-3-thioxo--1,4-benzoxazin-4-acetic acid.
In the same manner as in Example 1, from the starting compound 8-ethyl--2-isopropyl-2H-1,4-benzoxazin-3 (4H) -one, 8-ethyl-3,4-dihydro-2- - IZOPROPIL-3-TIOXO-2H-1,4-benzoxazin-4-acetic acid as yellow prisms (by recrystallization from isopropyl ether-hexane).
Melting point 117-118 ° C.
The overall yield was 73.1%.
Found, $: C 61.55, H 6.55; N4.81.
C, 5H N0.8
calculated,%: C 61.41; H 6.53, n4.77.
Example 13. Preparation of 3, DI-hydro-2- (1-methylpropyl) -3 thioxo-2H--1,4 benzoxazin-4-acetic acid.
In the same manner as in Example 1, from the starting compound 2- (1-methylprolyl) -2H-1,4-benzoxazin-3 (4H) -one (mixture of diastereoisomers in the ratio 1: 1), 3 4 -dihydro-2- - (1-methylpropyl) -3 thioxo-2H-1, 4-benzoxazin-4-acetic acid (mixture of diastereomers 1: 1) in the form of yellow prisms
In the same way as in re 1, from the starting compound 2-and propyl-6-methoxy-2H-1,4-benzox-3 (4H) -one, 3,4-dihydro-isopropyl-6-methoxy- 3 thioxo-2H-benzoxazin-4-acetic acid de yellow prisms (recrystallized from a mixture of isopropyl sir-hexa
(by recrystallization from isopropyl-JQ mixture, melting point 140-141 ° C.
purple ether-hexane), melting point
Yield 44.8%.
Example 14. Obtaining hydro-2-isopropyl-6-methyl-3 thioxo-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in example 1, from the starting compound 2-isopropyl-6-methyl 2H-1,4-benzoxazin-3 (4H) -one, 3 4-dihydro-2-isopropyl-6-methyl -3 thioxo-2H-1,4-benzoxazin-4 acetic acid as yellow prisms (recrystallization from isopropyl ether-hexane), melting point 144-145 ° C.
Overall yield 76j7%.
Example 15. Obtaining 3 4-di-hydro-2-isopropyl 7 methyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid.
In the same way as in example 1, from the starting compound 2-isopropyl-7 methyl-2H-1,4-benzoxazin-3 (4H) -one, 3 4-dihydro 2-isopropyl-7-methyl -3-thioxo-2H 1,4-benzoxazine-4-acetic acid as yellow prisms (recrystallization from isopropyl ether-hexane), melting point 146-147 ° C.
Overall yield 72.2%.
Example 16. Obtaining 7 Fluoro-3,4 dihydro-2-isopropyl-3-thioxo-2M- -1, C-benzoxazin-4-acetic acid.
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25
thirty
Total output 77,
Example 18. Obtaining 8-t-butyl-3, -dihydro-2-isopropyl-3ОКСО-2Н-1, 4-benzoxazin-4-acetic acid.
In the same way as in re 1, from the starting compound 8-t-butyl-2-isopropyl-2H-1,4-benzox-zin-3 (H) -one, 8-tert-butyl 20 3, -dihydro -2-Isopropyl-3-thioxo -1, -benzoxazine-A-acetic acid in the form of light yellow prisms (by recrystallization from isopropyl eff), melting point 188-18
Overall yield 68.9%.
Example 19. Preparation of 8-c loghexyl-3, -dihydro-2-isopropyl-thioxo-2H-1, -benzox ay n-k-uxoic acid.
In the same way as in re 1, 8-cyclohexyl-3H-1-benzoxazine-3 (H) -one is prepared from 8-c-letoxyl 3, -Dihydro-2-isopropyl-2H-1, -benzoxy-3 dihydro-2-isopropyl-3 thioxo-2H-1, k-benzo-zin-acetic acid in the form of light yellow prisms (recrystallized from ethanol). The temperature melted at 16 -165 ° C. /
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Total yield 81.7%.
