CH646694A5 - DERIVATIVES OF 3,4,5-TRIMETHOXY CINNAMOYLE PIPERAZINE AND THEIR PREPARATION PROCESS. - Google Patents

Description

The present invention also covers the pharmaceutically acceptable salts of the compounds of formula (I), namely the salts of non-toxic mineral and organic acids and in particular the salts of hydrochloric, oxalic, maleic acids.

The process according to the invention, for the preparation of the compounds of formula (I) with the exception of the compound of formula (I) in which Ar represents the unit:

in which Ri has the same meanings as in formula (I) and R'2 represents a methyl group, a linear or branched C3 to Cs alkyl group or a Cs or C6 cycloalkyl group, for carrying out the process according to claim 3. 25

7. Compounds of formula:

—O A /

SCH „

0 0

v_y and of the compound of formula (I) corresponding to the particular formula [form S (-)]:

TsO

C00

^ \ A

CHjO

(XIII)

CHjO

30

CHjO

/ ~ \ \ J

,

- ^ 3—00

ok ^ £

H

(the)

in which Ts is a p-toluenesulfonyl group, for carrying out the process according to claim 5.

consists in condensing in an alcoholic medium (methanol, ethanol, butanol, etc.) the 3,4,5-trimethoxy cinnamoylpiperazine of formula:

N H —H (II)

40

The present invention relates to new derivatives of 3,4,5-trimethoxycinnamoylpiperazine.

The new compounds correspond to the general formula:

with the epoxides of formulas (Illa), (Illb), (IIIc) and (Illd):

/ \ 0 —COCH.

0C2H5

in which Ar represents:

- or the 4-acetyl-2-ethoxyphenyl group of formula:

- or a benzodioxane group of the type:

in which R represents: 65

- the methylthio-2-ethoxy sequence of formula —0 //> s — SCH3;

- an ester group of the type - COORx, in which R! represents an element chosen from the following: methyl, n-propyl, n-butyl,

(Illa)

(Illb)

(IIIc)

(nest)

in which R, has the same meanings as in formula (I) and R'2 represents a methyl group, a linear or branched alkyl group having 3 to 5 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms.

The compounds of formulas (lila), (IIIb) and (IIIc) are new and sqnt obtained by condensation of epichlorohydrin or epibrom-hydria at reflux in acetonitrile (or acetone), in the presence of

646,694

potassium carbonate with the compounds of formulas (IVa), (IVb) and (IVc):

HOCOCH.

(IVa)

(IVb)

The new compounds of formula (Vc, d), for which R "2 represents the methyl, isopropyl, n-butyl, isobutyl and phenyl groups, are obtained by the action in toluene medium of the chloroformates of formula (VIII):

CI-CO-OR3 (VIII)

in which R3 represents the methyl, isopropyl, n-butyl, isobutyl and phenyl groups with the compound of formula (IX):

/ V

HO — A ^) —NH-COOR '

> = r o—

(IX)

(IVc)

in which R! and R'2 have the same meanings as in formulas (Illb) and (IIIc).

The new compound of formula (IIId) is obtained by condensation of epichlorohydrin at reflux in benzyl alcohol, in the presence of potassium carbonate with the compound of formula (IVd):

HO

-Çfs *

-coo- @

(IVd)

The new compound of formula (IVa) is obtained by a Fries reaction on 1-acetoxy-2-ethoxy-benzene of formula (Va):

15 described in Belgian Patent No. 865990.

The new compounds of formula (Vc, d), for which R "2 represents the n-propyl, 3-methyl butyl, cyclopentyl and cyclohexyl groups, are obtained by condensation of the alcohols of formula (X):

20 r4oh (X)

in which R4 represents the n-propyl, 3-methyl butyl, cyclopentyl and cyclohexyl groups with the isocyanate of formula (XI):

IT CO

O 0 \ t

(XI)

CH3C00_ ^ ^

w ~

(Go)

The new compound of formula (XI) is obtained by the action of phosgene on the compound of formula (IX).

The process according to the invention for the preparation of the compound of formula (I) in which Ar represents the group:

which is itself new and is obtained by the action of acetyl chloride on 2-ethoxyphenol.

The compounds of formulas (IVb), (IVc) and (IVd) are new and are obtained by hydrogenolysis in the presence of 5% palladium on carbon, in an ethanolic medium of the benzyl group of the compounds of formulas (Vb) and (Vc, d ):

O _ ^ ~ ^ -C00R1

0 0 V __ /

° \ y ~ m ~ C00R "2

r \ (vc, d)

0 0

35

> = C

'SCH'

<2> ^

consists in condensing in an ethanolic medium, in the presence of potassium carbonate 40, 1-chloro-2-methylthioethane with the compound of formula (XII):

in which R] has the same meanings as in formula (IVb) and R "2 represents a methyl group, linear or branched alkyl containing from 3 to 5 carbon atoms, a cycloalkyl group containing 5 or 6 carbon atoms or the nucleus phenyl.

The new compounds of formula (Vb) are obtained by a two-step esterification, which consists in treating with thionyl chloride the compound of formula:

O ^ VcOOH

') - ((VI)

O O \ /

described in Belgian patent N ° 865990, then reacting the alcohols of formula (VII) on the crude compound thus obtained:

RjOH (VII)

in which Rj has the same meanings as in formula (Vb).

(XII)

described in Belgian patent N ° 865990.

