SU1438611A3 - Method of producing derivatives of 1.5-benzoxathiepyn or acid-additive salts thereof - Google Patents

Abstract

Novel 1,5-benzoxathiepin derivatives represented by formula (I) wherein R1 and R2 each represents hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy, R3 and R4 each represents hydrogen, lower alkyl or optionally substituted aralkyl, or, when combined together, they form a ring together with the adjacent nitrogen atom, X represents hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally esterified or amidated carboxyl, Y represents <SIGN> C=O or <SIGN> CH-OR5 (wherein R5 represents hydrogen, acyl or optionally substituted amido), m represents an integer of 0 to 2, and n represents an integer of 1 to 6, and salts thereof have a serotonin S2 receptor-blocking effect, and are useful as agents for preventing or treating ischemic heart disease, thrombosis, and hypertensive.

Description

one

The invention relates to a method for producing new 1,5-benzoxateepine derivatives having specific serotonin 3 -receptor blocking activity, which can be used in medicine.

The purpose of the invention is to develop new derivatives of J, 5-6 benzoxcetiepine, which possess valuable biologically active properties.

An example. 44.7 g of 2-mercapto-4-labels of syphenol and 88 g of methyl bromoacetate are dissolved in 350 ml of acetone and 88 g of anhydrous potassium carbonate are added to the solution, followed by stirring at room temperature for 5 hours and then heated at boiling points. reflux for 5 h. After TorOj as the mixture is cooled, the inorganic substance is filtered, the filtrate is concentrated under reduced pressure. The residue is recrystallized from a mixture of ethyl acetate and hexane to give 65 g of colorless crystals of methyl 4-methoxy-2-methoxycarbonylmethylthiophenoxyacetate, mp,

Calculated,%: C 51.99, H.

 GE f6 4 S

Found,%: C 52.18; H 5.37.

Example 2. In 300 ml of N, N-dimethylformamide, 94.4 g of methyl 4-methoxy-2-methoxycarbonylmethyl-thiophenoxyacetate is dissolved, and 67% of sodium methoxide 28% is added dropwise to the solution. while cooling with ice n stirred. The reaction mixture is stirred for 1 h and dissolved in oh.

ice-laden water containing 40 times by stirring at 80-90 ° C in

for 30 minutes After cooling the reaction mixture, the 14 mmonium chloride, which is distilled off, is filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane, a mixture of colorless 7-methoxy-3-oxo-3,4-dihydro-2H-1.57 benzoxathiphen-4-carbonitrile prisms. Yield 5.1 g, m.p. 32-133 C.

Calculated,%: C 56.16; H 3.86; N 5.95.

hydrochloric acid, and the precipitate is collected by filtration, washed with water, dried and then recrystallized from a mixture of ethyl acetate and hexane, to obtain 58.7 g of colorless crystals of Methyl-7-methoxy-3-oxo-3, 4-dihydro-2H - I, 5-benzoxathiepin-4-carboxylate, so pl. 79-81 ° C.

Calculated: C 53.72; H 4.51,

Found,%; C 53.72; H 4.40.

Example4. 60 g of 2-mercapto-4-methoxyphenol and 67 g of chloroacetonitrile are dissolved in 600 ml of acetone to the solution. At room temperature, 125 g of anhydrous potassium carbonate is added under stirring at room temperature in a temperature of 50 ml of nitrogen gas.

C ,, HgN03

Found,%: C 56.08; H 3.79; N 5.85.

Example 15 g of 7-methoxy-3-oxo-3,4 dihydro-2H-1, 5-benzoxathiepine-4-carbonitrile is dissolved in 200 ml of methanol and the solution is saturated with dried N

3 hours and then heated under reflux for 5 hours. After the reaction mixture is cooled, the inorganic substance is filtered, the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethanol to give colorless 2 cyanomethylthio-4-methoxyphenoxyacetonitrile prisms. Yield 65 g, mp, 53-54 s. Calculated D: C 56j39; H 4.30; P, 96.

five

five

C.

N

0

0

j

Found,%: C 56.57; H 4.32; 11.78.

Example4. 30 g of 2 cyanomethylthio-4-methoxyphenoxyacetonitrile are dissolved in 120 ml of NL, N-dimethylformamide, 30 g of 28% sodium methoxide is added dropwise to the solution while cooling with ice and in a stream of nitrogen gas while stirring followed by stirring for 2 hours. The reaction mixture is poured into ice-cold water containing 12 g of acetic acid Lot, and the precipitate is collected by filtration, washed, washed with water and recrystallized from chloroform to give colorless 3-amino-2H- prism. 1,5-benzoxathiepin-4-carbonitrile, yield 19.5 g, mp 203-205 C.

