SU1376941A3 - Method of producing derivatives of pyrrolynone or acid-additive salts thereof - Google Patents

Abstract

Novel isoindolin derivatives represented by the following formula (I), (wherein ring A represents an optionally halogen-substituted benzene ring, X represents an optionally substituted cyclic group, Y represents an optionally esterified or amidated carboxyl group, and n represents an integer of 1 to 3), and the salts thereof. These compounds show a strong anti-anxiety effect, and are useful for prophylaxis and treatment of diseases such as psychosomatic disease and anxiety neurosis.

Description

The invention relates to the field of production of new pyrrolonone derivatives of the general formula

Z (A

about jn-x

(one)

where X is pyridyl, substituted by chlorine, unsubstituted phenyl or substituted by chlorine or methoxy group

Y is a group -COOH, -COOK, where R, C-C-alkyl, -CONR Rj, where R 2 and RJ are the same or different and each is hydrogen, C-C-alkyl, phenyl-C-C-al- kil, phenyl, thiazyl, benzothiazolyl, di-C-C-alkylamino-C, -C-alkyl, C-C5-alkoxycarbonyl-C, -C-alkyl, or RJ and RJ together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholino group, or thiazolidinyl, which are unsubstituted or substituted by hydroxyl, C-C alkyl, C5-C5-alkoxycarbonyl, unsubstituted phenyl or phenyl, substituted halogen, trifluorometkp, Z is a group or

Ring A may be substituted by halogen, if Z is a group of an integer from 1 to 3, or their acid addition salts, which have a calming central nervous system action and antispasmodic activity associated with diazepam.

The purpose of the invention is to develop, on the basis of known methods, a method for obtaining new compounds with valuable pharmacological properties with low toxicity.

Example 1. 3-Oxo-2-phenyliso indoline-1-acetic acid,

A. Concentrated hydrochloric acid (1 ml) is poured into a solution of 27 g of 3-hydroxy-2-phenylisoindolin-1-one in 300 ml of methanol and the mixture is heated at reflux for 1.5 hours. Then 200 ml of methanol are distilled off at reduced pressure and 500 ml of saturated sodium bicarbonate solution is added, followed by extraction from ethyl acetate. The extract is washed with water, dried, the solvent is distilled off and 28 g of crystals of 3-methoxy-2-fench1Oisoindolin-1-one are obtained, which, after recrystallization from ethyl acetate, have t, mp, 83-84 ° C,

Calculated,%: C 75.30; H 5.48; N 5, 85.

C ,, H ,, NO,

Found,%: C 75.57; H 5, 33;

15 N5.93,

B, A solution of 8.3 g of the above product and 6.7 g of malonic acid diethyl ester in 50 ml of dichloroethane is added dropwise to a suspension of 7.5 g

20 aluminum chloride in 80 ml of dichloroethane with stirring at room temperature. After the addition is complete, the mixture is heated at reflux for 40 minutes.

25 and then cooled. Then 300 ml in 6 is added and, the hydrochloric acid is stirred at room temperature for 1 hour, then 150 ml of dichloroethane is added, the mixture is shaken, the organic layer is separated, washed with water, aqueous sodium bicarbonate and water in that order and dried. Then, the solvent is distilled off to obtain 10.5 g of 3-oxo-2-fench1 isoindoline-1-malonic acid ethyl ester as an oil,

B. The resulting product (10.5 g) is dissolved in 20 ml of dimethylsulfoxy-40, 0.51 g of water and 1.7 g of sodium chloride are added to the solution and the mixture is stirred at 170-180 ° C for 3 hours. After cooling, the reaction mixture is poured into

.j 500 ml of ice water and extracted

400 ml of 1: 1 mixture of ethyl acetate and diethyl ether. After washing and dewatering, the solvent is distilled off. Crystalline residue. washed with hexane, collected by filtration, and 5.6 g of ethyl 3-oxo-2-phenylisoindoline-1-acetate are obtained, which is purified by recrystallization from diethyl ether, mp 109-110 ° C,