The process according to the invention for the preparation of the compound of formula (la) consists in condensing in an acetone or acetonitrile medium, in the presence of potassium carbonate, the compound of formula (II) with the compound of formula (XIII):

55 TsO ^^^ O

(XIII)

obtained by the action of pa toluenesulfonyl chloride on the 60 compound of formula (XIV):

r \ ^ ° —fy

OH OH

65 J q (XIV) [Configuration S]

\ -J

The latter is obtained by acid hydrolysis, in acetone medium of the compound of formula (XV):

5

646,694

o (XV) [Configuration S] 5

itself obtained by condensing the tosylate of formula (XVI):

H

OTs

(XVI) [Configuration S]

described in "J. Org. Chem. ”, 42, 1006 (1977), with the compound of formula (IVb) in which Rj represents the (methyl-3) -n-butyl group.

The following preparations are given by way of example to illustrate the invention.

Example 1:

(4-acetyl-ethoxy-2) phenoxy-1 [(trimethoxy-3,4,5 cinnamoyl-piperazine) -4] -3 propanol-2, Oxalate, hydrated (I)

Code number: 1

A solution of 3 g of trimethoxy-3,4,5 cin-namoylpiperazine (II) and of 2.7 g of (acetyl-4-ethoxy-2-phenoxy) -l-2,3-epoxy propane is brought to reflux for 3 h. (Illa) (prepared in stage 3 of Example 3), in 50 ml of ethanol. Then the solvent is evaporated, the residue is dissolved in acetone and an acetone solution of oxalic acid is added and the precipitate obtained is filtered to obtain 5.6 g of product.

Yield: 87%

Melting point: 160 ° C Raw formula: C31H40N2On + Va H20

Elementary analysis:

Calculated: C 57.61 H 6.47 N 4.34%

Found: C 57.57 H 6.24 N 4.33%

By the same process, but from the corresponding reagents, the compounds of formula (I) appearing in Table I and bearing the code numbers 3 to 19, 71 and 73 to 77 are obtained.

Table I

• Ar

(I)

Code number

0 — Ar

Form

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

Elementary analysis (%)

VS

H

NOT

1

"°" O "C0CH3

OV; H5

Hydrated oxalate

C31HH40N2O11 + 3A H20

646.16

160

87

Calculated Found

57.61 57.57

6.47 6.24

4.34 4.33

2

- ° ~ (p ^ - 0 ^ SGH3

Ô 0 v_y

Hydrated hydrochloride

c30h41cin2o9s

+ 7 / e H20

662.19

175

60

Calculated Found

54.41 54.31

6.60 6.37

4.23 4.07

3

_ C00CH,

O

Hydrated hydrochloride

c29h37cin2o10 + h2o

627.10

163

58

Calculated Found

55.54 55.48

6.27 6.21

4.47 4.41

4

- 0- £ V C0003H7n

<U

Hydrated hydrochloride

C3iH41C1N2o10

+ k6 h2o

658.13

145

65

Calculated Found

56.57 56.76

6.64 6.79

4.26 4.42

5

- ° -g- COOOI, H9 „

Hydrated oxalate

c34h44n2014

+ 3 / s H20

715.52

150

79

Calculated Found

57.07 57.34

6.37 6.47

3.92 4.04

6

-o- © - eoo / y

} (

<u>

Hydrated hydrochloride

c32h43cin2o10

+ 56 H20

672.76

160

82

Calculated Found

57.13 57.18

6.80

6.81

4.16 4.21

7

- 0 - ^ - COO

v_y

Hydrated hydrochloride

C33H5SC1N2oio + SA H20

687.68

160

75

Calculated Found

57.82 57.63

6.86 6.96

4.02 4.07

646 694 6

Table I (continued)

Code number

0 — Ar

Form

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

Elementary analysis (%)

VS

h n

8

- o coo-O

Hydrochloride c33h43cin2o10

663.15

160

57

Calculated Found

59.77 59.46

6.54 6.68

4.22 4.15

9

-o-§-coo-c8h17d

(not /

Hydrated hydrochloride

c36h5icin2o10

+ Ys h20

729.76

106

66

Calculated Found

59.25 59.52

7.25 7.29

3.84 3.81

10

- o eoo- ©

° JQ

Oxalate

Qäßl ^ onjo ^

724.70

136

51

Calculated Found

59.66 59.60

5.56 5.76

3.87 4.01

11

- o - ^^ - nh-coochg

Ö

Hydrated hydrochloride

c29h38cin3o10

+ 1.5 H20

651.10

141

64

Calculated Found

53.49 53.55

6.35 6.04

6.45 6.43

12

~ 0 nh-cooc3h7n \ - /

Hydrated hydrochloride

C3iH42C1N3O10 + 1.2 H20

673.75

155

48

Calculated Found

55.26 55.53

6.64 6.46

6.24 6.31

13

- O ^ -OOK

w

Hydrated hydrochloride

C31H42CIN3O10 + 1.2 H20

673.75

164

69

Calculated Found

55.26 55.29

6.64 6.42

6.24 5.97

14

-o- ^ nh-cooc ^ v_y

Hydrated hydrochloride

c32h44cin3o10

+ 1.75 H20

697.68

156

74

Calculated Found

55.09 55.34

6.86 6.63

6.02 6.54

15

- nh-coo ^ Y

Hydrated hydrochloride

c32h44cin3o10

+ 7s H20

691.37

175

73

Calculated Found

55.59 55.74

6.82 6.68

6.08 6.21

16

~ 0 nii-COOxnJs.