I

Example5. 60ml ethanol

6.0 g of 3-amino-7-methoxy-2H-1,5-benzoxathiepine-4-carbonitrile are suspended, 18 ml of concentrated hydrochloric acid are added to the suspension, after C, HgN03

Found,%: C 56.08; H 3.79; N 5.85.

Example 15 g of 7-methoxy-3-oxo-3,4 dihydro-2H-1, 5-benzoxathiepine-4-carbonitrile is dissolved in 200 ml of methanol and the solution is saturated with dried hydrogen chloride, kept at room temperature for 4 days. 10 ml of water are added to the reaction solution, the mixture is incubated overnight and it is concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent:

you-

611

Noah doublet, C ,, - H); (H, snng et.

C4-H).

Example P. 4-chloro-2-mercapta-phenol is treated with methyl bromoacetate in the same manner as in Example 1J to give methyl 4-chloro-2-methoxycarbonylmethylthiophenoxyacetate as colorless prisms (after

chloroform) to obtain 6.0 g of methyl-io steellation from a mixture of ethyl acetatehexiC

7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, together with 6.0 g of starting material, which is consumed.

Example, Similarly, as described in Example 1, methyl 2-methoxycarbonylmethylthiophenoxyacetate is prepared from 2-mercaptophenol and methyl bromoacetate. Recrystallization from a mixture of hexane-ethyl acetate gives a colorless 1e prism, t, mp, 65-66 °,

Calculated,%: C, 53.32; H 5.22.

C ft N, 4 058

Found,%: C 53.20; H 5.29,

Example 8. Ketil-2-methoxy-carbonylmethylthiophenoxyacetate is treated in the same manner as described in Example 2 to obtain a colorless oily substance methyl 3-oxo-3,4-dngydro-2H-1,5-benzoxate chiep-4-30 carboxylate.

Calculated,%: C 55.45; H 4.23.

C,

Found,%: C 55.33; H 4.41.

EXAMPLE 9, 2-Mercapto-4-methylphenyl is treated with methyl bromoacetate in the same manner as described in Example 1 to yield methyl 2-methoxy-carbonylmethylthio-4-methylphenoxy-20

25

San), Tpl, 1b-1TS. ViñisloD: C 47.30; H 4.30.

C iHjjClOjS

Found,%: With 47,40; H 4.29,

Example 12 Methyl-4-chloro-2-methoxycarbonylmethylthiophenoxyacetate is treated with sodium methylate in the same manner as described in Example 2 to obtain methyl 7-chloro-3-oxo-3,4-di-HYDRO-2H-1,5-benzoxate-naphyl- 4-carboxy silate in the form of colorless needles, T, pl, 92-94 ° C,

Calculated,%: C 48.45; H 3.33,

Cf HgClO S

Found ,, C, 48.45; H 3.06, Example 13, Mixture of 10 g methyl 7-metsxy-3-oxo-3,4-dihydro-2H-1.5 benzoxate-4-carboxylate, 9.8 3- (4-phenylpiperazin-1-yl ) -propyl chloride, 6.2 g of anhydrous carbonate catalysts, 3.0 g of potassium iodide and 150 ml of methyl ethyl ketone are stirred at reflux for 25 hours. After the mixture is cooled, the inorganic substance is filtered, the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, the solution of the protat in the form of colorless prisms after being washed with water and dried. Solvent

recrystallization from methanol, mp; 45-46 ° C;

Calculated,%: C 54.92; H 5.67,

1ZN, Oy8.

Found,%: C 55.10; H 5.70.

Example 10 Methyl 2-methoxycarbonylmethyl thio-4-methylphenoyl acetate (8.9 g) is treated with sodium methoxide in the same manner as described in Example 2 to give methyl 7-methyl-3-oxo-3, 4-DIHIDRO-2H-1,5-benzoxate-pin-4-carboxylate (5.8 g as a colorless oil. Mass spectrum (m / e): 252 (I),

IR,)

WUCTVlfi M "KS

cm

1730-1750 ()

55% found: C 63.50; H 6.37; N 5.71,

; Example 14. In a mixture of soluble MP (CDCl.j) tf: 2.23 (3N, s,), 40 ml of tetrahydrofuran and 200 ml 3.80 (3N, s, СООСН); 4.62 (2H, dichanol, 38 g of methyl 7-methane elimination from ethyl acetate – hexiC

San), Tpl, 1b-1TS. ViñisloD: C 47.30; H 4.30.