“Calculated,%: C 73.20; H 5.80j N 4.74,

with „n ,, mo,

Found,%: C 72.89; H 5.61; N 4.79,

D. The resulting crystals (5 g) are dissolved in 50 ml of methanol, 15 ml of a 15% aqueous solution of potassium carbonate are added to the solution and the mixture is heated at reflux for 1.5 hours. Methanol is distilled off under reduced pressure, after 100 ml of water and 100 ml of diethyl ether are added. The mixture is shaken, the aqueous layer is separated and acidified with concentrated hydrochloric acid. The crystalline precipitate is collected by filtration and dried. After recrystallization from methanol-ethyl acetate mixture, the indicated compounds are obtained, t. 204-205 ° C, yield 3.8 g

C, 71.90; H 4.90;

N

Calculated 5.24. uH, jNO,

Found,%: C 72.07; H 5.00; N 5.30.

Example 2. The following 3-oxo -2- (substituted-fensh1) isoindolin-1-acetic acids are obtained from the corresponding 3-hydroxy-2- (substituted-fensch 1) -isoindoline-1-itB in example 1.

A.3-Oxo-2- (2-chlorophenyl) isoindo lin-1-acetic acid.

T. pl. 163-165 ° C.

Calculated,%: C 63.82; H 4.00; M 4.64.

C ,, H ,, NO, C1

Found,%: C, 63.79 $ H, 4.12i N, 4.77.

B. 3-Oxo-2- (3-chlorophenyl) isoindo lin-1-acetic acid.

T. pl. 157-160 S.

Calculated,%: C 63.69 H 4.00; N 4.64.

SiN ,,, ШзС1

Found,%: C 63.82; H 4.04; N 4.46.

B.Z-Oxo-2- (4-chlorofensh1) isoindo lin-1-acetic acid.

T. pl. 204-205 S.

Calculated,%: C 63.69 H 4.00;

IN 4.64.

with ,, H, .NO, C1

Found,%: C 63.74; H 3.97 - N 4.16.

G. 3-Oxo-2- (4-methoxyphenyl) iso-indole-acetic acid.

T. pl. 222-223 ° C.

Calculated,%: C 68.67; H 5.08; N 4.71.

C ,, H ,, NO,

Found,%: C 68.49, - H 4.90; - N 4.69.

5 5

0

five

0

five

0

five

0

five

E. 3-Oxo-2- (5-chloro-2-pyridyl) and-zo - indole-1-acetic acid.

T. pl. ISQ-ieO C.

Calculated,%: C 59.51; H 3.66; N 9.25.

C ,, H ,, N, 0, C1

Found,%: C 59.76; H 3.66; N 9.11.

Example 3. 2-Phenyl-3-piperidinecarbonylmethylisoindolin-1-one.

A mixture of 1.8 g of 3-oxo-2-fench1isoin-dopine-1-acetic acid and 7 ml of thionyl chloride is heated at 70 ° C for 10 minutes, then the excess of thionyl chloride is distilled off under reduced pressure and the corresponding acid chloride is obtained. Triethylamine (1 ml) was added to a solution of 0.62 g of piperidine in 30 ml of methylene chloride, and this acid chloride was added portionwise to this solution while stirring at room temperature. The mixture is stirred at room temperature for an additional 30 minutes, 100 ml of netilenchloride are poured in and the entire mixture is washed with water. After dehydration, the solvent is distilled off and 1.8 g of crystals are obtained, which are recrystallized from ethyl acetate. T. pl. 122-123 ° C, 134-136 ° C (double melting point),

Calculated,%: C 75.42-, H 6.63; N 8.38.

With ,,, oi

Found,%: C 75.42; H 6.44; N 8.25.

Example 4, Analogously to Example 3. Obtain the compounds listed in Table. one.

Example 5. 3- (4-Benzylpiprazin-1-yl) carbonyl-6-phenyliso-indolin-1-on-oxalate.

The oily product (4.3 g), obtained from 2.67 g of 3-oxo-2-phenyliso-indoline-1-acetic acid and 1.94 g of 1-benzylpiperazine as in Example 3, is dissolved in 4 ml of methanol, to this solution is poured a solution of 1.5 g of oxalic acid dihydrate in 6 ml of methanol and the precipitated crystals are collected by filtration. Yield, 90 g, so pl. 207-2 ° С (recrystallized from methanol).