Hydrated hydrochloride

^ 33 ^ 400 ^ 502 0

+ ih2o

698.19

176

70

Calculated Found

56.76 56.85

6.93 7.10

6.02 6.15

17

- 0 - ^ NH-COO-Q

u>

Hydrated hydrochloride

C3 3II4Cl N 3 0 J Q + 1,2 H20

699.78

176

58

Calculated Found

56.64 56.32

6.68 6.29

6.01 5.95

18

- o - @ - nh-coo- £)

o

Hydrated oxalate

c36h47n30! 4

+ Vs h2o

760.17

182

64

Calculated Found

56.88 57.12

6.44 6.38

5.53 5.67

19

- 0 - ^^ nh-coo / v <ìS

<L ° ^

Hydrated hydrochloride

c35h42cin3o10

+ 1.2 h 20

721.79

171

53

Calculated Found

58.24 58.28

6.20 5.91

5.82 5.79

7

Table I (continued)

646,694

Code number

0 — Ar

Form

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

Elementary analysis (%)

vs.

H

NOT

71

—C00-YN V_ /

Hydrated hydrochloride

C34H47ClN2O10

+ S / 3 H20

703.2

175

40

Calculated Found

58.07 58.34

7.12 7.16

3.98 4.01

72

eoo

Q s (-)

Hydrochloride hydrate [aß0 = 7.8 ° (C = 2, CH3OH)

C33H45ClN2O10 + SA H20

687.68

162

37

Calculated Found

57.63 57.71

6.96 6.95

4.07 3.92

73

o - ^^ _ coo

° v 0 \ (

Hydrated hydrochloride

c32h41cin2o10

+ 1.3 H20

673.14

158

52

Calculated Found

57.09 57.23

6.54 6.15

4.16 4.01

74

^ C00nn \ _ /

Hydrated hydrochloride

c33h43cin2o10 +% h2o

684.17

178

41

Calculated Found

57.93 58.16

6.68 6.75

4.09 4.11

75

O ^ -COO ^ P

0 0

\ _y

Hydrated hydrochloride

C34H4sC1N2o10

+ S / 4 H20

699.69

168

29

Calculated Found

58.36 58.60

6.84 6.84

4.00 4.04

76

w

Hydrated hydrochloride

C34HI5C1N2o10 + Yï H20

698.79

164

71

Calculated Found

58.44 58.69

6.84 6.60

4.01 4.03

77

o- ^ coo ° \ _y °

Hydrated hydrochloride

c33h43cin2o10

+ 1.2 H20

had it

160

22

Calculated Found

57.88 57.98

6.68 6.37

4.09 4.09

Example 2:

[(2-methylthio-ethoxy) -4 ethylenedioxy-2,3-phenoxy] -l [(tri-methoxy-3,4,5 cinnamoyl) piperazine-4J-3 propanol-2 hydrochloride, hydrated (I)

Code number: 2

A mixture of 13.3 g of (hydroxy-2,3-hydroxy-2,3) phenoxy-1 [(trimethoxy-3,4,5 cinnamoylpipéra-zine-4)] - 3 propanol-2 is brought to reflux for 18 h. (XII), 3.5 ml of 1-chloro-methylthio-2 ethane and 10.3 g of potassium carbonate in 150 ml of ethanol. Then filtered, the filtrate is evaporated, the residue is taken up in chloroform and washed with water. The organic phase is dried over sodium sulphate, the solvent is evaporated and the residue is chromatographed on a silica column. Eluted with mixtures of pure chloroform and 99% chloroform / 1% methanol, 13 g of pure product are obtained which are dissolved in acetone and 4.5 ml of 6.5N hydrochloric ethanol are added. The precipitate obtained is filtered, dissolved in the minimum amount of alcohol and diluted with acetone. 9.35 g of product are obtained.

Melting point: 175 ° C Raw formula: C30H4IClN2O9S + 7A H20

Elementary analysis:

Calculated: C 54.41 H 6.60 N 4.23%

Found: C 54.31 H 6.37 N 4.07%

Example 3:

(2,3-epoxy propoxy) -4 '3-ethoxy acetophenone (Illa)

1st stage: Acetyloxy-1 ethoxy-2 benzene (Va)

To a solution of 30.4 g of 2-ethoxyphenol in 10 ml of tetra-50 hydrofuran and 29 g of triethylamine, 17.3 g of acetyl chloride are added while cooling, then the mixture is left for 24 h. contact, filter the precipitate, evaporate the filtrate and distill the residue. 27.2 g of product are obtained.

Yield: 69%

55 Boiling point Eb9 mmHg: 115 -► 123 C

Gross formula: C10HI2O3

NMR spectrum (CDCI3): 8 ppm = 7.00, m (4 benzenic protons); 4.00, q (-CH2 of 0-CH2-CH3); 2.25, s (-CH3 of OCOCH3); 1.32, t (- CH3 of O - CH2 - CH3)

60

2nd stage: Ethoxy-3 'hydroxy-4' acetophenone (IVa)

To a solution of 17.6 g of the compound of formula (Va) obtained in the preceding stage in 100 ml of nitrobenzene, 24 g of aluminum chloride are added and the mixture is left to stir for 20 h at room temperature. The reaction mixture is then poured into ice and concentrated hydrochloric acid and extracted with ether; the ethereal solution is extracted with a 2N sodium hydroxide solution, then the aqueous solution is acidified with concentrated hydrochloric acid and extracted with chloro

646,694

form. The solvent is evaporated off and the residue is chromatographed on a column of silica, eluted with 100% benzene. 50% of the expected compound (IVa) is obtained.