C iHjjClOjS

Found,%: With 47,40; H 4.29,

Example 12 Methyl-4-chloro-2-methoxycarbonylmethylthiophenoxyacetate is treated with sodium methylate in the same manner as described in Example 2 to give methyl 7-chloro-3-oxo-3,4-di-HYDRO-2H-1,5-benzoxiethiepin -4-carboxylate in the form of colorless needles, T, pl, 92-94 ° C,

Calculated,%: C 48.45; H 3.33,

Cf HgClO S

Found ,, C, 48.45; H 3.06, Example 13, Mixture of 10 g of methyl 7-metsxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate, 9.8 g of 3- (4-phenylpiperazin-1 -yl) -propyl chloride, 6.2 g of anhydrous potassium carbonate, 3.0 g of potassium iodide and 150 ml of methyl ethyl ketone are stirred at reflux for 25 hours. After the mixture is cooled, the inorganic substance is filtered, the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, the solution is evaporated under reduced pressure, the resulting residue is purified by chromatography on a silica gel column (eluant: hexane: ethyl acetate

3: 1) to obtain methyl 7-methoxy-3-ca- (4-phenyl-piperazin-1-yl) propyl-3, 4-dihydro-2H-1, 5-benzoxate-pin-4-carboxylate, Recrystallization from methanol gives white crystals

T, pl. 110-112 0. Output 2.1 g.

Calculated,%: C 63.81; H 6.43; N 5.95,

Found,%: C 63.50; H 6.37; N 5.71,

I toxi-3-oxo-4p- (4-phenylpiperizin-: - 1-yl) -propyl-3, A-dihydro 2H 1, 5-benzoxate-4-carboxylate obtained in example 1, to a solution with ice cooling and mixing pores; 3.7 g of sodium borohydride are added to cy. After completion of the reaction, the solution; The solvent was evaporated under reduced pressure: water was added to the residue, followed by extraction with ethyl acetate. The organic layers are combined, washed with water, dried, the solvent is ground under reduced pressure. The resulting residues from the jg-razin-bil) propyl 3-3,4-dihydro-2H-current are separated and purified using chro-1, 5-benzoxathiepine-4-carboxylate, silica gel como-graphy (eluent: hexane- ethyl acetate-methanol (20: 10: 1). From the first eluate, 12 g of a colorless oily substance is obtained - methyl trans-3 hydroxy-7-meth; si-4-C3- (4-phenylpiperazin-1-yl) propyl-3,4-DIGIDRO-2H-I, 5-benzoxate "-pin-4-carboxylate,

IR (pure), 3520, 25 C THgyNz tS

After recrystallization from acetate, n-hexane turns into colorless prisms. M.p. i68-170 ° C. 20 The structure of the product can be determined by the X-ray analysis of the crystals.

Calculated,%; C, 63.01; H 6.66; N 5.44.

.1720,

5ShR spectrum (CDCl1) / 3.45 (3N, singlet, OCHj); 3.60 (SN, singlet, OCHj),

The compound is powdered as the hydrochloride salt,

Calculated,%: C 54.15; H 6.36 $ N 5.05.

CzjHjiN OyS - 2HC1 .. 1/2 HjO

Found,%: C 54.27; H N 4.89.

From the subsequent eluate, 18 g of a colorless oily substance — methyl cis-3-hydroxy-7-methoxy-4-3- (4-feshpypiperazine-1-sh1) -propyl} -3.4-dihydro-2H-1, 5-benzoxathayeline are obtained. -4-car- boxylate

IR shutter (clean) cm; 3530, 1740,

NMR spectrum (CDC1) i 3.60 (EH, singlet, OSI ,.); 3.62 (ZN, singlet, OSI h).

The compound is in the form of hydrochloride salt, T, pl, 165-175 C (decomposed).

Calculated,%: C 54.15; H 6.36; N 5.05,

Cj5H3iN2p5S - 2HCl-l / 2 HjO

Found,% i C 54.02; H 6.33; N 5.00.

  Example 15: The compound obtained in Example 4 (0.5 g) was dissolved in pyridine (6 ml) and 3 ml of acetic anhydride was added to the solution,

thirty

Found,%: C 63.01; H 6.69;

N 5.40. t

Example 16, V5 ml of methanol

160 mg of methyl cis-3-hydroxy-7-methoxy-3- (4-phenyl-piperazin-1-yl) -propyl} -Zy4-dihydro-2H-1,5-benzoxy-thipin-4-carboxylate obtained in Example 1 is dissolved 14, 3 ml of 1N sodium hydroxide solution was added to the solution, followed by stirring for an hour. The reaction solution was concentrated under reduced pressure, and 5 ml of water was added to the residue. Make up the pH of the mixture to 3-4 mononormal

40

45

50

65

The solution is cooled with hydrochloric acid and cooled. The precipitate is collected by filtration and washed with acetone. 0.13 g is obtained in the form of white crystals of cis-3-hydroxy-7-methoxy-4-3- (4-phenylpiperzin-1-yl) propyl} -3,4-DIHYDRO-2H-1, 5-benzoxy-typin -4-carboxylic acid. M.p. 250-260 ° C (decomposition).

