Method of producing oxothiazolidine derivatives or their salts

专利摘要:
This invention provides a oxothiazolidine compound of the formula: wherein R1 is acyl; di(lower)alkylamino(lower)alkylcarbamoyl(lower)-alkyl; arylcarbamoyl(lower)alkyl; ar(lower)alkylcarbamoyl(lower)alkyl; heterocyclic carbamoyl(lower)alkyl; heterocyclic(lower)alkylcarbamoyl(lower)alkyl; thiazolidinylcarbonyl(lower)alkyl; morpholinylcarbonyl(lower)alkyl or a group of the formula : in which A is lower alkylene; n is an integer of 0 or 1; m is an integer of 2 or 3; X is -N-,O or -CH-and -N-R2 is hydroxy; lower alkyl which may have hydroxy; ar(lower)alkyl which may have halogen; arylthio which may have halogen; acyl or heterocyclic group and Y is or pharmaceutically acceptable salt thereof. This compound is useful as cognition activator. This invention further provides processes for the preparation of this compound and pharmaceutical composition comprising compound of the above formula.
公开号:SU1493107A3
申请号:SU874202533
申请日:1987-05-13
公开日:1989-07-07
发明作者:Уеда Икуо；Кацура Еусуке
申请人:Фудзисава Фармасьютикал, Ко, Лтд (Фирма)；
IPC主号:

专利说明:

where —S (0) A is low alkylene; R - diphenylmethyl, il) 1 of their salts, capable of activating muscle tissue, which can be used in medicine. The goal is to create more new active items of the specified class. Their synthesis is carried out by the reaction of compounds fl II and | F |
0 C-CH2-S-CH2-N-C (0) -OH ()
and MH (yN-R (III), where A and R are cm.
above, with the subsequent release of the caps product in free form or in the form of the required salt. Prepared drugs affect amnesia and provide a 33.6% recovery rate against 2.5% with a known analogue. 2 tab.
i
(L
WITH
four:

WITH
The invention relates to a method of obtaining new biologically active chemical compounds, in particular new oxothiazolidine derivatives or their salts, which have the ability to activate the effect, the indicated properties suggest the possibility of using these compounds in medicine in treating patients suffering from memory loss due to senile age and amnesia in the treatment of patients with varying degrees of inability to perceive learning.
The aim of the invention is to obtain new oxothiazolidine derivatives having an increased activity against amnesia.
The source compounds required to obtain the target compound by the proposed method can be Paluo

