Method of producing derivatives of 1,3-oxazolidin-2-one or acid-additive salts thereof

专利摘要:
1,3-Oxazolidine-one derivatives of the following formula <IMAGE> where R is straight or branched alkyl of C3-C8, X is hydrogen, halogen, lower alkyl or lower alkoxy and n is 4, 5 or 6, or their acid addition salts are effective for medicinal and agricultural use.
公开号:SU1402263A3
申请号:SU853902250
申请日:1985-05-30
公开日:1988-06-07
发明作者:Масаки Мицуо；Синозаки Харухико；Сато Мазару；Морито Наойя；Хасимото Коити；Кимисиро Тосиро
申请人:Ниппон Кемифар Ко, Лтд (Фирма)；
IPC主号:

专利说明:

(21) 3902250 / 23-04
(22) 30,05.85
(31) 59-203624
(32) 09/28/84
(33) JP
(46) 07.06.88. Bul Number 21
(71) Nippon Kemifar Co., LTD (JP)
(72) Mitsuo Masaki, Haruhiko Sinozaki, Mazaru Sato, Naoy Morito, Koichi Haimoto and Toshiro Kimisiro (JP)
(53) 547.787.1 (088.8) (56) Heterocyclic compounds. / Ed. R. Elderfield. - M.: - Foreign literature, 1954, v. 5, p. 316.
(54) METHOD FOR OBTAINING 1,3-OXAZOZOLIDIN-2-IT DERIVATIVES OR THEIR ACID-ADDITIVE SALTS
(57) The invention relates to derivatives of heterocyclic substances, in particular 1,3-oxazolidin-2-one of the common f-ly
one:
X-SbN4-CH-0-C (o) -ShS-SNK
where K- (SNg) (Zn2) n;
R is n- or iso-Cg alkyl; X — H, halogen, C — C-alkyl or C, —Cj— is an alkoxy group; n 4 to 6, or their acid addition salts exhibiting antiglutamine activity. The goal is to create more active substances of the specified class. Their synthesis is carried out from compounds of fl (II) and (III): (AB) (II), X — CjH — —CH (OH) —CRK (III), where A is Cl or C, —C-alkoxy; B is halogen; , - Alkoxy or tr11 chloromethyloxy; X, R, n, K are indicated above. The process is carried out at (-15) -20 ° C in the presence of a base or with additional heating to 90-140 ° C in the presence of aluminum isopropoxide or sodium methoxide. The desired product is isolated, in free form or in the form of an acid addition salt. New substances at a concentration of 20–10 mol / l provide a degree of glutamic acid blocking by 53–92% with an LDjo toxicity of 18–75.1 mg / kg. 2 ill., 4 tab.
i
ABOUT)
 about go
1HE
05
00

sn
The invention relates to a method for producing 1,3-oxazolO 1G derivatives of CH2CH2CH2H- (CH2) n
or their acid-salts with antiglutamine activity, which can be used in medicine and in agriculture.
The aim of the invention is the enhancement of anti-glutamine activity in a series of 1,3-oxazolidin-2-one derivatives.
Example 1. (4RS, 5SR) -4- (l-Methylethyl) -5-phenyl-3- (3-piperidino-propyl) -1, 3-oxazolidin-2-one,
(1RS, 23K) -3-methyl--1-phenyl-2- (3-piperidinopropylamino) -butan-1-ol dihydrochloride (755 mg, 2.00 mmol) is suspended in 12 ml of a 10% aqueous hydroxide solution sodium, followed by addition of 28 ml of diethyl ether. The mixture is stirred, and when it becomes clear, it is cooled with ice. A 20% solution of trichloromethyl chloroformate (TECH) in toluene (4.0 ml) is added dropwise over 1 hour. After addition of TEC, the mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed once with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product is purified by chromatography on a column of silica gel (7 g of silica gel, the solvent is chloroform methanol 20: 1), to give 613 mg the desired product in the form of light yellow crystals (yield 93%),
IR spectrum (KVG)
cm: 2930,
2860, 2760, 1730, 1605, 1440, 1415, 1125, 1030, 755, 695,
NMR spectrum (CDCl) chemical shift; 0.68 (3N, d, J = 7 Hz, SNCH,); 0.89 (3N, d, J = 7 Hz, CHCHj); 1.20-2.01 (9H, m, CH (CH5),
 V
CHjCHgN
.sn.