Calculated,%: C, 60.48; H 6.77; N 5.88.

C2.4H3UN205-S

Found,%: C 60.27; H 5.96; H. N 5.66,

Example 17 In the manner described in Example 13, methyl 3-oxo-3,4-DIHYDRO-2H-1,5-benzoxothiophen-4-carboxilate is subjected to condensation with 3- (4-phenylpiperazin-1-yl) -propyl 1-chloro- house and isolate methyl 3-oxo-3- (4-fept after which the mixture is kept at room temperature for 20 hours. The reaction solution is poured into ice-cold water and extracted with ethyl acetate. The organic layer is washed with an aqueous solution of acetic acid and a solution of bicarbonate. sodium and successively with water, dried over anhydrous and dried by drying under reduced pressure. after recrystallization from ethyl acetate-n-hexane to give 0.45 g of methyl cis-3-acetoxy-7-methoxy-4-SZ- (4-fenilpipe25 C THgyNz tS

After recrystallization from acetate, n-hexane turns into colorless prisms. M.p. i68-170 ° C. 20 The structure of the product can be determined by the X-ray analysis of the crystals.

Calculated,%; C, 63.01; H 6.66; N 5.44.

5 C THgyNz tS

0

Found,%: C 63.01; H 6.69;

N 5.40. t

Example 16, V5 ml of methanol

160 mg of methyl cis-3-hydroxy-7-methoxy-3- (4-phenyl-piperazin-1-yl) -propyl} -Zy4-dihydro-2H-1,5-benzoxy-thipin-4-carboxylate obtained in Example 1 is dissolved 14, 3 ml of 1N sodium hydroxide solution was added to the solution, followed by stirring for an hour. The reaction solution was concentrated under reduced pressure, and 5 ml of water was added to the residue. Make up the pH of the mixture to 3-4 mononormal

0

five

0

five

The solution is cooled with hydrochloric acid and cooled. The precipitate is collected by filtration and washed with acetone. 0.13 g is obtained in the form of white crystals of cis-3-hydroxy-7-methoxy-4-3- (4-phenylpiperzin-1-yl) propyl} -3,4-DIHYDRO-2H-1, 5-benzoxy-typin -4-carboxylic acid. M.p. 250-260 ° C (decomposition).

Calculated,%: C, 60.48; H 6.77; N 5.88.

C2.4H3UN205-S

Found,%: C 60.27; H 5.96; H. N 5.66,

Example 17 In the manner described in Example 13, methyl 3-oxo-3,4-DIHYDRO-2H-1,5-benzoxothiophen-4-carboxilate is subjected to condensation with 3- (4-phenylpiperazin-1-yl) -propyl 1-chloro- house and isolate methyl 3-oxo-3- (4-fe714386P8

nilpiperazin-1 yl) -propyl-3,4-dihydro-chromatography on a column of silica gel-RO-2H-1,5-benzoxate-4-carboxymelem (eluent: hexane-ethyl acetate 1: 1) lat in the form of the hydrochloride salt , and 50 mg are obtained as colorless. By recrystallization of a semi-oily product ethyl cis-3-o-white from methanol, white crystals are formed. T, pl. 176-178 s. si-7-methoxy-4-3- (4-phenylpiperazine CalcdO: C 59.67; H 6.26; I-yl) propyl} -3,4-dihydro 2H-1,5-benne- N 5.80 . oxoxathiepin-4-carboxylate, which

C2 HjgNj04S HC1 1/2 HjO turns into a white powder (amorph. Found,%: C 5H, 49; H 6.33; young powder) as hydrogen chloride - N 5.71. Of the salt. -

Example 18. The method described - Calculated,%: C 55,36; H 6.52; Nym in example 14, methyl hydrochloride- N 4.97.

3-oxo-3- (4-phenylpiperazin-1-yl) pro, 4N205S 2HCl 1/4 H / jO. pilZ-3,4-dihydro-2H-1,5-benzoxate- 15 Found,%: C 55.30; H 6.64; pio-4-carboxes1 restore N 4.94.

sodium borohydride. Implantation and purification. EXAMPLE 20 Methyl 7-methyl-i-flux is carried out using chromate. oxo-3,4-dihydro-2H-1,5-benzoxate graphene on a column of silica gel (elupine-4-carboxylate (1.7 g) is alkylated ent: hexane-ethyl acetate; ganol 10:10: 20 3- (4-phenylpiperazin-1-yl) propyl-chloro- 1). The trans and cis derivatives are obtained in the manner described in example 13 from the first and second eluant, respectively, and methyl 7-methyl-3-oxo-4-is obtained. C3- (4-phenylpiperazin-1-yl) - Propyl Methyl cis-3-hydroxy-4-f3- (4-phenyl-3,4-dihydro-2H-1, 5-benzoxathiepin-4-perazin-1-sh1) propyl-3,4-dihydro-2H-25 carboxylate (0.9 g) as colorless 1,5-benzoxathiepin-4-carboxylate di-oil.