cm
4, iTb, I ch l r l UlH TI, C: 1ODU 01ZYM FIT i; i m
Prig (1st tleice 1.
Ras TH (ip 4-ox (1T a: 1 solution per (30 g) and Tfi rac i harpfur i.e. (300 ml) add KaimHNfH to the suspension) 1 zin of narid hydride (B / / on suspension in mineral oil) (22, 6 g) in tetrahydrofuran (850 NLTI) at room temperature. After this, the mixture is heated to reflux II (heating the mixture with the reverse x hydrogenated). KannHNM ethyl bromide acetate (60 W - under the same mode. The mixture is heated with inverse - with a refrigerator for another 1 hour and then cooled. Insoluble substances are separated by filtration. The filtrate is evaporated in a vacuum and the residue ischayut by column chromatography on silica gel, used for elevation) from the adsorbent 1vki chloroform to give ethyl 4-oxo-3-tiazolidi1tal acetate (78.5 g) as a pale brown powder.
Melting point 35-39 C.
PC (Nujol): 1700, 1635.
NMR (deuterated chloroform, cl): 1.28 (3N, triplet, J 7 H), 3.58 (2H, triplet, J l, 0 H), 4, T2 (2I, singlet); 4.22 (2H, quartet, J 7.5, 48 (2H, quartet, J 1.02 H).
Cooking 2.
The following compounds are prepared in a manner similar to that specified in cooking and 1.
(1) Ethyl 3- (4-oxo-Z-thiazolidine nroshunat as a colorless oil,
IR (Nujol): 1720, 1660cm-.
NMR (deuterated chloroform, cG): 1.28 (GP, triplet, Y 7H) 2.62 (2H, triplet, Y 7 H); 2 H, triplet, J IH); 3.67 (2 H, triplet, J 7 H); 4.18 (2 N, quartet J 7 H) and 4.48 (2H, triplet, J
 1 Hj).
(2) Ethyl 2- (4-oxo-3-thiazolidi-
Nile) propionate as a colorless oil.
IR (film): 1725, 1670 cm.
5IMP (deuterated chloroform, 1.28 (3N, triplet, J 7.5 N,. I, 49 (3N, doublet, J 7.5 Hj); 3.57 (2H, triplet, J 1.0 H2) 4 , 19 (2H, quartet, J 7.5 N); 4.39 (1H, doublet, J 11.0 Ng); 4.51 (1H, doublet, J - 11.0 I) and 4.89 (1H, quartet, J 7.5 P). Preparation 3.
A solution of ethyl 2- (4-oxo-3-thiazolidinyl) g-propionate (2.60 g) in a mixture of 1 N. aqueous g of sodium hydroxide (12.8 ml) and methanol (64 ml) is entangled for 2 hours at room temperature. 0 After evaporation of the solvent in vacuo, 1 and 1 are added to the residue. hydrochloric acid (19.2 ml) and the mixture is stirred for a few minutes. After the mixture was evaporated to dryness, the residue was mixed with tetrahydrofuran (50 ml) and the resulting insoluble solid was filtered off.
The filtrate is evaporated in vacuo to give 2- (4-oxo-3-thiazolidinyl) pro-0 pionic acid (2.25 g) as
light yellow semi-liquid BeutecTBa. IR (Nujol): 1715, 1610 - 1680 cm NMR (deuterated chloroform, CO) i 1.52 (ZN, doublet, J 7.5 N); 5 3.65 (2H, singlet) - 4.44 (1H, doublet, L 11.0 H-,); 4.56 (1H, doublet, J 11.0 Ng), 4.93 (1H, quartet, J 7.5 I2) and 9.85 (1H, singlet).
Cooking 4.
0 Solution 4-oxothiaeolidine (3.00 g)
in tetrahydrofuran (40 ppm) is added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (1.28 g) in tetrahydrofuran (30 ml) at room temperature with stirring, 3-bromo-1-chloro- propane (3.15 ml) is added dropwise to the mixture under the action of a reflux condenser and left at reflux for 9 h at reflux. After the resulting precipitate is removed by filtration, the filtrate is evaporated in. The residue is chromatographed on basic alumina using g ethyl acetate to wash the adsorbent, then, for the same purpose, a 10: 1 mixture of toluene and ethyl acetate, which gives 3- (3-chloropropyl) -4-oxothiazolidine (2.60 g) as colorless oils. IR (film): 1760, 1650 cm- NMR (deuterated chloroform, o); 2.07 (211, quintet, J 7 H.) -, 3.55 (2H-, triplet, J 7 E);
3.57 (2H, triplet, J 7 H);
3.58 (2H, singlet) and 4.43 T2H, triplet, J IH).
Preparation 5.
The following compound is prepared by C (with the same signal as Preparation 3.
five
0
five
4-oxo-3-trnazolidinyl acetic acid.
Melting point 176-178 ° C (not recrystallized). , IR (Nujol): 1880, 1735 (shoulder), 1705, 1690 cm NMR (dimethyl sulphoxide-d,, (/):
3.53 (2H, triplet, 4.03 (2H, singlet) lash, J 1,5 Hj.).
J 1,5 N) -, 4.43 (2H, tri-Preparation 6.
Thionyl chloride (2.0 ml) was added dropwise to a solution of 4-oxo-3-thiazolidinyl acetic acid (1.60 g) in a mixture of dichloromethane (20 ml) and tetrahydrofuran (5.0 ml) at room temperature. After stirring the mixture for 5 hours at the same temperature, the solvent is evaporated in vacuo to give 4-oxo-3-thiazols, dinyl acetate chloride (1.78 g) as a semi-liquid brown substance.
IR (Nujol): 1770, 1710, 1650 cm.
Example 1. A mixture of ethyl 4-oxo-3-thiazolidinyl acetate (25.0 g) and 1-diphenylmethyl piperazine (67.0 g) is maintained at 135 ° C for 15 hours. The reaction mixture is chromatographed on basic alumina. The adsorbent is washed with a mixture of toluene and ethyl acetate (20: 1), which gives a light brown powder (46.4 g), which is recrystallized from a mixture of ethanol and n-hexane, which gives 1- (4-oxo-3- - thiazolidinyl) acetyl-4-diphenylmethyl piperazine (30.7 g) as brown prisms.
Melting point 147-148 ° C.
IR (Nujol): 1670 (shoulder), 1660 cm
NMR (dimethyl sulfoxide d, /): 2.10 - 2.38 (4H, multiplet)} 3.37- 3.63 (6H, multiplet) -, 4.13 (2H, singlet) -,
4.32 (1H, singlet); 4.37 (2H, singlet) and 7.07 - 7.52 (10 N, multiplet).
Example 2. The following compounds were prepared by the method of example 1.
(a) (4-Oxo-thiazolidinyl) - -propionyl} -4-diphenylmethyl piperazine in the form of slightly yellowish-brown prisms.
Melting point 184-185 ° C (recrystallized from ethanol / ethyl acetate).
IR (Nujol): 1655, 1635 cm