CH - CH;
}
din-2-one of the general formula
(I)
-n);
2.92-3.30 (1H, m, 0

3.54-4.00 (2H, m, JJ

about
5.60 (W, g, J 8 Hz, (CH-0); 7.16-7.48 (5H, m, aromatic ring protons).
(4RS, 53K) -4CH1-Methylethyl) -5-pheny-3- (3-piperidinopropyl) -1,3-oxazo-LIDIN-2-OH, fumarate.
The previous compound obtained (430 mg, 1.30) is dissolved in 4 ml of ethanol, 5 ml of a hot ethanolic solution of fumaric acid (151 mg, 1.30 mmol) are added. The solution is evaporated under reduced pressure, the residue is dissolved in acetone and allowed to stand overnight. After the mixture was cooled with ice, the precipitated crystals were collected by filtration, washed three times with acetone, to obtain 491 mg of the desired substance as white crystals (yield 85%), T, mp, 142-144 s (decomposed),
IR spectrum (Kvg), 3440, 2940, 2880, 1740, 1700, 1640, 1560, 1420, 1250, 1200, 980, 750, 700,
NMR spectrum (CBC1-CCHSOB 6: 1) - chemical, shift: 0.65 (G, d, J = 7 Hz, SNCH); 0.86 (ЗН, д, J 7 Hz, СИСНз); 1.35 - -g, 35 (9H, m, CH (CH,),
° rw
Ql2
2.70-3.88 (8H, m, CH2CH2CH2X y):
W s
55 4.04 (1H, doublets, J 8 Hz, 2 Hz,
}:
5.75 (IH, d, J 8 Hz, CH-0); 6.78 (2H, s,); 7.16-7.44 (5H, m, protons of the aromatic ring).
Example 2. (1RS, 2SR) -2-N-Ethoxycarbonyl-N- (3-pyLeridopropyl) amino-4-methyl-1-phenylpentane-1--ol.
To a solution of (1RS, 28K) -4-methyl-1-phenyl-2- (3-piperidinopropylamino) pentane-α-ol (637 mg, 2.00 mmol) in 6 ml of chloroform is added dropwise, with ice cooling and mixing half the solution (4 ml) of chloroic acid ethyl ester (543 mg, 5.0 mmol) in chloroform, keeping the reaction temperature below 15 ° C. After that, the remaining half of the solution and 8 m sodium hydroxide aqueous solution (200 mg, 5.0 mmol) is added dropwise, keeping the reaction temperature below 15 ° C so that the addition of both solutions is completed simultaneously. The resulting mixture was stirred at 5 C for 1 h, after which the chloroform layer was separated, dried over sodium sulfate and then evaporated under reduced pressure, to obtain 781 mg of the desired substance as a viscous light yellowish oil (yield 100%).
IR spectrum (pure oil) J „.) 3440, 2940, 2870, 2800, J680, 1465, 1420, 1310, J250, 1230, 1100, 750, 700.
YAME-spectrum (CDCl) chem. shear: 0.67 (3N, d. J -7,); 0.80 (ZN, d, J 7 Hz, raccoon) GO, 96-2.72 (18H, m, SNgSP (CH,),
ABOUT
7 Hz

COCH,). , 7fi S
 - -V) -5
00 (IH, m,
CH-0); 7.10-7.56 (5H, protons of the aromatic ring).
(4RS, 5SR) -4- (2-Methylprosh l) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazazolidin-2-one.
A toluene solution (12 ml) of the previous substance obtained (633 mg, 1.62 mmol) is heated in an oil bath to approximately 130 ° C to remove water present in the system. The bath temperature is lowered to 100 ° C and lzopropoxide aluminum (16 mg, 0.08 mmol) is added. Then
maintain the bath temperature at 130-140 s in order to remove the azeotropic mixture (9 ml) of ethanol and toluene by distillation for approximately 1 hour. After cooling
ethyl acetate is added to the residue. The solution is first washed with an aqueous solution saturated with sodium sulfate and then with brine. The resulting solution is dried over sodium sulfate and
evaporated under reduced pressure, get 558 mg of the target substance in the form of light yellowish crystals (yield 100%).
IR spectrum (pure)
 2930, 2800, 2770, 1750, 1490, 1460, 1440, 1410, 1375, J345, 1315, 1245, 1215, 1170, 1120, 1035, 1010, 755, 695.
NMR spectrum (HSCC) chemical shift:
0.44-0.68 (ЗН, m, sien,); 0.68-0.92 (GH, m, CHSNZ); 1.00-1.26 (ЗН, m, СН „СН (СН,).); 1.30-1.92 (8H, m
.CS2
OlgCHeN CHa 2.16-2.52 (bn, CH, /
m
.СН2
.v.n.z-
) G2,88-3,24 (W, m