Example 20. A mixture of 3,4-digo-2,8-diisopropyl-3-thioxo-2H-1, -benzoxazin-4-acetic acid (6.14 g), (3) -moleic acid methyl ester (8 , 32 g), 4-dimethyl nopyridine (1.22 g), dicyclohexy carbodiimide (4.9 g) and dichlorome (80 ml) are stirred at room temperature for 18 hours. The precipitate is filtered off and the filtrate is concentrated. Chromatograph the chromatography on silica gel (400 g) using hexane-ethyl ether as the eluant (in the ratio 95i5 by volume
35
In the same way as in example 1, from the starting compound 7 Fluoro-2-and zopropyl-2H-1, h-benzox zi-3 (H) - it gives 7 fluoro-3, -dihydro-2-isopropyl -3 ° thioxo-2H-1,4-benzoxazine-acetic acid in the form of yellow 50 prisms (recrystallization from isopropyl ether-hexane), melting point 113-H4BC.
Exit 62, k%.
Example 20. A mixture of 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid (6.14 g), (3) -methyl lactic ester (8.32 g), 4-dimethylaminopiridine (1.22 g), dicyclohexyl-carbodiimide (4.9 g) and dichloromethane (80 ml) are stirred at room temperature for 18 hours. The precipitate is filtered off and the filtrate is concentrated. The residue is chromatographed on silica gel (400 g) using hexane-ethyl ether (e.g., 95 to 5 by volume) as eluent.
Example 17: Preparation 4, and two compounds are obtained: (3) -methi-Thydro-2-isopropyl-6-methoxy-3-thiox-CO-2H-1,4-benzoxazin-4-acetic acid.
a new ester of 2-R (R) -3,4-dihydro-2,8-di-isopropyl-3-thioxo-2H-1,4-benzoxazin-4-yl acetoxypropionic acid
In the same manner as in Example 1, from the starting compound 2-isopropyl-6-methoxy-2H-1,4-benzoxazin-3 (4H) -one, 3,4-dihydro-2-isopropyl-6- methoxy-3 thioxo-2H-1,4-benzoxazin-4-acetic acid as yellow prisms (recrystallization from isopropyl ether-hexane),
 melting point 140-141 ° C.
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Total output 77,
Example 18. Preparation of 8-tert.-butyl-3, -dihydro-2-isopropyl-3-β-OXO-2H-1,4-benzoxazin-4-acetic acid.
In the same manner as in Example 1, from the starting compound 8-tert-butyl-2-isopropyl-2H-1,4-benzoxazine-3 (H) -one, 8-tert-butyl 0 3, - Dihydro-2-isopropyl-3-thioxo-2H- -1, benzoxazine-A-acetic acid as light yellow prisms (recrystallization from isopropyl ether), melting point 188-189 ° C,
Overall yield 68.9%.
Example 19. Preparation of 8-cyclohexyl-3, -dihydro-2-isopropyl-3-thioxo-2H-1, -benzox hey n-k-acetic acid.
In the same way as in example 1, from the starting compound 8-cyclohexyl 3, -dihydro-2-isopropyl-2H-1, -benzoxazin-3 (H) -one, 8-cyclohexyl-3, -dihydro -2- Isopropyl-3-thioxo-2H-1, k-benzoxazine-acetic acid as light yellow prisms (by recrystallization from ethanol). Melting point 16 -165 ° C. /
0
Total yield 81.7%.
Example 20. A mixture of 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid (6.14 g), (3) -methyl lactic ester (8.32 g), 4-dimethylaminopiridine (1.22 g), dicyclohexyl-carbodiimide (4.9 g) and dichloromethane (80 ml) are stirred at room temperature for 18 hours. The precipitate is filtered off and the filtrate is concentrated. The residue is chromatographed on silica gel (400 g) using hexane-ethyl ether (e.g., 95 to 5 by volume) as eluent.