hydrochloride. Recrystallization: from the Mass spectrum (ha / e) 454 (M). methanol-ethyl acetate get colorless-. , cleansing .t ,,., „. ... records. M.p. 196-198 0. m-ks. cm: 1760, 1730 ().

Calculated,%: C 55.92; H 6.26; 30 CR (CDCl1) “, ppm: 2.22 (3N, N 5.43 singlet,); 3.72 (SN, singlet,

C24H3cN, 204S - 2HC1CO-ghosn), 4.62 (2H, double doublet.

Found,%: C 55.73; H 6.15; ). N 5.51. Hydrochloride, white crystals,

Methyl trans-3-hydroxy-35 dihydrochloride, 35 t.p. 140-150 ° C (decomposition). (4-Phenylpiperazin-1-yl) propyl J-Calculated,%: C 55.96; H 6.20;

3,4-dihydro-2H-1,5-benzoxathiepin-4-N 5.22.

carboxylate. White powder (amorphous C / jH - 2HC1 1/2 HjO.

powder). Found,%: C 56.11; H 6.19; N5.11.

Calculated,%: C 55.28; H 6.31; 40 EXAMPLE 21 Methyl 7-chloro-3-C5N5, 37.co-3,4-dihydro-2H-1,5 - benzoxate C4-C 4HccM 048 2HC1-1 / 3H O4 -carboxylate is alkylated with 3- (4-phenyl; Found,%: C 55.29; AND 6.49; N5.11 piperazin-1-yl) propyl chloride with a sample of Example 19. Vzml ethanolab, described in example 13, and half-dissolved 0.12 g of cis-3-hydroxy-7-marks-45-methyl methyl 7-chloro-3-oxo-4- 3- (4-fes-4- 3 - (4-fenztiperazin-1-sh1) -propyl-piperazin-1-yl) propyl-3,4-dihyd-,

, 4-DIHIDRO-2H-1,5-benzoxate-ro-2H-1,5-benzoxathiepin-4-carboxypin-4-carboxylic acid, obtained: lat, which is isolated as a hydro- in example 16, and to a solution chloride (white crystals) was added, m.p. 197-50 mg of diethyl sulfate and 100 mg of acidic 50.

th sodium carbonate followed, Calculated,%: C 52.18; H 5.38;

by heating at reflux-N 5.07.

matsii for 3 h, Reakhshonon rast-C 4N27Cur4 C 2HC1-1 / 4

the thief is poured into water with the subsequent ex-Found,%: C 52.11; H 5, 1;

traction with ethyl acetate. Organic 55 N 4.98.

the layer is washed with water, dried with a solution of PRI me R 22. Methyl 7-methyl-spectator is evaporated under a carbonated pressure-oxo-4-g- (4-phenylpiperazin-1-yl) treatment. The residue obtained is purified, 4-dihydro-2H-1, 5-benzoxate-.

pin-4-carboxylate (0.9 g) is reduced by sodium borohydride using the procedure described in Example 14, and methyl cis- and trais-3-oxo-7-methyl-4-phenyl-piperazin-J-yl (propyl) - 3,4-di-HYDRO-2H-J1,5-benzoxathiepin-4-carboxylate, Cis-isomar (colorless oil).

IR cm-: 3540 (OH)} 1740 (C "0).

NMR (CDCl1) t / ppm; 2.35 (ZN, singlet, C., - CHj), 3.75 (ZN, singlet,).

Hydrochloride cis isomer (white powder). .. ...

Calculated,%; C, 58.73; H 6.60 | N 5.48.

C-j yHaiN O S 1,5 HCl

Found,%: C 58.68; H 6.96j N 5.31.

Trans isomer (colorless oil).

IR

mock C3550 (OH); 1730

()

NMR (CDCl 2), ppm: 2.25 (3N, singlet, C7-CH3) | 3.52 (ZN, singlet,).

Hydrochloride trans-isomer, white crystals, mp, 145-155 ° C.

Calculated,% s C 56.23; H 6.51 | N5.25.

CjjHg NjrO S 2HC1 1/4

Found,%: C 56.39; H 6.53; N 5.24.