five
0
CH2 3.32-3.72 (1H,
Y o
3.84-4.12 (1H, m, G /)
 T o
); ABOUT
n
 )
3.52
55
(IH, d, J 8 Hz,); 7.33 (5H, m, aromatic protons).
Example 3. (4S, 5R) -4- (2-Methylpoopil) -5-phenyl-3- (3-piperidinopropyl) -, Z-oxazolidin-2-one, fumarate,
(1R, 23) -4-Methyl-1-phenyl-2- (3-piperidinopropylamino) -pentan-1-ol di-hydrochloride (1.0 g, 2.56 mmol). It is dissolved in water and basified with an aqueous 15% NaOH solution, followed by extraction with chlorophor. The chloroform extract is washed with water and an aqueous saturated solution of NaCl. After drying the chloroform extract with NajSO, the solvent is removed.
The fresh layer was extracted with benzene (200 ml). After washing, first with water, then with an aqueous solution of sodium hydrogencarbonate and saline, the combined organic layer is dried over sodium sulfate and then evaporated under reduced pressure. The residue is treated with ethanol to obtain crystals, which are dissolved in 80 ml of ethanol when heated, and 60 ml of hexane are added. The precipitated crystals are filtered and washed with a mixed wound under reduced pressure. The residue 15 with a stack (240 ml) of ethanol and hexane (820 mg) was dried in vacuo and diluted (1: 2) and then hexane. The crystals are entrained in diethyl carbonate (0.9 ml), K is dried in air, and 74.6 g of the title compound are obtained as white crystals (73% yield).
NaOMe (4 mg) is added to the resulting solution and the mixture is stirred at 95 C for 30 minutes. The reaction mixture is evaporated under reduced pressure and the residue is extracted. The ether solution is washed. water and aqueous saturated NaCl solution, dried over. The solvent was distilled off under reduced pressure and the residue (820 mg) was dissolved in EtOH (2.5 ml), followed by the addition of fumaric acid (277 mg, 2.38 mmol). The mixture is dissolved with heating of 30 acid (440 ml) in fumaric acid, keeping the temperature of the resulting solution allowed to stand overnight at room temperature. The precipitated crystals are collected by filtration, washed twice with EtOH (1.5 ml) and then dried to obtain 825 mg of the title compound as white crystals (yield 70%).
Getting the original compounds.
Example A. 2- (1,3-dioxo-2-aza-indan-2-yl) -4-methyl-l-phenylpentan-1-one.
Thionyl chloride (3.8 ml, 480 mmol) was added to a mixture of 2- (1,3-dioxo-2-azaindan-2-yl) -4-methylpentanoic acid (83.6 g, 320 mmol) and 320 ml of benzene. The mixture is refluxed for 2 hours. The solvent and the excess thionyl chloride are removed by distillation under reduced pressure, and 320 ml of benzene is added. The benzene is removed and a fresh portion (480 ml) of benzene is added to form a solution. At once
The reaction mixture was kept below 30 ° C. The resulting mixture was stirred at room temperature for an additional 3 hours and 1 L of chloroform and 1.4 L of hydrogen were added. The organic layer is separated and washed twice with water, once with an aqueous solution of sodium bicarbonate and once with brine. After drying over sodium sulfate, the orthoganic layer is evaporated under reduced pressure to obtain 142 g of white crystals. These crystals are loaded onto a chromatographic column with silica gel (2.8 kg of silica gel, solvent - benzene), are obtained first
94.3g (1RS, 2SR) -H30Mepa in the form of white crystals (yield 66%) and then
48.4g (1RS, 2RS) -isomeri in the form of white crystals (yield 34%).
50 PRI me R B. (1RS, 2RS) -2- - (1,3-dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol.
Aluminum isopropoxide (125.6 g, 615 mmol) is added to suspension 2; anhydrous chloris-55 Cl, 3-dioxo-2-azaindan-2-yl) -4-melted aluminum (106.7 g , 800 mmol) and thyl-1-phenylpentan-1-one (72.3 g, the mixture is stirred at room temperature - 225 mmol) in isopropyl alcohol for 5 hours. The reaction mixture is high (1000 ml). This mixture was boiled with inverted ice water (700 ml). 6.5 hours water cooler. Isopropyl
The fresh layer was extracted with benzene (200 ml). After washing first with water, then with an aqueous solution of sodium hydrogencarbonate and saline, the combined organic layer is dried over sodium sulfate and then evaporated under reduced pressure. The residue is treated with ethanol to give crystals, which when heated are dissolved in 80 ml of ethyl alcohol, and 60 ml of hexane are added. The precipitated crystals are filtered and washed with a mixed solution (240 ml) of ethanol and hexane (1: 2) and then with hexane. Crystals
air-dried to obtain 74.6 g of the title compound as white crystals (yield 73%).
Example B. (1RS, 2SR) -2- - (1,3-Dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol and (1RS, 2RS) - -2 - (1,3-dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol.
Sodium cyanoborohydride (177 g, 2.82 mmol) was added over 3 hours to a solution of the substance (141.4 g, 440 mmol) obtained in Example 1, in chloroform (660 ml) and in acetic acid
The reaction mixture was kept below 30 ° C. The resulting mixture was stirred at room temperature for an additional 3 hours and 1 L of chloroform and 1.4 L of hydrogen were added. The organic layer is separated and washed twice with water, once with an aqueous solution of sodium bicarbonate and once with brine. After drying over sodium sulfate, the optic layer is evaporated under reduced pressure to obtain 142 g of white crystals. These crystals are loaded onto a chromatographic column with silica gel (2.8 kg of silica gel, solvent - benzene), are obtained first
94.3g (1RS, 2SR) -H30Mepa in the form of white crystals (yield 66%) and then
48.4g (1RS, 2RS) -isomeri in the form of white crystals (yield 34%).
50 PRI me R B. (1RS, 2RS) -2- - (1,3-dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol.
Aluminum isopropoxide (125.6 g, 615 mmol) is added to a suspension of 255 Cl, 3-dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-one (72.3 g , 225 mmol) in isopropyl alcohol (1000 ml). This mixture was heated under reflux for 6.5 hours. Isopropyl alcohol was removed by distillation under reduced pressure, 800 ml of ethyl acetate and an aqueous solution of sodium sulfate were added to the residue. The organic layer formed is decanted and the residue is washed twice with ethyl acetate (200 ml). The combined organic layer was washed with brine. The organic solution is dried and the solvent is removed by distillation under reduced pressure. The residue is recrystallized twice from benzene, to obtain 29.3 g of the target substance in the form of white crystals (yield 40%).