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 and two compounds are prepared: (3) -methine ester 2-Ј (R) -3,4-dihydro-2,8-di-isopropyl-3-thioxo-2H-1,4-benzoxazin-4-yl acetoxypropionic acid
in the form of oil,
11 exit
1538895
1.55 g +
ten
20
25
b1,2 ° (c 0.35, methanol). D
Nuclear Magnetic Resonance Spectrum (SDS1) S: 0.97 (3N, I 7.5 Hz), 1.07 (3N, d, 5 Hz) 1.20 (3N, d 5 Hz), 1.27 ( ZN, d, 5 Hz), 1.55 (ZN, d., 5 Hz), 2.35 (1H, sextet, 5 Hz), 3.43 (1H, quintet, 5 Hz), 3 , 77 (ZN, s),, 73 OH, d, Hz), 4.87 (1H, d, 5 Hz), 5.23 (1H, apt.,, 5 Hz), 5.93 (1H, d, Hz), 6.71-7.08 (3N, multiplet) and (S) -methyl ester 2- (3) -3,4-dihydro-2,8-diisopropyl-3- -TIOXO-2H- 1-, 4-benzoxazin-4-yl ace-
toxipropionic acid in the form of a masa. The output of 1.2 g leUj1-5- 78 ° (4, methanol).
Nuclear Magnetic Resonance Spectrum (SDS1) (: 0.98 (3N, d, 5 Hz), 1.05 (3N, d, 5 Hz), 1.18 (3N, d, 5 Hz), 1.30 ( ZN, d, 5 Hz), 1.48 (ZN, d, 5 Hz), 2.45 (1H, sextet, 5 Hz), 3.25- 3.58 (1H, m), 3, 73 (MN, s), 4.7 (1H, d, 5 Hz), 5.00 (1H, d, Hz), 5.18 (1H, apt., 5 Hz), 5.60 (1I , d, Hz), 6.73-7.05 (ЗН, m).
Example 21. Preparation of (R) - (+) - 3,4-dihydro-2,8-diisopropyl-3-TIOXO-2H-1,4-benzoxazin-4-acetic acid.
A stirred solution of (S) -methyl ester of 2- (K) -3,4-dihydro-2,8- -diisopropyl-3-thioxo-2H-1,4-bemcoxazin-4-yl1-acetoxypropionic acid in a mixture of dioxane (10 ml) and methanol (10 ml) are treated with 2N. sodium hydroxide (10 ml) at room temperature for 30 minutes. The mixture is acidified with hydrochloric acid, diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over magnesium sulfate and concentrated. The residue is treated with hexane and 0.12 g of crystals (1) of 3 4-dihydro 2,8-diiso-propyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid are obtained, which is formed as a result of the weak racemization of the product. The mother liquor is concentrated and the residue is dissolved in hexane. If the solution is kept, then (K) - (+) - 3,4-dihydro-2,8 Diiso propyl-3-thioxo-2H-1,4-benzoxazine is obtained - -4-acetic acid in the form of crystals (0.55 g), melting point 110 ° C
f h (pl
35
40
55
11GS, nol).
f
107.2 (with 0.45, meta30 n (n 1 (
50
12
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Found: C 62,79; H 6.99; N4,52,
Calculated,%: C 62.51, H 6.89, N 4.56.
Example 22. Preparation of (S) - (-), 4-dihydro-2,8-diisopropyl-3-thio-CO-2H-1,4-benzoxazine-4-acetic acid.
(3) -methyl ester 2- (S) -3,4-dihydro-2,8-diisopropyl-3-thioxo 2H-1,4-benzoxazin-C-yl acetoxypropionic acid (1.1 g) hydrolyzed are treated and treated in the same manner as in Example 21, and (8) - (-) - 3,4-dihydro-2,8-diisopropyl-3-TIOXO-2H-1,4-benzoxazin-4 is obtained α-acetic acid (0.53 g), melting point 109-110 ° C. / o -105a (p. 0.48, methanol).
Found,% C 62.86; H 6.935 N4.55,
C 6H2iN03S
Calculated,%: C 62.51, H 6.89, N 4.56.