Calculated,%: C, 66.40; H 5.76, N 8.01.

C, H ,, N., Ov 1 / 2H, 0

Found,%: I 8.17.

C, 66.26; And 5.63;

Example 6. () KCO-2-phenyl iso-iidolin-1-propioic acid,

A, Ethyl-3-oxo-2 phenylisoindoline -1 -1 acetate (5.9 g) was dissolved in tetra hydrofuran, 0.88 g of lithium borohydride was added to the solution, the mixture was stirred for 48 h, after which the decomposition was carried out 20% acetic acid and extraction with ethyl acetate. The extract is washed with water and dried. The solvent is then distilled off and the residue is treated with a mixture of ethyl acetate and diethyl ether, to obtain 4.1 g of crystals of 3- (2-oxyethyl) -2-phenylisoindolin-1-one, m.p. 143-144 ° C.

Calculated,%: C, 75.87; H, 5.97; 5.53.

N

C ,, H ,, NO,

Found,%: C 75.88-, H 5.87 N 5.29.

B. Methylsulfonyl chloride (4.1 ml) is added to a solution of 11.0 g of the obtained crystals and 9 ml of triethylamine dichloromethane and the mixture is stirred for 10 minutes. The reaction mixture is washed with water, dried and concentrated and the residue is taken up in diethyl ether to obtain crystals (13.6 g) of 3- (2-methylsulfonyloxy-ethyl) -2-phenyl-ioindolin-1-one, mp. 100-101 ° C.

Calculated,%: C 61, 6U H 5.17; N 4.23.

C ,, H ,, NO, 5

Found,%: C 61.52; H 4.98; N 4.20.

B. The resulting mesylate (4.97 g) is dissolved in an aqueous solution of ethyl alcohol, 3.0 g of potassium cyanide is added to the solution and heated with mixture at reflux for 3 hours. Water is added and the mixture is extracted with ethyl acetate, washed with water, dried , concentrated and get crystals (3.4 g) 3-oxo--2-phenylisoindoline-3-propionitrile, so pl. 144-145 ° e.

Calculated,%: C 77.84j, H 5.38; N 10.68.

,, N, 0

N

Found,%: С 77.71 Н 5.18 $ 10.55.

D. The resulting nitrile (3.1 g) is dissolved in concentrated hydrochloric acid and the solution is heated at reflux for 15 hours. After cooling, the precipitated crystals

collected by filtration and obtain 3.3 g of 3-oxo-2-phenylisoindoline-1-propionic acid, so pl. 186 - 187 ° С.

Calculated,%: C, 72.58; H 5.37 N 4.98.

five

0

five

0

five

0

five

0

five

0 n

C ,, N „NOE Found 4.99. Prime

C 72.49-, And 5.10;

p 7. 3-Piperidinecarbonyl-2-phenylisoindolin-1-one.

Thionyl chloride (5 ml) was added to 1.4 g of 3-oxo-2-phenylisoindoline-1-propionic acid and the mixture was heated at 70 seconds for 10 minutes. To remove excess thionyl chloride, the corresponding acid chloride is obtained. The acid chloride thus obtained was added to a mixture of 0.51 g of piperidine and 1, 0 ml of triethylamine in dichloromethane, the mixture was stirred, washed with water, dried and the solvent was evaporated. The residue is taken up in ethyl acetate and crystals are obtained, m.p. 144-145 ° C.

Example 8. 3- (4-Methylpiperazin-1-yl) carbonylethyl-2-phenylisoin-dol-1-one.

In analogy to Example 7, but using 11-methylpiperazine instead of piperidine, the indicated compound was obtained. T. Sh1. 204-205 ° C.

Example 9. 3-Piperidinecaro-6-methylmethyl-2- (5-chloro-2-pyridyl) -isoINDOL-1-OH.

3-Oxo-2- (5-chloro-2-pyridyl) isoinDOL-1-OH.