-
-
ten
15
4931076
NMR (deuterium 1 & h.gor (tform, G): 2.28-2.45 (4H, multiplet); 2.58 (MN, triplet, J 611,); g3.35-3.72 (8H, multiplet );
4.25 (1H, singlet) -, 4, D8 (2H, triplet, J 2H2) and 7.08-7.48 (10 N, multiplet).
(b) 1-L2- (4-Oxo-Z-thiazolidinyl) propionyl J-4-diphenylmethylphenazine, in the form of brownish prisms.
Melting point 151-152 ° C (recrystallized from a mixture of ethyl acetate and n-hexane).
IR (Nujol): 1670, 1640 cm V
NMR (deuterated chloroform, tf): 1.33 (3N, doublet, J7H) -, | 2.40-2.48 (4H, multiplet); 3.37 - 3.68 (6H, multiplet), 4.20 (1H, singlet); 4.40 (2H, triplet, J IH); 5., 11 (IH, quartet, J 7 H and 7.08 - 7.48 (10 N, multiplet).
Example 3. The following compound was prepared analogously to example 1.
(a) The salt of 1- (4-oxo-3-thiazolidinyl) acetyl-4-diphenylmethyl-homopiperipine formed by mono-sulfuric acid (recrystallized from ethanol).
Melting point 198-199 C.
IR (Nujol): 1665, 1645 cm
NMR (dimethyl sulfoxide - d, cG): 1.83-2.20 (211, multiplet);
2.97-3.97 (8H, multiplet); 3.52 35 (2H, singlet); 4.23 (2H, singlet); 4.42 (2H, singlet), - 5.70 (1H, singlet) and 7.17-7.83 (10 N, multiplet).
20
25
thirty
Example 4. To 1- (4-oxo-3-β-thiazolidinyl) adethyl-4-diphenylmethyl piperazine (1.00 g) water (1.5 ml) and 1N hydrochloric acid (3.5 ml) are added. . The mixture was vigorously stirred for 10 minutes, left to stand for 10 minutes at and stirred for 30 minutes at, then 24 hours at ambient temperature until crystals precipitated. The crystals are separated by filtration and dried under reduced pressure to give a salt of 1- (4-ocean-3-thiazolidinyl) N-acetyl-4-diphenylmethyl piperazine formed in monochlorine acid (0.9 g).
Melting point 220-222 ° C (decomposition).
IR (Nujol): 1680 (shoulder), 1660 cm 1 The following salts are prepared by the method of examples 1-4.
714931
(a) Salt of 1- (4-oxo-3-thiazolondyl) acetylL-4-diphenylmethyl piperazine, formed by 1/2 sulfuric acid.
IR (Nujol): 1650.
(b) Salt of 1- (4-oxo-3-thiazolidyl-yl) -acetan-4-diphenyl-methyl-aperisine formed by monobromic acid.
IR (Nujol): 1650 cm. U
Example 5. a) To a solution of 4-oxo-3-thiazolidinyl-acetic acid ethyl ester (145 g) in 1.45 l of acetic acid, a solution of potassium permanganate | 5 (206 g) in 3 is added dropwise. , 19 liters of water at at a time of an hour. 19 g of sodium hydrosulfite is slowly added to this mixture until the color of the mixture disappears. Sodium chloride is added to the reaction mixture until saturation, and the mixture is extracted with 1 l of chloroform (2 times), the combined extracts are washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. 25 The mixture is filtered and the filtrate is evaporated to dryness to give a residue. Ethyl alcohol is added to this residue and the mixture is evaporated in vacuo. This operation is repeated. Diethyl ether was added to the residue, and the mixture was stirred for one hour while cooling with ice to obtain crystals. These crystals are filtered, washed with diethyl ether and evaporated to dryness to give 4-oxo-3-thiazolidinyl-acetate--1,1-ethyl ethyl ester (137.8 g). Melting point 52-54 C.
IR spectrum (potassium bromide)
1740-1660, 1460 cm.
NMR spectrum (deuterium chloroform, ppm). 1.30 (ZN, triplet, J 7 Hz, (3.88) 2H, singlet (4.26) 2H quartet, J 7 Hz (4.29) 2H, (singlet), 4.68 (2H, singlet) .
b) A mixture of 4-oxo-3-th-3-thiazolidinyl acetate-1,1-dioxide ethyl ester (137.7 g) 1 n. An aqueous solution of sodium hydroxide (622 NP) and 124 ml of methanol are stirred for 2 hours at room temperature. This mixture was evaporated under vacuum to give a residue. The residue is acidified to pH 2 with six-normal hydrochloric acid under ice-cooling to precipitate crystals. These crystals are filtered, washed with ice water, dried under vacuum to give 4-oxo-3-thiazol35
50
, - 55
,
-
YU
| 5 20 25 of
Q