Example G. (1RS, 2SR) -2-Amino-4-methyl-1-phenylpentan-1-ol.
Heating (50 ° C) dissolves (1RS, 25K) -2- (1,3-dioxo-2-azaindan--2-yl) -4-methyl-1-phenylpentan-1-ol (80.0 g , 247 mmol) in 800 ml of ethyl alcohol, after which a mixture of 85% hydrazine hydrate (J9.0 ml) in 200 ml of ethyl alcohol is added. The resulting mixture is boiled under reflux for 3 hours and, after cooling with ice, 700 ml of hydrochloric acid (4N) are added. The mixture was stirred at room temperature for 30 minutes. The undissolved substance is removed by filtration through celite and then washed with 140 ml of hydrochloric acid (4N). The washing liquid is added to the filtrate, and ethyl alcohol is removed from the solution by condensation under reduced pressure. Under ice cooling, 6N sodium hydroxide solution (570 ml) was added and the mixture was extracted three times with chloroform. After drying over sulfate. The organic layer was evaporated. 43.2 g of the title compound were obtained as white crystals (yield 91%).
Example D. 4-Methyl-1- (4-methylphenyl) -2- (1,3-dioxo-2-az aindan--2-yl) -pentan-1-one.
Mix 2-bromo-4-methyl-1- (4-methylphenyl) -pentan-1-one (13.5 g, 50 mmol) and potassium phthalimide (9.26 g, 50 mmol) thoroughly and heat at 160 C for 2 hours. After cooling, 100 ml of ethyl acetate and 50 ml of water are added to the reaction mixture. The organic layer is separated and washed with brine. The organic solution is dried over sodium sulfate and evaporated under reduced pressure. The residue was subjected to recrystallization, which was treated with hexane, and the resulting crystals were subjected to recrystallization from hexane, to obtain 12.2 g of the intended compound as white crystals (yield 73%).
Example E. (1RS, 2RS) -1-phenylheptan-1-ol.
Acetic anhydride (10 np) was added to (IRS, 2SR) -2-aMHHO-l-phenylheptane -1-ol (4.15, 20 mmol) and the mixture was heated at 70 C for 10 minutes. After cooling, the reaction mixture is poured into 100 ml of water, to which chloroform is added and gradually an aqueous solution of sodium hydroxide. The alkalized solution is extracted with chloroform, the extract is dried. The solvent was removed by distillation under reduced pressure to give a colorless oil. This oil is cooled with ice and 20 ml of thionyl chloride are added. The mixture is stirred at room temperature for 20 minutes. With precautions, water (30 ml) is added in small amounts and the mixture is heated and refluxed for 2 hours. The mixture is cooled, water is added. After the mixture was washed with ether, the resulting aqueous layer was separated and basified with an aqueous solution of sodium hydroxide. The mixture is extracted three times with chloroform and dried. The organic solution is evaporated. wave under reduced pressure to give white crystals. These crystals are recrystallized from hex. san, 2.73 g of the expected compound are obtained in the form of white crystals (yield 66%).
Example J. (1RS, 28P) -2-Amino- -1- (4-methoxyphenyl) -4-methylpentane-1- -ol.
Dissolve in 88 ml of acetic acid 2-oxyimino-4- (4-methoxyphenyl) -4- -methylpentan-1-one (8.72 g, 36.1 mmol. To this solution add 0.87 g of catalyst - 5% palladium on activated carbon, and the reagent is catalytically hydrogenated at normal pressure and 80 ° C until a threefold molar amount of hydrogen is absorbed with respect to the reagent. After removing the catalyst by filtration under reduced pressure, acetic acid is removed. in 80 ml of hydrochloric acid (1N). This solution is washed twice with 30 ml of ether, the aqueous layer is alkalinized 20% aqueous sodium hydroxide solution.
The aqueous layer thus treated is extracted three times with chloroform, the extracts are combined and washed with brine. The extract is dried over sodium sulfate, the solvent is removed by distillation under reduced pressure, to obtain light yellow crystals (6.80 g). These
53K) -A-methyl-5-phenyl-3- (2-pyrrolidinoethyl) -, 3-oxazoliding-2-one (compound 5),
Biological experience I. Effect on anemic decerebration rigidity.
A sample of anemic decerebration rigidity is prepared in accordance with the crystals subjected to recrystallization with the Fukuda method and co-workers, and the samples from benzene and hexane are obtained: Wistar female rats (body weight 5.24 g of the target substance in the form of 350 g) are kept on the back and under the loose crystals (yield 63%), their neck is cut with ether anesthesia.
Example I. (IRS, 25E) -4-Methyl - After the trachea and common sleep- -1-phenyl-2- (| 3-piperidinopropylamino) - 15 arteries open, in the trachea
20
pentan-1-ol, dihydrochloride.
A mixture of (IRS, 25P.) - 2-amino-4-methyl--1-phenylpentane-1ola (40.6 g, 210 mmol) and.1- (3-chloropropyl) piperidine (34.0 g, 210 mmol) alloyed together at 50-70 ° C under nitrogen. The mixture is heated in an oil bath to 110 to 120 C for 3 hours. After cooling, the reaction mixture is dissolved in 750 ml of ethanol with heating, and 17 ml of concentrated hydrochloric acid are added. The mixture is cooled and the precipitated crystals are filtered off. These crystals are again suspended in 1200 MP of ethlnol and refluxed for 1 hour. The mixture is cooled, the precipitated crystals are filtered, washed and dried, to obtain 58.8 g of the title compound as white crystals (yield 72%), t, mp, 268-270 s (decomposed)
Table 1 shows the physico-chemical characteristics of the new compounds (l).
The efficacy of the compounds of formula (l) is determined by the blocking effect on glutamic acid, the relaxing effect on the muscles of the spinal cord (decreased stiffness and the releasing effect on samples of anemic cerebral stiffness) and toxicity levels. The following compounds are used for comparative purposes; toluperion hydrochloride (compound 1); 50 hydrochloride (4Ra, 53E) -4-methyl-5-phenyl-3- (2-piperidinoethyl) -1,3-oxazo-LIDIN-2-OH (compound 2); (4RS,