3-Oxo-2- (5-chloro-2-pyridsh1) iso-indole-1-acetic acid (1 g) and triethylamine (0.8 g) are dissolved in 20 ml of anhydrous tetrahydrofuran and under ice cooling and while stirring in portions, 0.39 g of ethoxycarbonyl chloride is added. The mixture is stirred for 30 minutes, 0.56 g of piperidine is added and the whole mixture is stirred for another 30 minutes. The reaction mixture is poured into 500 ml of ice-cold water, after which it is extracted with ethyl acetate. The extract is washed with water and dried. The ethyl acetate is then distilled off and the residue is treated with diethyl ether. The crystals of the target compound thus obtained are collected by filtration and recrystallized from ethyl acetate to obtain 0.32 g of colorless crystals, m.p. 1b5-166 ° C.

P p and ep 10. In analogy to Example 9, but with the exception that 4-methylpiperazine is used instead of piperidine, 3- (D-methylpiperazin-1-yl) carbonylmethyl-2- (5- -chloro- 2-pyridyl) isoindolin-1-one, so pl. 190-193 ° C.

Example 11, Methyl-3-oxo-2- - (5-chloro-2-pyridyl) isoindoline-1-acetate.

To 1 g of 3-oxo-2- (5-chloro-2-pyridyl) isoindoline-1-acetic acid, 20 ml of 10% methanolic acid is added, and the mixture is heated at reflux temperature. After 5 hours, the reaction mixture was concentrated under reduced pressure, 100 ml of an aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed with water, dried, concentrated, and about 1 g of crystals are obtained, which are recrystallized from a mixture of ethyl acetate and dithyl ether. T. pieces 110-11GS.

Calculated,%: C 60.67; H A, 13; N 8.84.

C ,, H, N, 0, C1

Found,%: C 60.50-, H 4.13- N 8.78.

Example 12. In a manner similar to Example 11, methyl 3-oxo-2- (4-methoxyphenyl) isoindoline-1-acetate is obtained. T. pl. 80 ° C.

Calculated%: C 69.44 H 5.50 -, N 4.50.

S, VN "W,

Found,%: C 69.56; H 5.07; N 5.62.

Example 13. Analogously to Example 1 (paragraphs AB), the following compounds are prepared:

Ethyl-3-oxo-2- (3-chlorophenyl) -isoindoline-1-acetate, mp. 82-83 S.

Calculated C, 65.55; H 4.89; N 4.24.

C, gH ,, NO, Cl

Found,%: C 65.51; H 4.73; N 4.11.

Ethyl-3-oxo-2- {4-chlorophenyl) isoin of valleys-1-acetate, m.p. 55-56 ° C.

Calculated,%: C 65.55; H 4.89; N 4.24.C „H,

Found,%: C 65.27-, H 4.64 N 4.00.

Example 14. 6- (5-Chloro-2-pi ndyl) -6,7-dihydro-7-hydroxy-5H-pyrrho

to

15

„

3769418

(3,4-b) pyrazin-5-one (1.05 g) and ethoxycarbonylmethylene triphenylphosphorane (1.39 g) are dissolved in anhydrous toluene (30 ml) and the solution is heated at reflux temperature for 6 hours. the solvent is distilled off and the residue is purified by silica gel column chromatography. The fractions eluted with a mixture of dichloromethane and ethyl acetate (2: 1) are collected, the solvent is distilled off and crude crystals are obtained. After recrystallization from a mixture of diethyl ether and dichloromethane (5: 1), 1.2 g of 6- (5-chloropyridyl- 6,7-β-dihydro-7-ethoxycarbonylmethyl-5H-β-pyrrole (3,4-b) pyrazin-5-one.

five

0

five

0

five

0

five

170-17GS.

Calculated,%: C 54.14; H 3.94; N 16.84.

With .jH,

Found,%: C 54.01; H 4.00; N 16.84.