Example 23. Methyl 7-chloro-3-ca-4-C3- (4-phenylpiperazin-1-yl) pro-, 4-dihydro-2H-1, 5-benzox-pin-4-carboxylate is reduced by sodium borohydride described in example 14, and get methyl cis - and. trans-7-chloro-3-hydroxy-4- 3- (4 phenylpiperazin-1-yl) propyl, 4-di HYDRO-2H-1, 5-benoxoxiepin-4-carb-oxylate.

Calculated,%: C, 51.578; H 5.77; N 5.01.

Ca HjjNiO S -1/2

Found,% g C 51.77; H 5.79; N4.97.

Hydrochloride trans-isomer, white crystals, m.p. 15O-160-C (decom.)

Calculated,%: C, 52.42; H 5.68; N 5.09.

Ci4Hi9N.i04SCl - 2HC1

Found,% C 52.24; H 5.76; N4.97.

1438611

ten

PRI me R 24. Optical resolution of I ± I methyl cis-3-hydroxy-7-methoxy-4-t 3 - (4-phenyl-shterazin-1 -yl) propyl-3,4-dihydro-2H-1, 5-benzatoxypin-4-carboxylate.

(t) Methyl cis-3-hydroxy-7-methoxy-4- 3- (4-phenylpiperazin-1-yl) propyl-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate (1, 3 g) and S - (+) -, G binaphthyl-2,2-diyl acid phosphate (1.0 g) was dissolved in methanol (50 ml). The solution is evaporated in vacuo. The residue is dissolved in acetone-methanol and kept in a refrigerator. The crystalline precipitate is filtered off and recrystallized three times from an acetone-methanol mixture, to obtain white crystals of 1 of +175.5 (, 01, methanol).

A suspension of the obtained crystals in methylene chloride is treated with 1N, sodium hydroxide solution. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. A free base is obtained in the form of a colorless oil. The resulting base is dissolved in ethanol, treated with hydrogen chloride and evaporated in vacuo. The residue is triturated with a mixture of methanol-ether and get / - / methyl cis-3-hydroxy-7-methoxy-4-f3- (4-phenylpiperazin-1-yl) propyl} -3, 4-dihydro-2H-1, 5-benzoxathiepin-4-carboxylate dihydrochloride as an amorphous powder,

, 0 (, 54 in methanol). Calculated,%; C 54.15; H 6.36; N 5.05.

 -ZHCl 1/2 Found: C 53.98; H 6.18; N 4.83.

EXAMPLE 25. In the manner described in Example 12, salt (t) methyl cis-3-hydroxy-7-methoxy-4-C 3- (4-phenylpiperazin-1-yl) propyl 3-3.4- dihydro-2H-1,5-benzoxathiepin-4-carboxylate. and R - / - / - 1,1-binaphthyl-2,2-diyl acid phosphate was recrystallized three times from an acetone-methanol mixture to obtain white crystals -172 (, 03, methanol). The resulting salt is treated with 1N, sodium hydroxide solution, followed by treatment with hydrogen chloride and get / + / methyl cis-3-hydroxy-7-methoxy-4- 3- (4-phenylpiperazin-1-yl) propane-3,4DIGIDRO-2H -1, 5-benzoxathiepin-4-carboxylate dihydrochloride as an amorphous powder.

, + 110.8 ° (, 48.in methanol)

Calculated,%: C 54.15} H, 6.36; N 6.05.

Czf nNiOfS 2HC1 1/2 H-jO

Found,%: C 54.11; H 5.93; N 4.80.

An example of experiment 1.

Surotinin - receptor blocking by the proposed compound.

The experimental method.

The experiment was carried out according to the method of Bevan and Osher with some changes. The heart of a pig just killed in a slaughterhouse was preserved by cooling with ice, and the left coronary artery was dissected no later than 3 hours. The coronary artery was cut into an annular preparation, approximately 3 mm wide, which was placed with Kryuchkov vapors in a dividing vessel containing 20 ml of Krebs-Hensel solution. One of the hooks was attached to the bottom of the tub, while the second was connected to the strain-gaige sensor

Thus, it was isometric for 30 sterile conditions under general anesthesia with

measured and recorded on a polygraph compression of the ring preparation of the coronary artery of the pig. The bath temperature was maintained at 37 ° C, and the Kresbagenzelet solution, consisting of 118.3 mg / molecule iJaCl, 4.7 mmol KC1, 1.2 mmol KH2P04, 2.58 mmol CaC1 -2H-p, 1.15 mmol MgS04 7H20, 25 mmol of mansous and 11.1 mmol of glucose were mixed with mixed gas of 97% 3% CO.