Melting point: 66 ° C Raw formula: C10H12O3

NMR spectrum (CDCl3): 8 ppm = 7.50, m and 6.95, d (3 benzene portions); 6.72, s (—OH); 4.10, q (—CH2 of —O — CH2 — CH3); 2.55, s (-COCH3); 1.20, t (-CH3 of —O — CH2 — CH3)

50% of its isomer, ethoxy-4 'hydroxy-3' acetophenone, is then obtained.

Melting point: 100 ° C

NMR spectrum (CDCl3): 5 ppm = 7.9, m and 6.90, d (3 benzene protons); 6.55, s (OH); 4.10, q (-CH2 of 0-CH2-CH3); 2.50, s (CH3CO—); 1.40, t (-CH3 of 0-CH2-CH3)

(the structural assignment of the two isomers was confirmed by an NMR study of the influence of complexation with euro-pium salts [EU (C104) 3] on the chemical displacement of aromatic protons; solvent CD3OD) .

3rd stage: (2,3-epoxy propoxy) -4 '3-ethoxy-acetophenone (Illa) A mixture of 6.2 g of compound of formula (IVa) obtained in the preceding stage is brought to reflux for 5 h, of 5 g of epibromhy-drine and 14 g of sodium carbonate in 70 ml of acetonitrile. Then filtered, the filtrate is evaporated, the residue is taken up in a mixture of water and chloroform, the organic phase is dried over sodium hydroxide and the solvent is evaporated. 6.5 g of product are obtained.

Efficiency: 76%

Melting point: 90 ° C Raw formula: C14Hlfi04

NMR spectrum (CDCl3): 5 ppm = 7.5, m and 6.95, d (3 aromatic protons); 4.20, m; 3.4, m and 2.8, m (5 protons

NMR spectrum (CDCl3): 8 ppm = 4.10, q and 1.40, t (O — CH2 —CH3); 2.50, s, COCH3

Example 4:

(2,3-epoxypropoxy) -5-8-methoxycarbonyl-1,4-benzodioxane (Illb)

Code number: 36

Stage 1: Benzyloxy-5 methoxycarbonyl-8 benzodioxane-1,4 (Vb)

Code number: 20

To a toluene solution of 28 g of (5-benzyloxy-benzo-dioxane-1,4) -yl-8-carboxylic acid (VI), 50 ml of thionyl chloride are added and the mixture is brought to 70-80 ° C. for 2 h. Then the solvents are evaporated, the residue is dissolved in 200 ml of tetrahydrofu-

ranne and add 8 ml of methyl alcohol and 38 ml of triethylamine. The mixture is brought to 60 ° C. for 3 h, then the precipitate formed is filtered,

evaporate the filtrate and chromatograph the residue on a column of silica, eluted with 100% methylene chloride. 20 g of product are obtained.

Yield: 74%

Melting point: 100 ° C Raw formula: C17H1605

The product is used crude in the synthesis of the compound of formula (IVb) corresponding to the compound of code number 28 appearing in Table II.

By the same process, but from corresponding reagents, the compounds of formula (Vb) appearing in Table II and bearing the code numbers 21 to 27 and 78 to 83 are obtained.

2nd stage: Hydroxy-5 methoxy carbonyl-8 benzodioxane-1,4 (IVb)

Code number: 28

Hydrogenolysis is carried out at ordinary pressure and temperature, in the presence of 2 g of 5% palladium on carbon, a solution of 20 g of the compound of formula (Vb) with code number 20 obtained in the preceding stage in 200 ml of ethanol. Then filtered, evaporated the solvent and obtained 13 g of crude product.

Melting point: 153 ° C. Crude formula: C10H10O5 (crude employee in the synthesis of the compound of formula (Illb) corresponding to code number 36 and appearing in table II).

By the same process, but from the corresponding reagents, the compounds of formula (IVb) appearing in Table II and bearing the code numbers 29 to 35 and 84 to 89 are obtained.

3rd stage: (2,3-epoxy propoxy) -5-8-methoxycarbonyl-1,4-benzo-dioxane (Illb)

Code number: 36

A mixture of 13 g of the compound of formula (IVb) obtained in the preceding stage, 25.5 ml of epibromhy-drine and 25.5 g of potassium carbonate in 250 ml of acetonitrile is brought to reflux for 4 h. . Then filtered, the filtrate is evaporated, the residue is taken up in methylene chloride, washed with water, then using an IN sodium hydroxide solution, dried over sodium sulfate and the solvent is evaporated. The residue is recrystallized from ethyl acetate and 11.4 g of product are obtained. Yield: 69%

Melting point: 122 ° C Raw formula: C13H1406

By the same process, but from the corresponding reagents, the compounds of formula (IIIb) are obtained, appearing in Table II and bearing the code numbers 37 to 43 and 90 to 95.