B. The obtained compound (1.2 g) is dissolved in 30 ml of methanol, 200 mg of sodium hydroxide are added to the solution and the mixture is heated to 60 ° C. After 1 h, the reaction mixture is neutralized using a mixture of 3N. hydrochloric acid and methanol and the resulting precipitated sodium chloride is filtered off. Then the filtrate is concentrated and a crystalline residue is obtained which is crude 6- (5-chloro-2-pyridyl) -6,7-dihydro-5H-pyrrol ( 3,4-b) pyrazin-5-one-7-acetic acid. This product is dissolved without purification in 20 ml of anhydrous dimethylformamide. The solution is cooled by ice and 0.5 g of K-methylpipe-azine and 0.5 ml of triethylamine are added to it, and then 0.82 g of diethyl phosphorocyanidate is added. The mixture was stirred under ice cooling for 3 hours. 100 ml of water was added to the reaction mixture, followed by extraction with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulphate. The solvent is distilled off and crude crystals are obtained. This product is recrystallized from a mixture of diethyl ether and dichloromethane (3: 1), and 1.0 g of 6- (5-chloro-2-pyridine 1) -6,7-DIHYDRO-7- (4-methyl-1-piperazine-1) is obtained. -Sh1) carbonylmethyl-5H-pyrrol (3,4-b) -pyrazin-5-one. T. pl.

 244-246 0.

Calculated,%: C 54.61; H 5.09; N 21.23.

C, jH „ClNtO, 1/2 HjO

Found: C, 54.80; H, 4.74; N, 21.21.

Example 15. A. A mixture of 3 chloro-3-hydroxy-2- (4-methoxyphenyl) isoindolin-1-one (34 g) and ethoxycarbonylmethylenetriphenylphosphorane (47 g) in dry toluene (500 ml) is carefully boiled t under reflux for 1 h. After cooling, the solvent is removed under reduced pressure

and an oil is obtained which is dissolved 15 (15.9 g) in the form of prismatic crises with ether (300 ml). After standing at room temperature for 4 hours, the separated crystals are collected by filtration to remove the triphenylphosphine oxide 20 formed during the reaction. The filtrate is concentrated and crude crystals (36 g) are obtained, which are recrystallized from a mixture of sulfuric ether: n-hexane (2: 1) and obtained pure 5-chloro-3-ethoxycarbon-25-bonylmethyl-2- (4-methoxyphenyl) iso-in-VOLIN -1-OH (32.1 g) in the form of needle-like crystals melting at 129-131 ° C.

Calculated,%: C 63.42; H 5.04; ZO N 3.89.

C, 5H jClN04

Found,%: C 63.41; H 5.07; N 3.92.

B. A mixture of 5-chloro-3-ethoxycarbonylmethyl-2- (4-methoxyphenyl) isoindolin-1-one (12.4 g) and potassium carbonate (9.1 g) in methanol: water (3: 1 ) (250 ml) is heated at 4 hours. After cooling, the solution is adjusted to pH 2.0 with 5% hydrochloric acid to isolate crystals. The crystals are collected by filtration, then they are washed with water, dried, and pure b-chloro-3-oxo-2- (4-methoxyphenyl) isoindoline-1-acetic acid (11.0 g) is obtained in the form of needles, melt at 250-251 C.

Calculated,%: C, 61.54; H 4.25; N 4.22.

G ,, H „CINO

Find about%: C 61.61-, H 4.31; N 4.23.

B. N-Methylpiperazine (8.8 g) is added to a solution of b-chloro-3-oxo-2- - (4-methoxyphenyl) isoindoline-1-acetic acid (13.3 g) and triethylamine (8.1 g ) p N, N-dimethylformamide

35

40

45

50

tal melting at 169-171 ° C.

Calculated,%: C 63.84; H 5.84; N 10.15.

C.H.,

Found,%: C 63.97; H 5.93; N 10.15.

Compounds (I) affect the central nervous system by exerting a strong sedative effect, as shown by anti-conflict tests on rats. The minimum lethal dose (honey) of the proposed compound is at least 500 mg / kg for mice, and the minimum effective dose (MED) is no more than 2.5 kg / mg for rats. Since the safety factor of a compound is very large and it has very weak narcotic and relaxing effects as side effects compared to existing benzodiazepine tranquilizers, it can be used safely and effectively as a tranquilizer.

The pharmacological properties of compounds (I) are investigated by determining their replacement power for radioactive diazepam at the benzodiazepine receptor.

Test Method Specific binding of the benzodiazepine receptor is carried out by a known method (Braestrup C. Sguires R.F. European I. Pharmacol. 1978, v. 48, p. 263-270).