Example
five
0
five
23. Preparation of (S) - - (-) - 3,4-dihydro-2,8-diisopropyl-3 -TIOXO-2H-1,4-benzoxazin-4-acetic acid.
(1) To a solution of (5) -2,8-diisopropyl-2H-1,4-benzoxazine 3- (4H) -one (4.66 g) in dimethylformamide (60 ml) 60 parts % sodium hydride in oil (0.84 g). The mixture was stirred at room temperature for 10 minutes and a solution of bromoacetic acid methyl ester (2.0 ml) in dimethylformamide (6.0 ml) was added to it. The reaction mixture is stirred at room temperature for 30 minutes, diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried (magnesium sulfate) and concentrated. The residue is crystallized from hexane and 3 (3) dihydro-2,8-di-isopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid (S) -methyl ester is obtained in the form of crystals (4.95 d). Recrystallization from hexane gives colorless needles, those0
melting point 67-68 ° C +
R
D
+ 3 °, 7 ° (from 0.95, methanol).
Found,%: C, 66.90; H 7.69; N4,56,
Ct H2iN04
Calculated,%: C, 66.86; H 7.59; N 4.59.
(2) A mixture of (3) -methyl 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazin-4-acetic acid (3.05 g), 2,4- Bis (methylthio) -1, 3,2,4-dithiadiphosphetan-2,4-bisulfide (Devi methyl reagent) (2.84 g) and toluene (60 ml) are stirred at 50 ° C for 6k hours. Insoluble the substance is filtered off and the filtrate is concentrated. The residue is purified by chromatography on a silica gel column (100 g) using hexane-ethyl ether (ratio 85:15 by volume) as the mobile phase and 3,4-dihydro-2,8-diisopropyl methyl ester is obtained -3- -TIOXO-2H-1,4-benzoxazin-4-acetic
ten
16.5 Hz), 6.87-7.07 (MN, multiplet).
Example 26. 3,4-Dihydro-2,8-diisopropyl-3-thioxo -2H-1,4-benzoxazin-4-acetic acid methyl ester (4.75 g) was hydrolyzed with 2N. NaOH (15.5 ml) under the conditions given in table. 1, to obtain 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1, 4-benzoxazin-4-acetic acid.
The dependence of the yield on the synthesis conditions is given in Table 1.
acids in the form of oil (3.00 g).
(3) The oil obtained in step (2) is dissolved in a mixture of dioxane (9 ml) and methanol (9 ml), and 2N is added to the solution. sodium hydroxide (9.3 ml).
15
The results of biological tests.
one . Inhibition of aldose reductase (in vitro study).
Partially purified aldosoreduk. The mixture was stirred at room temperature — the human placenta was used for 45 minutes, diluted with water, to determine the effect of inhibition, acidified with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried (MgSOjj) and concentrated. The remainder of the 25 cents inhibition is presented
no aldose reductase. The inhibitory activities of each compound at and at 10 M, expressed in terms of processing with hexane, give the racized compound (+) - 3,4-β-dihydro-2,8-diisopropyl-3 thioxo-2H-1,4-benzoxazin-4 α-acetic acid (0.8 g). The mother liquor is concentrated, the residue is crystallized from hexane and (5) - (-) - 3,4-dihydro-2,8-diisopropyl-3 thioxo-2H-1,4-benzoxazin-4 is obtained. α-cyclic acid (1.28 g, 41.7%), melting point 109.
 101.1 ° (c 0.71, methanol).
Example 25. Obtaining the alkali metal salt of the target product.
To a solution of 3,4-dihydro-2,8-diisopropyl-3-TIOXO-2H-1,4-benzoxy of n-4-acetic acid (307 mg) in CH3OH (2.0 ml) is added NaOCH3 (28% in CH3, 1.8 ml), after which the solvent was removed by evaporation. The residue thus obtained was treated with (CrH5) hO to form 3,4-dihydro-2,8-diisopropyl 3-thioxo-2H-1,4-benzoxazin-4-sodium acetate as pale yellow crystals (253 mg,
35
40
45
7b, 9%). Melting point 250-254 ° C.