8

5

10

15

20

25

30

35

40

45

Table II r ^ cq 0re

O

Code number

Ri rs formula

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

NMR spectrum or elementary analysis

20

(Vb)

ch3

-ch2 ~ ^

C17H16Os

300.70

100

74

NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.4, m and 5.2, s (7 protons - O — CH2 3.8, s (COOCH3)

21

(Vb)

c3h7 „

-ch2- ©

C19H20O5

328.35

101

66

NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.6, m and 5.2, s (7 protons - CH2 - (JS))

4.3, m; 1.7, m and 1.00, t (7 protons COOC3C3H7n)

22

(Vb)

C4H9n

-ch2 ~ ®

C20H22O5

342.38

<50

70

NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.6, m and 5.2, s (7 protons - CH2— ^ 3 ^)

4.3, m and 0.8 to 1.6, m (9 COOC4H9n protons)

23

(Vb)

ch3

-ch2- ©

C20H22O5

342.38

63

60

NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.4, m and 5.2, s (7 protons - O — CH2 - ^ 3 ^)

4.1, d; 2, m and 1, d (9 COO protons ^^ / 2)

24

(Vb)

/ h

° Y / D,

-ch2 ~ ^

C21H2405

356.40

<50

64

NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.4, m; 5.2, s (7 protons - O —CH2)

4.3, m; 1.7, m and 0.9, d (11 COO protons)

25

(Vb)

îû

-ch2 ~ 0

C21H220S

354.39

87

38

NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.4, m and 5.2, s (7 protons - O —CH2)

5.2, m and 1.8, m (9 protons)

26

(Vb)

-C8HI7n

-ch2-0

C24H30O5

398.48

oil

79

NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 7.5, m and 5.2, s (7 protons - O — CH2)

4.3, m and 0.8 to 1.6, s (17 protons - COO - C8 - H17n)

£ ON 0 \

E

Table II (continued)

Code number

Formula

Ri

Rs

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

NMR spectrum or elementary analysis

27

(Vb)

-ch2-0

C22HI805

362.36

144

28

NMR (cdci3): 7.6, d; 6.6, d and 4.3, s (6 benzodioxane protons) 7.4, m and 5.2, s (7 protons —O — CH2- ^ J ^) 7.4, m (5 COO protons)

28

(IVb)

-ch3

H

C10H10O5

210.18

153

93

NMR (cdci3): 7.3, d; 6.5, d and 4.3, s (6 benzodioxane protons) 10.00, s (OH)

3.8, s (cooch3)

29

(IVb)

-C3HVn

H

Ci2H14Os

238.23

73

98

NMR (cdci3): 7.5, d; 6.6, d and 4.3, s (6 benzodioxane protons) 6.8, s (—OH)

4.3, t; 1.8, m and 1.00, t (7 COOC3H7n protons)

30

(IVb)

—C4H9n

H

CI3H16Os

252.26

79

98

NMR (cdci3): 7.5, d; 6.6, d and 4.3, s (6 benzodioxane protons) 7, s (OH); 4.3, m and 0.9 to 1.8, m (9 COOC4H9n protons)

31

(IVb)

/ yh3

ch3

H

C13H1005

252.26

66

96

NMR (cdci3): 7.4, d; 6.6, d and 4.3, s (6 benzodioxane protons) 6.95, s (OH)

4.2, d; 2, m and 1, d (9 COOr \ S protons)

32

(IVb)

oh3

/ H = \ Ach3

H

c14h1805

266.28

69

98

NMR (cdci3): 7.5, d; 6.6, d and 4.3, s (6 benzodioxane protons) 4.3, m; 1.7, m and 0.9, d (11 COO protons ^^^)

33

(IVb)

ì2)

H

C14H1605

264.27

95

95

NMR (cdci3): 7.4, d; 6.6, d and 4.3, s (6 benzodioxane protons) 6.8, m (—OH)

5.4, m and 1.8, m (9 protons ~ \ /)

34

(IVb)

C8H17n

H

C17H24Os

308.36

63

98

NMR (cdci3): 7.5, d; 6.5, d and 4.3, m (6 benzodioxane protons) 4.3, m and 0.8 to 1.8, m (17 COO protons — C8H17n)

35

(IVb)

H

c1sh1205

272.25

156

93

NMR (cdci3): 7.65, d; 6.6, d and 4.3, s (6 benzodioxane protons)

7.25, m (5 protons - COO- ^ J ^)

6.15, s (OH) X: 1 /

p \

Table II (continued)

Code number

Ri rs formula

Brute formula

Molecular weight

Melting point ro

Yield (%)

NMR spectrum or elementary analysis

36

(Illb)

ch3

/ CH2V-2X

ClìH ^ Og

266.24

122

69

NMR (CDCI3): 7.5, d; 6.6, d and 4.35, s (6 benzodioxane protons)

4.3, m; 3.4, m and 2.8, m (5 protons QA /, Q \)

3.8, s (COOCH3)

37

(Illb)

c3h7 „

/ CH2V ^

CisH180, j

294.29

100

85

NMR (CDCI3): 7.4, d; 6.7, d and 4.3, s (6 benzodioxane protons)

4.3. m: 3.4. m and 2.8. m (5 Drotons OCH- ,. / ® \)

4.3, t; 2.8, m and 1.00, t (7 COO protons — C3H7n)

38

(Illb)

C4H9n

/ CHgv2x c16h20o6

308.32

105

85

NMR (CDCI3): 7.5, d; 6.5, d and 4.3, s (6 benzodioxane protons)

4.3, m; 3.4, m and 2.8, m (5 protons)

4.3, m and 0.8 to 1.7, m (9 COOC4H9n protons)

39

(Illb)

CH_

/ ■ w3

ch3

/ ch2v ° \

C, 6H20O6

308.32

110

83

NMR (CDCI3): 7.4, d; 6.5, d and 4.35, s (6 benzodioxane protons)