So, the raw mitochondrial fractions obtained from the cerebral cortex of rats (males) of the SD type at the age of 9-10 weeks are suspended in 50 mM Tris-HC1 buffer solution (pH 7.4) and incubated with the proposed compound at one of the concentrations and ( H) diazepam (final concentration 2 nM) at 4 ° C for

(200 ml). The mixture is cooled to, after which diethylphosphorocyanic acid (7.8 g) in N, N-dimethylformamide (10 ml) is added to the solution. The reaction mixture was stirred for 4 hours. Water (500 ml) was added to the solution and the separated crystals were collected by filtration. After washing with water, the crystals are dried, recrystallized from sulfuric ether to obtain pure 5-chloro-2- (4-methoxyphenyl) -3- (4-methylpiperazin--1-yl) carbonylmethylisoindolin-1-one

0 5

ABOUT

five

0

five

0

tal melting at 169-171 ° C.

Calculated,%: C 63.84; H 5.84; N 10.15.

C.H.,

Found,%: C 63.97; H 5.93; N 10.15.

Compounds (I) affect the central nervous system by exerting a strong sedative effect, as shown by anti-conflict tests on rats. The minimum lethal dose (honey) of the proposed compound is at least 500 mg / kg for mice, and the minimum effective dose (MED) is no more than 2.5 kg / mg for rats. Since the safety factor of a compound is very large and it has very weak narcotic and relaxing effects as side effects compared to existing benzodiazepine tranquilizers, it can be used safely and effectively as a tranquilizer.

The pharmacological properties of compounds (I) are investigated by determining their replacement power for radioactive diazepam at the benzodiazepine receptor.

Test Method Specific binding of the benzodiazepine receptor is carried out by a known method (Braestrup C. Sguires R.F. European I. Pharmacol. 1978, v. 48, p. 263-270).

So, the raw mitochondrial fractions obtained from the cerebral cortex of rats (males) of the SD type at the age of 9-10 weeks are suspended in 50 mM Tris-HC1 buffer solution (pH 7.4) and incubated with the proposed compound at one of the concentrations and ( H) diazepam (final concentration 2 nM) at 4 ° C for

II

20 minutes. The suspension is then filtered through a Whatman CF / B glass fiber filter and the radioactivity (H) of diazepam on the filter is determined using a liquid scintillation method. The concentration of the proposed drug, which causes a 50% inhibition of specific binding (H) diazepam, is taken as the value of IR Sibinging concentration),

The test results in comparison with the closest compound in this area - 6- (5-chloropyrid-2-yl) -5- - (4-methyl-piperazin-1-yl) -carbonyl-OXI-7-OXO-5,6 -dihydropyrrolo- (3,4-b) -pyrazine (Zopiclone) are given in Table 2,

Claims (1)