Nuclear Magnetic Resonance Spectrum (DMSO-o): 0.90 (ZN, Hz), 1.05 (ZN, doublet, 1 6 Hz), 1.13 (ZN, doublet, Hz), 1.22 (ZN, doublet, Hz ), 2.30 (1H, sextet, Hz), 3.33 (1H, quintet, Hz, 4.45 (1H, doublet, 5 Hz), 4.71 (TH, Hz), 5.18 (1H , doublet, I50
55
in tab. 20
2. Inhibition of sorbitol accumulation in tissues in rats with experimentally induced diabetes.
Spraque-Dawley rats were fed on an empty diet for 18 hours (males at the age of weeks, five animals per group), after which they received an injection of 70 mg / kg of streptozocin into the caudal vein under anesthesia with ether and thus received diabetic rats. Immediately after the injection of streptozocin, these rats received orally the test compound at the rate of 50 mg / kg and 30 mg / kg in the form of a 5% suspension of arabic gum twice a day (at 10 am and 5 pm) for two days . At this time, the rats received the CE-2 diet and water on demand. On the third day in the morning (at 9 am) the rats were killed (decapitation and venesection) and the sciatic nerves were immediately isolated, from which sorbitol was extracted. The results are expressed as a percentage of the value for the untreated (control group, taken as 100%, and are shown in Table 2.
As shown in the table. 2, the compounds obtained were equally effective or even somewhat less effective in inhibiting aldose reductase in vitro than the control compounds, but their inhibition
16.5 Hz), 6.87-7.07 (MN, multiplet).
Example 26. 3,4-Dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazin-4-acetic acid methyl ester (4.75 g) is hydrolyzed with 2N. NaOH (15.5 ml) under the conditions given in table. 1, to obtain 3,4-dihydro-2,8-diisopropyl-3-thioxo-2H-1, 4-benzoxazin-4-acetic acid.
The dependence of the yield on the conditions of the synthesis is given in Table 1.
15
 cents of inhibition are presented
no aldose reductase. Inhibitory activities of each compound at and at 10 M, expressed in about 30
35
40
five
0
five
in tab. 20
2. Inhibition of sorbitol accumulation in tissues in rats with experimentally induced diabetes.
Spraque-Dawley rats were fed on an empty diet for 18 hours (males at the age of weeks, five animals per group), after which they received an injection of 70 mg / kg of streptozocin into the caudal vein under anesthesia with ether and thus received diabetic rats. Immediately after the injection of streptozocin, these rats received orally the test compound at the rate of 50 mg / kg and 30 mg / kg in the form of a 5% suspension of arabic gum twice a day (at 10 am and 5 pm) for two days . At this time, the rats received the CE-2 diet and water on demand. On the third day in the morning (at 9 am) the rats were killed (decapitation and venesection) and the sciatic nerves were immediately isolated, from which sorbitol was extracted. The results are expressed as a percentage of the value for the untreated (control group, taken as 100%, and are shown in Table 2.
As shown in the table. 2, the compounds obtained were equally effective or even somewhat less effective in inhibiting aldose reductase in vitro than the control compounds, but their inhibitory activity of sorbitol accumulation in vivo was superior to the inhibitory activity of sorbitol accumulation by control compounds. The distinction becomes particularly apparent when comparing compound 2 with compound A, and compounds 9 and 11 with compounds B and C, which are paired compounds, which have comparable substituents. The treatment of diabetes patients usually requires a long period and therefore it is to be expected that the compounds according to the invention exhibiting a brilliant effect in low doses are useful as medicaments.
3. Inhibitory effect on platelet aggregation.
The effect of 3-dihydro 2.8 diisopropyl 3 thioxo-2H-1, h-benzoxazin-4-acetic acid on platelet aggregation was tested using washed rat blood plates.
(1) Methods.