,
35
50
55
078
di-1-acetic acid - 1,1-dioxide (63.73 g). The filtrate is washed with liquid, evaporated to dryness, to obtain a residue. Tetrahydrofuran is added to this residue. This mixture is stirred and filtered. The filter residue is washed with tetrahydrofuran. The filtrate and washes were combined and evaporated in vacuo to give a stat. This residue is washed with ethyl ether, and the mixture is stirred to precipitate crystals. These crystals are filtered, washed with diethyl ether and dried, yielding 22.65 g of 1,1-dioxide-4-oxo-3-thiazolidinyl-acetic acid.
Melting point 174 ° C (decomposed). PC spectrum (Nujol): 1740, 1655 cm -
NMR (in solid water ppm): 4.33 (2H, singlet) 4.66 (2H, singlet), 4.88 (2H, singlet).
c) To a mixture of 86 g of 4-α-oxo-3-thiazolidinyl acetic acid 1,1-dioxide, 860 ml of dichloromethane and 10 ml of dimethylformamide, 63.6 g of thionyl chloride are added at room temperature, and 1 mixture is heated to boiling refluxed and stirred for 1 hour. This reaction mixture is cooled to a temperature below. To this mixture, 112.34 g of 1- (diphenylmethyl) piperazine and 54.1 g of triethylamine in a solution of 500 ml of dichloromethane are added dropwise at a temperature below 10 ° C for 15 minutes. The reaction mixture is stirred for 2 hours at the same temperature. The precipitated crystals are filtered, washed with water and then with chloroform, evaporated to dryness and subjected to recrystallization from a mixture of 1 l of dimethylformamide and 2 l of ethyl alcohol, to obtain 60.7 g of 4-oxo-3- (4-diphenylmethyl piperazine -1 -1 ylcarbonylmethyl) thiazolidine-1,1-dioxide.
IR (Nujol): 1675, 1670, 1420 cm.
NMR (deuterated chloroform): 2.17-2.55 (4H, multiplet); 3.2-3.7; (4H, multiplet); 3.78 (2H, singlet), 4.25 (3N, singlet); 4.65 (2H, singlet), and 6.95-7.55 (YUN, multiplet) ..
Subsequent testing is given to clarify the pharmacological efficacy of new oxo-thiazolidine derivatives by the proposed method.
Test 1 (the effect of new oxothiazolidine derivatives on memory loss caused by electroconvulsive shock).
Animals: Male ddY male, 6 weeks old, weighing 30–35 g, were used in groups of 20 individuals.
Equipment: The equipment eliminating the possibility of a passive transition consists of two V-shaped sections of the same size (light and dark), which are separated by a falling door. The camera has the following dimensions, cm: bottom diameter A, upper diameter 10, height: 10, length 14.
Light camera is made of transparent plastic. This camera is illuminated from a 60 W source located above the camera at a height of about 10 cm. The dark camera is constructed from plastic painted black. The floor of each chamber consists of 24 stainless steel rods with a diameter of 2 mm, located at a distance of 5 mm one from the other, pulses of alternating current of direct voltage are applied to the rods, causing shock by impact on the legs.
Shock generator: Ohara - Ika-Sangyo.
Procedure: The animal is subjected to training treatment by placing in a light chamber. The animal is tamed for 30 seconds and the falling door is opened. As soon as the animal places all 4 paws on the grid formed by the rods on the floor of the dark chamber, the falling door is lowered and thereafter apply a shock effect of 60 V for 3 s. The door is opened again to move the animal back into the light chamber. Immediately after the passive elimination of the response has been achieved, electroconvulsive shock is produced through the ears, after which the dosage of the test compound is administered by oral intake. A test compound suspended in a 0.5% methylcellulose solution was administered, also 1 hour before the test. Animal after 24 h using the same procedure except for shock. The animal is patented for passage through a dark cell.
If the animal does not take a nocTvna- tional step over a dark chamber for 300 s, the experiment was taken as past the established period.
Test compounds.
I (compound of the invention)
S9-0
CH2CO-N (
II (connection according to the invention)
OiS-1
N CH2CO-N (yNCH
25
A (known compound)
thirty
Bo
N
CF,
(
2HC1
Test result:
The effect of the test compounds on the loss of memory caused by electroconvulsive shock (E, S) is shown in Table 1.
Electroconvulsive shock after passive reinforcement from tempering leads to a complete loss of memory.
On the other hand, the introduction of tested new oxothiazolidine derivatives for therapeutic purposes prevents to a large extent the electroconvulsive shock from passing through the memory of the mouse, which manifests itself in the passive elimination of the response, i.e. as a result of treatment with the above compounds, the reduced retention time is increased.
The effect of oxothiazolidine derivatives on memory loss caused by electroconvulsive shock is given in: tab. one.