4.2, m; 3.4, m and 2.8, m (5 protons)

4.3, d; 2, m and 1.00, d (9 COO protons)

40

(Illb)

EYELASH

/ CH2 \ A

7 chb

0k2 - ^ \

CI7H22O6

322.35

91

82

NMR (CDCI3): 7.4, d; 6.5, d and 4.38, s (6 benzodioxane protons)

4.2, m; 3.4, m and 2.8, m (5 protonsQ A / ® \)

4.2, m; 1.7, m and 0.9, d (11 Q / \ ^ \ protons)

41

(Illb)

0H2-ÌA

CI.H.OO,

320.33

85

98

NMR (CDCI3): 7.4; 6.7, d and 4.3, s (6 benzodioxane protons)

4.3, m; 3.4, m and 2.8, m (5 protons O 5.3, m; 1.8 (9 protons)

42

(HIb)

QHl7n

C2oH28OÖ

364.42

95

85

NMR (CDCI3): 7.5, d; 6.5, d and 4.3, s (6 benzodioxane protons)

4.3, m; 3.4, m and 2.8, m (5 protonsO / v2 \)

4.3, m and 0.8 to 1.5, m (17 COO protons — C8H17n)

Table II (continued)

9 \

Code number

Formula

Ri

R5

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

NMR spectrum or elementary analysis

43

(Illb)

AT

CH2-ÌA

CisHifiOe

328.31

104

71

NMR (CDCI3): 7.7, d; 6.6, d and 4.4, s (6 benzodioxane protons) 7.15, m (5 protons - COO)

4.3, m; 3.4, m and 2.8, m (5 protonsO AZ2x)

78

(Vb)

And

-CH -CH

d VEt

- <VO

C22H26O5

370.43

liquid

98

NMR (CDCI3): 1.4, d; 6.5, d and 4.22, s (6 benzodioxane protons) 7.18, s and 5.05, s (5 protons —CH2—0);

And

4.1, d COOCH2-; 1.4, m and 0.95, m (~ CH <^)

And

79

(Vb)

-CH2- <J

- ™ a-0

C20H20OS

340.36

95

95

NMR (CDCI3): 7.4, d; 6.5, d and 4.75, s (6 benzodioxane protons) 7.18, s and 5.22, s (5 protons - CH2—0);

4.1, d (COOCH2—); and 0.9, m U ^)

80

(Vb)

-chg-D

C2xH2205

354.38

76

99

Elementary analysis:

Calculated: C 71.17 H 6.26% Found: C 70.93 H 6.13%

81

(Vb)

-CH2-CH2-tÛ

-ch2- ©

C22H24O5

368.41

62

76

Elementary analysis:

Calculated: C 71.72 H 6.57% Found: C 71.60 H 6.53%

82

(Vb)

-cvn

C22H24O5

368.41

(rubber)

94

NMR (DMSO): 7.3, d; 6.70, d and 4.22, s (6 benzodioxane protons) 7.4, s and 5.18, s (5 protons —CH2—0);

4.1, d (COOCH2-); 2.3, m and 1.5, m (f ^ j)

83

(Vb)

-ch2-ch ^

-CH2- ©

C21H22O5

254.39

(rubber)

72

NMR (CDCI3): 7.4, d; 6.7, d and 4.2, s (6 benzodioxane protons) 7.35, s and 5.2, s (5 protons —CH2—0);

4.15, t (COOCH2—); 1.9, m; 1.5, q and 0.9, m (-CH2- <7)

84

(IVb)

And

-ch -ch./

^ And

-H

C15H20O5

280.31

80

70

NMR (CDCI3): 9.5, s (OH); 7.38, d; 6.5, d and 4.25, s (6 benzodioxane protons); 4.1, d (COOCH2—);

And

1.4, m and 0.95, m (-CH <)

And

Table II (continued)

Code number

Ri r5 formula

Brute formula

Molecular weight

Melting point (° c)

Yield (%)

NMR spectrum or elementary analysis

85

(IVb)

- ° h2 ~ v

-H

c13h14o5

250.24

70

82

Elementary analysis:

Calculated: C 62.39 H 5.64% Found: C 62.09 H 5.69%

86

(IVb)

-ch - □ 2

-H

c14h16o5

264.27

84

98

NMR (DMSO): 10.0, s (OH); 7.25, d; 6.5, d and 4.25, s (6 benzodioxane protons); 4.08, d (COOCH2—);

2.5, m and 1.95, m (| |)

87

(IVb)

-ch2-ch2-D

-H

Ci5h18o5

278.29

75

99

Elementary analysis:

Calculated: C 64.73 H 6.52% Found: C 64.84 H 6.42%

88

(IVb)

"CH2l2l

-H

c15h18o5

278.29

(rubber)

99

NMR (DMSO): 10.0, s (OH); 7.22, d; 6.5, d and 4.85, s (6 benzodioxane protons); 4.05, d (COOCH2—);

2.3, m and 1.5, m (-f ^)

89

(IVb)

-ch2-ch2 - //

-H

Ci4H16Os

264.27

(rubber)

98

NMR (CDCl3): 7.4, s (OH); 7.4, d; 6.7, d and 4.2, s (6 benzodioxane protons); 4.25, t (COOCH2—);

1,5, qetO, 9, m (-C.H2— <j)

90

(III)

^ And

-CH2- <And

-ch2-XA

c18h24o6

336.37

110

72

NMR (CDCI3): 7.42, d; 6.5, d and 4.28, s (6 benzodioxane protons); 4.2. m: 3.4. m and 2.8. m (—O — CH- ,. / 0 \):