Invention Formula The method of obtaining pyrrolinone derivatives of the general formula de X - pyridyl, substituted chlorine, unsubstituted phenyl or pups with chlorine or methoxy group Y is a COOH group, -COOR, where 35 R, -C-C-alkyl -CONR Rj, where R, and R 3 are the same or different, each is hydrogen C-C-alkyl, phenyl-C, kil, phenyl, thiazyl, benz-40 thiazolyl, di-C-C -alkylamino-C-C-alkyl, C-Su-alkoxycarbonyl-St-C-alkyl, or, R 2 and RJ together with the nitrogen atom, to which they are attached, 45-dinenes form pyrrolidinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholino, or thiazolidinyl, which are unsubstituted or substituted by hydroxyl, alkyl, C —C-alkoxycarbonyl, unsubstituted phenyl, or phenyl, substituted halide, trifluoromethyl pi- 55 Ridil or piperidil. five 6941J2 Z - group or ring A may be substituted by halogen, if Z is a group An integer from 1 to 3, or their acid addition salts, characterized in that the compound of the general formula ABOUT z to ScN, -01 20 where X, cheni; A, Z, n-have the indicated zn5 0 Q-group is SOOYA, where lower alkyl, or CN group, hydrolyzed followed by isolation of the desired product as the free acid or its acid addition salts, or the resulting acid is esterified with an alcohol of the general formula R, OH, where R is as defined or amidated with an amino compound of the general formula HN .R, Jaz R, and Rj have neither. Uk c Priority by featured; 02.04,82 with Z - group, A - unsubstituted ring, X - phenyl, unsubstituted or substituted by chlorine or methoxy group, or pyridyl substituted by chlorine, Y - COOH, COOR ,,, where R is lower alkyl, CONR jR, where R and RJ have the meanings indicated by the invention, in form - 1.3,  10.10.82 when Z is the group —N CH — CH N—, 05.02.83 at Z - the group —CH — CH — CH — CH—, A — ring, replaced by iibe with chlorine. Table 1 .Xx CHjCOK CFS Nf N-CH-, 145-148 C, jH ,, N, 0, 74.79 / 74.94 7.48 / 7.3310.06 / 10.04    " 200-201 С „НЦИ, 0, 79.00 / 79.01 6.38 / 6.39 6.83 / 6.74 136-161 C ,, H ,,, N, 0, 72.18 / 72.17 6.63 / 6.5512.03 / 11.82 wNHl / lC HsOH 238-244 C ,, H ,, N, 0 ,. 63.87 / 63.73 6.38 / 6.03 10.64 / 10.93 "HCl 1/2 C, HjO H N (JN-O 168-190 C, jH ,,, 75.89 / 75.82 6.12 / 6.29 10.21 / 9.94  GN-Q 166-180 C, jH, 4ClN, 0, 70.02 / 70.04 5.43 / 5.32 9.42 / 9.34 H C O192-206С „Н ,, 79 / 72,635,87 / 6,1013,58 / 13,50 AND H ГG SNt / L ° 207-210С, H „H4 O, 66.40 / 66.265.76 / 5.638.01 / 8.17  COOH, H, 0 "- 1 / 2H, 0 J / 2H, 0 H wQN-COOCjHs ® "at l ° 467.79 / 68.006.18 / 6.0810.31 / 10.22 H VQO144-146С, .Н „Н ,, 41 / 71,495,99 / 5,838,33 / 7,95 IN-О177-178С „Н“ 11,0.77.17 / 77,403.30 / 5.37в, 1в / 8.2г NN "with", eao;. ", 139-140C" N "M" 68,17 / 67,855,72 / 6,127,95 / 7,77  ky5 . HH (™,  M (3 0-C1 wQw-CHj-C1 nQ -C1 NQtbcHj P-CI "O p-ci kon-sh p-oce ,, wQ P-OCB, WQN-CH H hZ H  iWiH- JCCHi i  O-q HCt f 347-248 DSCN, 0.865.31 / 65.394.33 / 4.2112.03 / 11.46 265.5267 ,, 869.15 / 69,324.29 / 4.2410.52 / 10.46 oilC ,, H, R, 0, 72.30 / 70.517.45 / 7.4911.50 / 11.32 139-140C ,, H ,, HiO, Cl6v, 3b / 6b, 415.73 / 5.577.59 / 7.38 132-134С „Н„ Н, 0, С165,70 / 65,575,77 / 5,7610,95 / 10,61 123-124С „Н„ Н, 0, С168,38 / 68,135,73 / 5,537,59 / 7,34 126-1 7С „Н, И, 0, С165,70 / 65,805,77 / 5,6010,95 / 10,89 128-129C ,, H ,, N OtCl68.38 / 68,535,73 / 5,767,59 / 7,42 154-155Ct, H ,, H /), Cl65.70 / 65.475.77 / 5.7910.95 / 10.6 (1 86-88C ,, H, iH, Oj72.5) / 72,546.64 / 6,797.69 / 8.00 138-140CuHtjH., 63 / 69,596.64 / 6, 11.08 / 11.10 175-176C, jH ,, J, 0, S67.43 / 67.39 5.36 / 5.358.28 / 8.08 48-62 Ct, Hi ,. 70.39 / 70.55 7.63 / 7.54 10.26 / 10.10 4CH, a) 102-135 C ,, 0 ,. 62.85 / 62.88 4.88 / 4.94 8.14 / 8.12 "EC1  Dual temperature pajlvvi. About EYL eine taVl. one II NHC Table 2 ZOPIKLON