After 1-2 hours, when the blood vessel preparation showed stable bath at an interval of approximately 1 hour, to check the reaction, the preparative tension, the rest, the tension resting in the femoral vein, was observed brought to 2 g and 10 M serotonin ( a temporary hypertonic response to the last concentration was added depending on the dose, and when 30 mg / kg

serotonin was administered, for example, again with an interval of 30 minutes, then it was withdrawn). When the blood vessel gg reaction is labeled with a reductive hypertonic reaction, 2-3 serotonin supplements are stacked. Therefore, 30 g / kg of serotol is stable, the concentration of test compound was added to the bath 10 minutes before the next addition of serotonin. The serotonergic blocking effect of the test compound has been applied to the sub-oral regimen to study the effect of oral administration of the proposed compound. After 55 it was confirmed that 2-3 intravenous administration of 30 g / kg serotonin with an interval of about 30 minutes gave a stable hypertonic response. Compound (1) (Example

the amount of compression caused by her-rotonin before and after adding the test compound.

The results of the experiment regarding 1-el Proposed compounds are shown in Table i.

Experiment Example 2 In the same manner as described in the first Experiment Example, the serotonergic effect of blocking the test compound was measured.

The results of the study of biological activity for example 13; concentration 10; number of cases 3; serotonin contraction inhibition 70.71 ± 2.0%.

Experiment Example 3

The oral serotonergic effect of blocking the proposed compounds.

Experimental method

The experiment was carried out on male short-horned dogs weighing 10-14 kg. Polyethylene tubes were pre-implanted in the femoral arteries and veins to change the systematic blood pressure and, accordingly, for intravenous administration of the test compound. A surgical procedure for the implantation of polyethylene tubes was performed in

used sodium rbital pentob (30 mg / kg intravenous use). The other ends of the polyethylene tubes were connected subcutaneously to the dorsal part of the body and brought out.

The experiment was carried out 2–3 days after surgery. A polyethylene tube inserted into the artery was connected to a pressure transducer and the systemic blood pressure was measured and continuously recorded on a polygraph. When 3 to 30 mg / kg of serotonin was injected intravenously: through a polyethylene tube, insert serotonin was administered, for example, again with an interval of 30 minutes, then a reducing hypertonic reaction was noted. Therefore, 30 g / kg seroto-

Nina was used to investigate the effect of oral administration of the proposed compound. After it was confirmed that 2-3 intravenous administration of 30 g / kg serotonin with an interval of about 30 minutes gave a stable hypertonic response. Compound (1) (Example

13

2, cis-omer-dihydrochloride) was orally administered in doses of O, li 0.3, k}, 0 mg / kg and the hypertonic response to 30 | M g / kg serotonin was constantly tested until it received a hypertonic level reactions equal to the level before the drug is given.

The results of the experiment.

The results of the experiment of the compound of Example 2 (cis-isomer-dihydro-chloride) are listed in Table 2. Use in doses of at least 0.1 mg / kg has shown a dose-dependent and sustained inhibition of hypertensive reaction to serotonin.

Experiment Example 4,

The experimental method.

The mesentery in a rat with spontaneous hypertension (age A weeks, male) was removed and the Krebs-Genzeleite solution was sprayed through the spray artery and heated to 37 C. The main current was approximately 4 ml / min, with a perfusion pressure of about 40 mm Hg . Used as an indicator of calcium antagonism, the inhibition of the growth of perfusion pressure is caused by the injection of 10 mg of KC1 preparation into the sprinkling artery. The test compound was introduced into the artery 30 minutes before

KC1 injections.

The results of the experiment.

The results are shown in table 3. In cases when the control group was not used, the increase in the perfusion pressure due to KC1 was 73120 (the value for 8 cases was ± 8ЕМ / m Hg, which was indicated in Table A as 1Ov%). The compound of Example 2, when used in doses of 0–3–10, showed, depending on the dose, significant inhibition caused by KC1 increase in perfusion pressure.

Experiment Example 5

Diuretic action

The experimental method.

In the experiment, four of the five groups of rats with spontaneous hypertension (at the age of 13 weeks, males) were used. The experimental compound was suspended in an isotonic salt with a small amount of gum ARABIC and taken orally in an amount of 25 ml / kg. An isotonic salt containing only gum ARABIC was also given to the control salt. After application, each rat was planted for 5 hours in the metabolism cage for

one

The amount of urine and if - to

86111

urine collection

honestly urinary Na and K were measured. The concentrations of Na and K were determined using a flame spectrophotometer (Hitachi type 205DT). The results of the experiment. The results are shown in table 4. The compound of example 2 (cis-isomer-dihyd-) Q rochloid) when administered orally in doses of 3 mg / kg has a tendency to

to promote urine excretion, as well as Na and K, and when administered orally in doses of 10 mg / kg, a significant increase in the amount of urine and an increase in the excretion of Ka and K. 30 mg / kg lead to a significant increase in the amount of urine n and K excretion.