And

4.2, d (COOCH2); 1.5, m and 0.9, m (-CH <)

And

91

(III)

-ch2Y

-OH ^ -A

C16H1806

306.30

128

65

Elementary analysis:

Calculated: C 62.74 H 5.92% Found: C 62.45 H 5.93%

92

(IH)

-ch2-0

-ch2-A

ci7h20o6

320.25

114

68

Elementary analysis:

Calculated: C 63.74 H 6.29% Found: C 63.57 H 6.15%

93

(III)

-ch2-chJ ^ -J

-ch2-A

c18h2206

334.35

87

82

Elementary analysis:

Calculated: C 64.66 H 6.63% Found: C 64.40 H 6.66%

o \

■ b.

o \

9 \ N / A

646,694

NMR spectrum or elementary analysis

Elementary analysis:

Calculated: C 64.56 H 6.63% Found: C 64.55 H 6.71%

Elementary analysis:

Calculated: C 63.74 H 6.29% Found: C 63.57 H 6.36%

Yield (%)

O

r-

Melting point (° C)

102

o o

H

Molecular weight

334.35

320.33

Brute formula

"O

"S N

X

CO

u

O

o

NOT

X

r-

u

&

oCl

'OJ

M O 1

o

NOT.

'OJ

you

0

1

£

at

M ™ O 1

> •

OJ

w

0

1

OJ M O 1

Formula

S

H-4

1—1 1 — I

Code number

94

95

Example 5:

(2,3-epoxy propoxy) -5 methoxycarbonylamino-8 benzodioxane-1,4 (IIIc)

Code number: 62

1 "stage: Benzyloxy-5 methoxycarbonylamino-8 benzodioxane-1,4 (Vc, d)

Code number: 44

To a solution cooled to 0 ° C of 25 g of 5-amino-8-benzyloxy-1,4-benzodioxane (IX) in 250 ml of tetrahydrofuran and 17.6 ml of triethylamine, 1 ml of chlorofor-miate is slowly added methyl, then allowed to stir for 7 h. It is filtered, the filtrate is washed with a dilute solution of hydrochloric steel, with water, with a solution of baking soda and with water. The solvent is evaporated and the residue is crystallized from ethyl acetate. 17.8 g of product are obtained.

Efficiency: 58%

Melting point: 100 ° C Raw formula: C17H17N05

NMR spectrum (CDCl3): 8 ppm = 7.4, d; 6.5, d and 4.3 s (6 benzodioxin protons); 6.82, s (NH — COO—); 7.4, m and

5.18,); 3.76, s (COOCHj)

IR spectrum (KBr): carbamate bands at 3420 and 1715 cm-1 By the same process, but from the corresponding reagents, the compounds of formula (Vc, d) appearing in Table III and bearing the code numbers 46 are obtained , 47, 48 and 52.

2nd stage: Hydroxy-S methoxycarbonylamino-8 benzodioxane-1,4 (IVc)

Code number: 53

Hydrogenolysis at ordinary pressure and temperature in the presence of 2 g of 5% palladium on charcoal a solution of 17.8 g of the compound of formula (Vc, d) with code number 44 obtained in the preceding stage in 400 ml of ethanol , then filtered, the filtrate is evaporated and 11.5 g of crude product is obtained, used as it is in the following stage.

Efficiency: 90%

Melting point: 150 ° C

NMR spectrum (CDCl3): S ppm = 7.95, s (OH); 7.30, d; 6.50, d and 4.3, s (6 benzodioxane protons); 7, s (NH—); 3.78, s (COO-CH3)

IR spectrum (KBr): carbamate bands at 3410 and 1710 cm-1 By the same process, but from the corresponding reagents, the compounds of formula (IVc) bearing the code numbers 54 to 60 are obtained as well as the compound of formula (IVd) of code number 61 appearing in table III.

3rd stage: (2,3-epoxy propoxy) -5 methoxycarbonylamino-8 benzodioxane-1,4 (IIIc)

Code number: 62

A suspension of 11 g of the compound of formula (IVc) with code number 53 obtained in the preceding stage, 23 ml of epibromhydrin and 17 g of potassium carbonate in 200 ml of acetonitrile is brought to reflux for 3 h. then filtered, the filtrate is evaporated and the residue is taken up in chloroform, washed with water and the solvent is evaporated. 13 g of crude product are obtained which is used as it is in the synthesis of the corresponding compound of formula (I) with code number 11 and shown in Table I.

Melting point: 134 ° C

NMR spectrum (CDCl3): 8 ppm = 7.5, d; 6.6, d and 4.35, s (6 benzodioxane protons); 6.90, s (—NH—); 4.20, m; 3.4, m and

2.80, m (5 protons 0 / S | ^^; 3.82, s (COOCH3)

IR spectrum (KBr): carbamate bands at 3380 and 1730 cm-1 By the same process, but from the corresponding reagents, the compounds of formula (IIIc) of code numbers 63 to 69 appearing in Table III are obtained.