cannulas are inserted, and then a double ligature is applied to the bilateral common carotid arteries and the esophagus and they are cut off. After this, the occipital bone is exposed, through which a round hole is drilled, in order to double the ligature on the extending central artery. When the rat starts out. 25 from the anesthetized state, its front ends are becoming rigid. The measurements are carried out by recording electromyographic (EMG) response from the pulse, the EMG pulses are converted into integrated ones for every 10 s and recorded on the recorder as a histogram.
The effect of each test substance on rigidity is estimated as the degree of inhibition. This degree is first calculated by determining the area of the portion with a reduced EMG pulse on the histogram 10 minutes after the introduction of the physiological saline solution of each test compound (dose 3 mg / kg through the femoral vein and then according to the following equation:
The degree of suppression (O) is 100 a / A, where a is the reduced area of the EMG pulse as a result of the introduction of the test compound; A is the area of the EMG pulse,; when no test compound is introduced (control). The results are shown in Table. 2, Biological experience 2, Blocking action against glutamine
40
45
5RS) -4-methyl-5-phenyl Z- (2-piperidinoethyl) -1,3-oxazolidin-2-one, hydrochloroacid in neuromuscular compounds
RID L compound 3); , (4RS, 55H) -4-me-cancer,
tyl-5-phenyl-3- (2-pyrrolidinoethyl) -. .
-1,3-oxazolidin-2-one, hydrochloride. Follow the method described by Ishida
(compound 4); hydrochloride (4RS, "sotr., t, e, as materials
-
140226310
53K) -A-methyl-5-phenyl-3- (2-pyrrolidinoethyl) -, 3-oxazoliding-2-one (compound 5),
Biological experience I. Effect on anemic decerebration rigidity.
Sample Anemic Decerebration
cannulas are inserted, and then a double ligature is applied to the bilateral common carotid arteries and the esophagus and they are cut off. After this, the occipital bone is exposed, through which a round hole is drilled, in order to double the ligature on the extending central artery. When the rat starts out. from the anesthetized state, its anterior ends become stiff. Measurements are made by recording electromyographic (EMG) response from the pulse, EMG pulses are converted into integrated ones for every 10 s and recorded on the recorder in the form of a histogram.
The effect of each test substance on rigidity is evaluated as the degree of inhibition. This degree is calculated first by determining the area of the portion with a reduced EMG pulse on the histogram 10 minutes after the introduction of the physiological saline solution of each test compound (dose 3 mg / kg) through the femoral vein and then using the following equation:
The degree of suppression (O) is 100 a / A, where a is the reduced area of the EMG pulse as a result of the introduction of the test compound; A is the area of the EMG pulse,; when no test compound is introduced (control). The results are shown in Table. 2, Biological experience 2, Blocking action against glutamine
acids in neuromuscular compounds
zu of the first walking legs of the cancer; the neuromuscular sample is kept in a bath, with the help of which saline composition, mmol: NaCl 195; CaCl 18; KCl 5.4; Tris-maleate buffer (pH 7.5) 10; glucose 11, for use in cancer tests, is perfused at room temperature and at a constant flow rate. Glass microelectrodes, each of which is filled with a ZM solution of potassium chloride, are inserted into the central part of the muscle fiber in order to record intracellularly changes in the membrane potential of the myecetic cell.
The blocking effect of each test substance on glutamic acid is estimated as the degree of depolarization inhibition, which is caused by using a bath of L-gluc acid in direct proportion to the amount.
FIG. Figure 2 shows the recording of the rate of ignition of a cortical neuron excited by an iontophoretic glutamine pulse (0.2 Hz, duration 2 seconds). The proposed compound 10 reduces the frequency of action potentials caused by L-glutamic acid, as well as by three glutamate receptor agonists, i.e. digenic acid, quisquelic acid and 15 M-methyl-B-aspartic acid.
From the above results, it follows that the test compound inhibits the glutamate response in rat cortical neurons.
Biological experience 4. Acute toxicity.
Using the ddN male e according to the up and down method, the level of acute toxicamino acid (10 mol / l) is determined at
Five minutes pretreatment of each test substance.
ke solution of the test substance, Some of the test substances are the results presented in Table. 3
Biological experience 3. Inhibitory effect in response to L-glutamic acid and its analogs in rat cortical neutrons.
steep in physiological saline and injected through the tail vein. The results are presented in table. four.
Thus, compounds (l) by their biological activity with respect to anemic decerebral rigidity and blocking glutamino-L-glutamic acid and the compound (4s, 5E) -4- (2-methylpropyl) -3-C. Thus, compounds (l) of their biological activity in wearing anemic decerebration rigidity and glutamide blocking
- (perhydroazepin-1-yl) propyl-5-ferric acid is superior
 1-1J- I / - - OO
nyl-1,3-oxazolidin-2-one is ionophoresed into the cortical neuron. rats using a multi-cylinder glass micropipette filled with L-glutamic acid (III) and 40 with a 40.05M test compound}. The tip of this micropipette is fixed using a micromanipulator in a position where the greatest glutamine response is obtained, which is represented by extracellularly recorded action potentials induced by iontophoretic administration of L-glutamic acid. FIG. Figure 1 shows the recording of the firing rate, gQ, of a cortical neuron at time. the introduction of L-glutamic acid with stable constant fluxes in the presence or absence of the proposed EG compound with various amounts of gg (ordinate axis - frequency of action potentials, abscissa axis - time).
The above results (Fig. 1) mean that the proposed connection
compounds. The proposed compounds can be used in medicine.