Experiment Example 6. Antithrombotic effect on the coronary circulation of anesthetized dogs.

The experimental method. Adult non-purebred dogs were subjected to a Taracotomy under the anesthesia of sodium pentobarbital. Intracoronary thrombosis was performed according to the method of Folts et al. The arterial canal was inserted into the left surrounding coronary artery, and arterial blood was drawn from the common carotid artery through the extracorporeal-. arterial perfusion circuit.

Coronary blood flow was measured using an electromagnetic flow probe placed in an extracorporeal circuit. The plastic constrictor is located around the surrounding coronary artery to constrict by 70–80%. The formation of intracoronary thrombosis was established by the periodic occurrence of a decrease and increase in coronary blood flow,

Since it has been shown that thrombotic thrombosis is formed in the constricted yacTKe due to the turbillent blood flow and is reduced by an elevated pressure gradient. Pure education and

elimination of thrombosis leads to periodic changes in the coronary flow. Thus, in vivo, the antithrombotic effect was determined by the efficacy of the experimental compound in terms of the frequency of changes in the oronary blood flow.

The experimental compound was administered intravenously.

15

The results of the experiment.

When the constrictor on the surrounding coronary artery was installed, the coronary blood flow gradually decreased from a initial 20-30 ml / min to a few ml / min and increased dramatically.

The decrease and increase in coronary blood flow were periodically repeated with a frequency of 5-15 / 30 minutes.

The compound of example 2 (cis-isomer-dihydrochloride) when administered intravenously at doses of 1 mg / kg or more leads to a decrease in the frequency of periodic changes in coronary blood flow depending on the dose (Table 5), indicating that the compound of example 2 prevents the formation of intracortical narny thrombosis caused by a violation of blood flow in vivo.

Toxicity.

The compound of Example 2 (cis-isomer-hydrochloride) was subcutaneously injected with 1c1: iCR in mice (4 weeks of age) and 1c1: Wister to rats (5 weeks of age) and the acute toxicity was calculated

Gagging

Mice

Rats

LD 50 mg / kg

1000-2000

5000

Claims (1)

Formula Method for preparing benzoxoxiepine derivatives of general formula I X  O-tV JMob-g 11, uh iV 2 3- ON - Q Table Serotonin receptor blocking effect in the preparation of coronary ar, pigs 1116 where R, is hydrogen or halogen, lower apkyl or lower alkoxy; X is a carboxy group or lower alkoxycarbonyl; Y is a group, CH-OH or CH-0-C-CH ,, p about or its acid addition salts, characterized in that the compound of the general formula II X where R and X have the indicated meanings. condense with the general formula III X1 by compound W- (CH2) 5-K (jNH where W is a halogen or a Fo1M4ule group where R 1 is lower alkyl, phenyl or p-tolyl, at the boiling point of the reaction mixture and gave the compound of formula 1 where Y is a group, or is reduced at 0-25 ° C and a compound of formula I is selected, where Y is a CH-OH group, or is acylated and the desired product of formula I is isolated, where Y is the group "CH-0-C -CHj, in your g ABOUT in the form of a bodice or in the form of an acid additive salt. 10 10- 10- 10- 0lo- f 1010-Ch-6 ten ten -S 0 -6 table 2 Inhibition of hypertonic reaction to serotonin (30 | U / g / kg intravenously) in short-legged hounds without anesthesia Continuation of table 1 93.3t 6.9 73.51 10.2 00 83.31 1.0 100 100 77,100 77,100 85 nineteen Antagonistic action of calcium in isolated perfused rat sprinkling preparations Dose, Change Group M perfusion pressure at injection KC1,% (case number) Control100 8 Zrimer 2 (cisG10 84 ± 3 (3)  It 14 (5) W CHO 30 ± 2 (3) P 0.05 Table 4 Diuretic effect on rats with spontaneous hypertension Dose, Number of urine, Na K Group mg / kg Livestock / 100 g / 5 h orap-nyml / 100 g / 5 h but control -51,02 ± 0,10128 ± 15 59t 8 Example 2 35l, 4ltO, 18160119 7715 CNS) 1051.74 to, 15 169t20 81 ± 8 3051.9710.20 192 + 15 88i 9 P 40.05; 0.01. Table 20 21 Effect on the frequency of periodic changes in coronary blood flow Dose, | Wr / kg 1 8.861, 94 5.71 t 1.06 3 7.25 ± 1.03 4.75 tJ, 80 10 8.0 1 1.73 0.3310.33 note Values indicate frequency periodic changes in coronary blood flow in 30 minutes by parameters; average value t standard mistake 143861122 Table 5 3,812,62 ABOUT ABOUT P 0.05; P 0.001.