150,2t5,4
 P 0.05 P 0.01; significant difference
from E.
The proposed oxothiazolididine derivatives were compared by their activity against amnesia with a known compound.
In order to detect activity against amnesia, the proposed test method was used - the action of electroconvulsive shock-induced amnesia.
Test data are shown as activity against amnesia (% recovery).
Activity against amnesia is calculated according to the following equation:
C - B
% recovery
A - B
to 100,
And the delay time (s) for the untreated group
B - time delay (s) for the group that received electroconvulsive shock
C is the delay time (s) for the group that received electroconvulsive shock plus the medication used.
The activity of oxothiaoolidine derivatives against amnesia is given in gabl. 2
table 2
 P 0.05
For statistical analysis of the scatter, the test is used.
ti
Test compound: Described in example 2 (a)
But
N //
(CH2) 2CON (; NCH
/.
(by
However, in example 5 (c),
one
(CH,) COKQNCH
(in
Test method
After the test compound was orally given to mice of 1CR age line at 6 weeks as a 0.5% aqueous suspension of methylcellulose, the mice were monitored for 3 days.
3. The test results, U gg test compounds II and III 1000 mg / kg and 1000 mg / kg, respectively.

权利要求:
Claims (1)
[1]
40 claims
The method of obtaining derivatives of oxoca.s OLI dina formula
U
.
RI
about
where R, is a group of the formula
-A-CO - NQN-R2,
Y —S— or 50, where A is lower alkylene, E} -diphenyl methyl,
or nx eagles, distinguished by the fact that the reactive
13149310714
according to the carboxyl group, the derivative De Y and A - have the indicated compounds of the formula
subject to interaction) with a compound of the formula / -
ThrHp NQN-Rj
 R has the specified value
I and the target product is isolated in free form or as its salt.

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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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GB858512163A|GB8512163D0|1985-05-14|1985-05-14|Oxothiazolidine compound|

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