权利要求:
Claims (1)
[1]
Formula invented
The method of obtaining derivatives of 1-oxazolidin-2-one of the general formula
O.TG-CH2CH2CHNT- (CH
about
where R is an alkyl group with direct
or branched chain, having 3-8 carbon atoms;
X hydrogen, halogen. C, -Shch C, -C3-alkoxy groups E 4 ,,. 6, an integer, or their acid addition salts, characterized in that the compound of the general formula
acid in direct proportion to the amount.
FIG. Figure 2 shows the recording of the rate of ignition of a cortical neuron excited by an iontophoretic glutamine pulse (0.2 Hz, duration 2 seconds). The proposed compound decreases the frequency of action potentials caused by L-glutamic acid, as well as by three glutamate receptor agonists, i.e. digenic acid, quisquelic acid and M-methyl-B-aspartic acid.
From the above results, it follows that the test compound inhibits the glutamate response in rat cortical neurons.
Biological experience 4. Acute toxicity.
Using males ddN e according to the up and down method, the level of acute toxicity is determined in physiological saline solution and injected through the tail vein. The results are presented in table. four.
Thus, compounds (l) in their biological activity with respect to anemic decerebral rigidity and glutamic acid blocking are better than
compounds. The proposed compounds can be used in medicine.
Invention Formula
The method of obtaining 1,3-oxazolidin-2-one derivatives of the general formula
O.TG-CH2CH2CHNT- (cH2) p
about
where R is an alkyl group with direct
or branched chain, having 3-8 carbon atoms;
X hydrogen, halogen. C, - C alkyl. Br, C, -C3-alkoxy; F 4, 6, an integer, or their acid addition salts, distinguished by the fact that the compound of the general formula
13
ML- CHjCtttCHjH CHi n
where R, X and n have the indicated meanings,
subjected to interaction with carbonic acid derivatives of the general formula
with “o
 U -CRjCH
CH,
S 48, 5R 174-176
 -9.7 (p. 1, (p "zlag" ets. SYS1) fumamart)
.dlj
"-Otss and
CHj
5 I. SSULV decomposes 2920, 2860, 2790, 1750, H60, 1440, 1405, 1360,
 9.7 to 47-49; 174-176 1245, 1200, 1160, 1PO, 1030, 1000, 755, 740, 690
(from 1.12} SNF1) (fumarate) (Ig)
SJ1
- CH | XIAN
5 "S, 5S WJ 160-161 10, (fumarate)
(from 1.13; СНС1,)
-CRiOT and CKj
S 4R, 5 "Wy - 160-162 - -10, (fumart)
(from l.tJ; SIS1,)
-CHj CHj
4 4 & S, 5RS
145-147 (41yrarat)
-with .
CHj
4 4Я, 5SR
169-170 (fumarate)
xCHj
CHj
4 4ilS, 51tS
U7-t48
(fumarate)
402263U
where A is chlorine or C is C alkoxygroup,
B is halogen, C, -Cj-anKOKCHrpynna 5 or trichloromethyloxy, with (-15) in the presence of a base or with additional heating to 90-140 ° C in the presence of aluminum isopropoxide or sodium methoxide with 10 release of the desired product in the free in the form or in the form of its acid additive salt.
t a 3 l X a a I
750, 695 (Ig)
2920. 28вО, 2790, 2780, 1750, 1460, 1440, 1405, 1360, 1243, 200, 1160, 1110, 1030, 1000, 755, 740, 690 (clean)
2930, 2760, 1750, U60, 1440, 1410, 1370, 1340, 1310, 1245, 1210, 1165, FROM 1115, 1055, 1030, 1005, 750, 690 (clean)
2930, 2760, 1750, U50, 1440, 1410, 1370, 1340, 1310, 1245, 1210, 1165, I13oi 1115, 1055, 1030, 1005, 750, 590 (clean)
2960, 2880, 2790, 1750, 1445, 1420, 1230, 1030, 755, 700 (clean)
2960, 2880, 2790, 1750, 1605, 1450, 1410, 1145, 1030, 1010, 755, 700 (clean)
2960, 2880, 2790, 1750, 1605, 1415, 1245. 1145, 1040, 1010, 760, 695 (CHIST1L)
15
. ± lTLlinii.lJI
Sya |
tr-CH | SYai, MW. 171-1732920, 2860. 2810,,,, 1360, I02S, 1005,
CH | -10, (p zl g "ts 1.760, S95 (h cr)
(from 1.13 (СНС1,) funat)
x-CH)
II-CMTCHJ-Oli 5 M, SSR
Qft,
"." Rf- M -CH SIE-SJ, 5 R8,
NE |
Jsr
24
CHj 3-CH, 5RS
SWE
, 01J
1402263
(6
Continuation of table 1
152-1532950, 2880, 2820, 27ВО, 1760, U "5, UJO, 17E5, IJ20,
(decomposed, ISO, 1040, 1010, 755 (parts)
Ftmar t)
2930, 2860, 2760, I7M, 1605, 14 "0, (" 05, 1120,
1075, 750
2920, 2860, 2760, 1750, U35, U05, 1370, MI5, 1030, 775, 750, 690 (clean)
2940, 2880, 2780, 1760,,, 1125,, 1015, 815, 760 (cmstl)
2940, 2870, 2770, 1755, 1605, 1410, 1250, 1120, 1035, 1010, 810, 755 (clean)
2930, 2760, 1750, 1610, 1510, 1435, 1250, 1170, 1030, 825, 750 (clean)
2930, 2850, 2750, 1720, 1605. 1505, 1445, 1410, 1360, 1225, 1150, 1120, 1030, 990, 845 810, 755 (Ig)
2930, 2870, 2800, 2770, 1750, 1605, 1510, 1470, 1445, 1415, 1225, 1155, 1120, 1030, 1005, 830, 760 (clean)
2940, 2860, 2820, 2770, 1735, 1605, 1495, U50, 1425, 1370, 1350, 1250, 1235, 1215, 1125, 1090, 1025, 1010, 995, 945, 820 CUL)
2940, 2870, 2850, 2810, 2770, 1750, 1600, 1490, 1465, 1440, 1410, 1250, 1120, 1090, 1030, 1005, 820, 750 (net)
2920, 2840, 2760, 1740, 1600, 1440, 1415, 1240, 1120, 1030, 1000, 755, 695 (net)
2,930.2870.2770.1740, 1440, 1410, 1010, 770, 705 (KVg)
2940.2860.2770.1750, 1605, 1450, 1415,, 1230,
1120,1035,1000,755, 695 (pure)
2,930.2860.2760.1750, 1605, 1450, 1410, 1120,
I030i1010,755, 695 (clean)
2940.2860.2800.2770, 1755, 1450, 1415, 1375,
1240,1230,1120,1035, 1000, 755, 695 (ASTM)
2,930.2860.2800.2760, 1750, 1445, 1410, 1245,
1225.11 120.1030.1010, 755, 695 (clean)
17
 CHi
39- (cHi) tar n
CHi
4 - mibcVQ,
41- (sa,), cn, n
42- (CB,), CB, n
; 4RS, R5
54IIS, SSK
54RS, 5SR
5 "US, 5SR
125-126 (maleate)
138-139 (fumarate)
29iO, 2S70, 27YO, 1755, 1610, lliO, 1420, I2i0, I PO, 1040, 1010, 760, 700 total)
2920, 2850, 2740, 1740, 1600, 1440, 1115, 1025, 1005, 745, 690 (hard)
92-94 (fumarate) 2920, 2850, 2770, 1750, 1450, 1410, 1230, 1120, 1030, 1010, 755, 695 (net)
121-123 (fumarate)
2930, 2850, 2770, 175P, 1605, 1450, 1410, 1120, 1035, 760, 700 (net)
Test substance
table 2
Degree of suppression. %
Offerable 1
2
3
four
five
6
7
eight
10 14 17 25 27
29
Comparative
one
2 3 4 5
12.0 19.8 18.0 21.2 37.7 14.9 64.8 12.0 18.7 10.2 93.0 10.9 8.4 9.9
4.8 3.6 2.2 1.0 3.0
1402263
18 Continuation of table 1
7
29iO, 2S70, 27YO, 1755, 1610, lliO, 1420, I2i0, I PO, 1040, 1010, 760, 700 total)
2920, 2850, 2740, 1740, 1600, 1440, 1115, 1025, 1005, 745, 690 (hard)
2930, 2850, 2770, 175P, 1605, 1450, 1410, 1120, 1035, 760, 700 (net)
Table 3
Test substance
0
five
The concentration of the test substance in the solution, 10 MOL / L
The degree of blocking with respect to glutamic acid,%
Proposed
320
420
520 720
13 20
17. 20
352
362
372
402
412 Comparative
220
420
89 88 91 92 80 90 68 53 58 61 69
4 45
19140226320
Table 4
I
3
: h
. J5
4i vj
S §§
il