The blood of the rats was collected in a plastic syringe filled with one tenth of the volume of 3.8% sodium citrate from the abdominal aorta of 6–7 week old samcr of Spraque Dawley rats under general anesthesia. Platelet-rich plasma was obtained by centrifuging the blood at 150 x revolutions for 15 minutes at room temperature. In order to prepare washed platelets, plasma-rich plasma was centrifuged at 1500 Ј rpm for 10 minutes, and the precipitated blood plates were resuspended in Tyrode solution. The number of platelets used in the experiment was 7x10 cells / mm4. Platelet aggregation was measured by a nephelo-geometrical method using an aggregometer (Nikko Bioscience model PAR-4M).
The test compound was dissolved in 10 µl of water and added to 250 µl of a clean platelet suspension and incubated at 37 ° C for three minutes, after which 10 µl of an aggregating agent (5 µL / ml collagen, Nikk Bioscience, or 10 µmol adenosine di-phosphate (ADP) 5 Shigma, Ts Louis, Mo at final concentration). The percentage inhibition of platelet aggregation by the test compound was calculated by dividing the resulting value of aggregate 0
five
0
five
0
five
on the value observed in the control series, and multiplied by 100.
(2) Results.
The test compound inhibited the aggregation of pure platelets, caused either by collagen or adenosine diphosphate, depending on the dose (Table, 3). Its inhibitory effect was stronger than the effect of indomethacin in inhibiting the induced adenosine diphosphate platelet aggregation.
I A study of the inhibitory effect on platelet aggregation is given in Table. 3k. Acute toxicity.
Acute toxicity of 3, -dihydro-2,8-diisopropyl-3 thioxo-2H-1, J} - -benQQasin-ycyctic acid was tested in mice and rats.
(1) Methods.
Different doses of the test of the dynenium compound suspended in 5% gum arabic solution were administered to n% - orally male 1CR mice (aged k weeks) and male Wistar rats (5 weeks old) and mortality was observed for 14 days. Each group consisted of 5 animals.
(2) Results.
The lethal dose of ldeoD for mice i860 mg / kg, for rats 2830 mg / kg.
Thus, the compounds obtained are of low toxicity and have a high activity of inhibiting aldose reductase and platelet aggregation.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of thiolactam-K-acetic acid of the general formula
h
 S
where X is an oxygen or sulfur atom} R, is a hydrogen or halogen atom, C1-C4-alkyl, C, -C2-alkoxy- or cyclohexyl; R, is in the 6- or 7 position of the benzene ring and means a hydrogen atom or halogen, methyl or methoxy, and
17
R, and Lg can not simultaneously have values other than a hydrogen atom; R3 is a hydrogen atom or methyl, or their salts with alkali metals, characterized in that the compound of the general formula
1538
CHCHU. CH2SOOYA
X, R ,, R2 and Kg have specified
 value;
R4 is a lower alkyl, free or substituted by a lower carbalkoxy group,
oh, soy
53889518
subjected to alkaline hydrolysis in a solvent environment such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, dioxane, tetrahydrofuran, dimethoxyethane, acetonitrile or acetone, at 10-60 C followed by, if necessary, by reaction treatment mixture of mineral or carboxylic
The tO is acid and the desired product is isolated in free form or in the form of its alkali metal salt.
Priority signs: 17.0.86 with R, - cyclohexyl, X,
15 RЈ and c3 have the indicated meanings.
06/20/86 with R, is a hydrogen or halogen atom, C, -C 4 -a a kil, alkoxy group; X, R have the indicated meanings.
Table 1
Note:
1) Styodent's criterion:
x p "0.05
to p 0.02
 p 0.01
 PL1
p 0,001
2) A - 6-fluoro 3, -dihydro-3-thioxo-2H-1,4-benzoxazin-4-acetic acid B - 3 -Hydro-3-thioxo-2H-1-benzthiazine-acetic acid
C - 3, -dihydro-2-methyl 3-thioxo 2H-1,4-benzthiazine-acetic acid.
Table 3
table 2

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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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JP8929586|1986-04-17|

---

JP14594186|1986-06-20|

---