I
ri
20
YU
20nA
..
ZOPA
YupA
A & Aii & AAAiJkiAiiA
Time IG
PA She
time
1 minute
ig.1
Time IG
go s

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1402263A3|1988-06-07|Method of producing derivatives of 1,3-oxazolidin-2-one or acid-additive salts thereof

---

SU1428199A3|1988-09-30|Versions of method of producing derivatives of 2,2,3-iminobisethanol or acid-additive salts thereof,or stereochemical isomeric forms thereof

---

USRE33024E|1989-08-15|Bronchodilating 8-hydroxy-5-|-1-hydroxy-2-|-2-|-1-methylethyl)-amino)ethyl) carbostyril and intermediates thereof

---

SU969164A3|1982-10-23|Process for producing derivatives of phthalimidine or their salts

---

CA1121361A|1982-04-06|Spiro-oxazolidindiones

---

CH616673A5|1980-04-15|

---

US5874438A|1999-02-23|2,2&#39;-bridged bis-2,4-diaminoquinazolines

---

CA1237129A|1988-05-24|Aminoguanidine derivatives and a process for thepreparation thereof

---

JP2001512727A|2001-08-28|Bicyclic compounds as ligands for the 5HT-1 receptor

---

DE2461802A1|1975-07-17|PYRAZINE DERIVATIVES

---

FI67544C|1985-04-10|PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL PROPERTIES OF IMMEDIATE INSULATION

---

SU1620049A3|1991-01-07|Method of producing derivatives of 4-|-pyperidine butanamide or their stereo isomers, or pharmaceutically acceptable acid-additive salts

---

CA1240326A|1988-08-09|2-|-AND 2-|- 3-|-PHTALIMIDINES

---

CS264332B2|1989-07-12|Process for preparing aminoalcohols

---

EP0256181B1|1991-01-23|Novel quinaldinamide derivatives and their preparations

---

US3954765A|1976-05-04|Piperazines derivatives

---

DD208799A5|1984-04-11|PROCESS FOR PREPARING 3-PHENOXY-1-CARBONYLAMINOALKYL-AMINOPROPANOL-2-EN

---

CS270556B2|1990-07-12|Method of alkylendiamine derivative preparation

---

US4169106A|1979-09-25|Antiarrhythmic N,N&#39;-bis|amidines

---

CA1120041A|1982-03-16|.alpha.-HALOMETHYL DERIVATIVES OFAMINO ACIDS

---

US4500531A|1985-02-19|Therapeutical use of | piperazine derivatives

---

EP0573392A1|1993-12-08|Thiosemicarbazones derivatives and their use as pharmaceuticals

---

CA2001641A1|1990-05-04|Compounds for the treatment of urinary incontinence

---

GB2162843A|1986-02-12|Piperazine derivatives

---

SU1398771A3|1988-06-15|Method of producing substituted benzamides

同族专利:

---

公开号 | 公开日

---

ES8800571A1|1987-11-01|

---

DK230185D0|1985-05-23|

---

ZA854001B|1986-01-29|

---

PH20852A|1987-05-19|

---

IN162060B|1988-03-19|

---

MX161397A|1990-09-20|

---

AU566419B2|1987-10-22|

---

IT8567500D0|1985-05-30|

---

RO91422B|1987-07-02|

---

FR2571052A1|1986-04-04|

---

NL193191C|1999-02-02|

---

CS273606B2|1991-03-12|

---

ATA165685A|1990-07-15|

---

GB2165237B|1987-12-09|

---

ES543517A0|1987-11-01|

---

GB2165237A|1986-04-09|

---

MX21592A|1994-01-31|

---

DK165952C|1993-07-05|

---

US4644063A|1987-02-17|

---

RO91422A|1987-06-30|

---

AT392069B|1991-01-25|

---

NZ212143A|1987-11-27|

---

CS392785A2|1990-08-14|

---

SE463100B|1990-10-08|

---

NL193191B|1998-10-01|

---

GB8513685D0|1985-07-03|

---

HU199132B|1990-01-29|

---

KR860002502A|1986-04-26|

---

GB8512975D0|1985-06-26|

---

BR8502707A|1986-05-27|

---

MY102081A|1992-03-31|

---

HUT39168A|1986-08-28|

---

DE3519261C2|1997-01-16|

---

SE8502525L|1986-03-29|

---

ES8802152A1|1988-04-01|

---

JPS6183170A|1986-04-26|

---

AU4469785A|1986-04-10|

---

DK230185A|1986-03-29|

---

KR900004323B1|1990-06-22|

---

ES557075A0|1988-04-01|

---

FR2571052B1|1988-03-04|

---

SE8502525D0|1985-05-22|

---

AR240924A2|1991-03-27|

---

SU1431679A3|1988-10-15|

---

CH663207A5|1987-11-30|

---

DK165952B|1993-02-15|

---

AR240924A1|1991-03-27|

---

IT1208807B|1989-07-10|

---

NL8501579A|1986-04-16|

---

DE3519261A1|1986-04-10|

---

CA1252092A|1989-04-04|

---

JPH0469150B2|1992-11-05|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2437389A|1948-03-09|Oxazoeidones and erocesstok |

---

FR366M|1959-05-08|Knoll Ag|Medicines based on phthalimidine derivatives used as a cough sedative and as a local anesthetic.|

---

FR1301267A|1961-04-04|1962-08-17|Science Union Et Compagnie Soc|New derivatives of oxazolidinone-2 and their preparation methods|

---

FR3166M|1963-03-13|Smith Kline French Lab|Bronchodilator drug based on a new derivative of oxazolidone.|

---

US3576808A|1967-09-15|1971-04-27|Miles Lab|N-4-phenyl-1-piperazinylalkyl-5-phenyl-oxazolidinones|

---

GB1222708A|1968-10-22|1971-02-17|Delalande Sa|Novel 5--2-oxazolidinones and their process of preparation|

---

FR2179582B1|1972-04-13|1975-10-10|Synthelabo|JPH0517900B2|1984-09-28|1993-03-10|Nippon Chemiphar Co|

---

JPH0759570B2|1986-05-06|1995-06-28|三井東圧化学株式会社|Method for producing 2-oxazolidinones|

---

JPH0713017B2|1986-06-18|1995-02-15|日本ケミファ株式会社|Pharmaceutical composition having brain cell protective action|

---

DE3877470T2|1987-09-10|1993-06-24|Merck Sharp & Dohme|OXAZOLES AND THIAZOLES FOR TREATING SENILE DEMENTIA.|

---

EP0334674B1|1988-03-24|1994-06-01|Sankyo Company Limited|Use of isoxazolinones as cerebro-active drugs|

---

JPH0314562A|1988-04-11|1991-01-23|Nippon Chemiphar Co Ltd|Novel alkylenediamine derivative and glutamic acid-blocking agent|

---

US5187171A|1989-01-09|1993-02-16|G. D. Searle & Co.|Use of a glycine b partial agonist as an antipsychotic|

---

PH31474A|1992-07-14|1998-11-03|Nippon Chemiphar Co|N-aminoboalkyl-substituted nitrogen-containing five membered heterocyclic compounds.|

---

DE69407607T2|1993-09-15|1998-08-06|Merck Sharp & Dohme|IMIDANOLON AND OXANOLONE DERIVATIVES AS DOPAMINE ANTAGONISTS|

---

DE4425613A1|1994-07-20|1996-01-25|Bayer Ag|5-membered heteroaryl oxazolidinones|

---

US6037354A|1997-06-18|2000-03-14|Merck & Co., Inc.|Alpha 1a adrenergic receptor antagonists|

---

WO2014139975A1|2013-03-14|2014-09-18|Akzo Nobel Chemicals International B.V.|Cellulose ether as a drift control agent and rainfastness agent|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

JP59203624A|JPH0469150B2|1984-09-28|1984-09-28|

---