14

5

10

15

20

25

30

35

40

45

50

55

60

65

Table III "" fi- HH-COO-A

v_ /

Code number a

Formula rs

Brute formula

Molecular weight

Melting point (° c)

Yield (%)

NMR spectrum and IR spectrum or elementary analysis

44

ch3

(Fr, d)

CH., - ©

c17h17no5

315.31

100

58

NMR (CDCI3): 7.4, d; 6.5, d and 4.3, s (6H benzodioxane); 6.82, s

(NH —COO—); 7.4, m and 5.18, s (-CH, -®); 3.76, s (COOCH3) IR (KBr): 3420 and 1715 cm "1

45

C3H7n

(Fr, d)

c19h21no5

343.37

156

68

NMR (CDCI3): 7.4, d; 6.5, d and 4.3, s (6H benzodioxane); 7.4, m and 5.10, s

(CH2); 7, s (NH); 4.10, t; 1.70, m and 1, t (COOC3HVn)

IR (KBr): 3420 and 1720 cm'1

46

- "K

(Fr, d)

c19h21no5

343.37

124

81

NMR (CDCI3): 7.6, d; 6.5, d and 4.2, s (6H benzodioxane); 7.4, m; 5.05, s.

(-CH2- ^); 6.90, s (NH); 5.02, m; 1.15, d (COO - <^)

IR (KBr): 3430 and 1710 cm "1 (NH-COO - <^).

47

C4hg „

(Fr, d)

ch2 ^

c20h23no5

357.39

-

65

NMR (CDCI3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 7.4, m and 5.08, s

(CH2 ^)); 6.90, s (NH); 4.10, t and 1.20, m (COOC4H9n)

IR (KBr): 3420 and 1720 cm "1 (NH-COOC4H9n)

48

C "2- <

(Fr, d)

"V ©

q0h23no5

357.39

-

47

NMR (CDCI3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 7.4, m and 5.10, s

(CH2); 6.90, s (NH); 3.95, d; 2.05, m and 1.0, d

(COO-CH2— <[)

IR (KBr): 3420 and 1720 cm "1 (NH-COO-CH2 - <^)

49

a / f

(Fr, d)

CV <2>

c21h25no5

371.42

-

48

NMR (CDCI3): 7.5, d; 6.5, d and 4.2, s (6H benzodioxane); 7.4, m and 5.08, s

(CH2- ^); 6.90, s (NH); 4.12, t; 1.6, m and 1, d (COOCH2 / \ ^) IR (KBr): 3420 and 1720 cm "1 (NH-COO / ^ Aj

50

ì2)

(Fr, d)

CV <3>

c21h23nos

369.40

-

78

NMR (CDCI3): 7.4, d; 6.5, d and 4.2, s (6H benzodioxane); 6.85, s (NH);

5.05, m and 1.80, m (—COO—); 7.4, m and 5.05, s (CH2) IR (KBr): 3425 and 1710 cm "1 (NH-COO-f ^)

Table III (continued)

Code number

AT

Formula

R5

Brute formula

Molecular weight

Fusion point

(° C)

Yield (%)

NMR spectrum and IR spectrum or elementary analysis

51

X)

(Vc, d)

"V ©

C22H25NO5

383.43

178

78

Elementary analysis:

Calculated: C 68.91 H 6.57 N 3.75% Found: C 68.71 H 6.36 N 3.41%

52

(Vc, d)

CV ©

c22h19no5

377.38

-

67

NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6H benzodioxane); 7.4, m and 5.10, s (CH2- ^); 7.02, m (COO- ^); 6.85, s (NH)

IR (KBr): 3415 and 1710 cm-1 (NH — COO - ^^)

53

-ch3

(IVc)

H

c10hi1no5

225.10

150

90

NMR (CDCl3): 7.95, s (OH); 7.30, d; 5.50, d and 4.3, s (6H benzodioxane);

7, s (NH); 3.78, s (-COOCH3)

IR (KBr): 3410 and 1710 cm "1 (NHCOOCH3)

54

-C3H7n

(IVc)

H

c12h1sno5

253.25

-

83

NMR (CDCl3): 7.55, s (OH); 7.30, d; 6.50, d and 4.3, s (6H benzodioxane);

6.55, s (NH); 4.10, t; 1.70, m and 1, t (COOC3H7n)

IR (KBr): 3360 (OH), 3380 and 1710 cm "1 (NH-COOC3H7n)

55

- "X

(IVc)

H

c12h15no5

253.25

-

99

NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6H benzodioxane); 6.70, s (NH);

5.0, m and 1.22, d (COO - <(); 5.6, m (OH)

IR (KBr): 3380 (OH and HN), 1710 (NH-COO—)

56

C4H9n

(IVc)

h c13h17no5

267.27

-

95

NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, s (NH);

4.10, t and 1.20, m (COOC4H9n); 5.20, m (OH)

IR (KBr): 3360 and 1715 cm "1 (NHCOOC4H9n)

57

"CH2 ~ <C

(IVc)

H

c13h17no5

267.27

-

90

NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, s (NH); 9.95, d; 2.05, m and 9.95, d (COOy-y ')

IR (KBr): 3360 and 1715 cm "1 (NHCOO / \ £)

58

-ch ^ Y

(IVc)

H

ci4hi9no5

281.30

-

98

NMR (CDCl3): 7.4; 6.5, d and 4.3, s (6H benzodioxane); 6.85, s (NH);

4.15, t; 1.62, m and 0.95, d (COO ^ yl ^); 5.28, m (OH)

IR (KBr): 3360 and 1710 cm- '(NHCOO)

Table III (continued.)

Code number a

Formula

Rs

Brute formula

Molecular weight

Melting point (° c)

Yield (%)

NMR spectrum and IR spectrum or elementary analysis

59

Ì3

(IVc)

H

C14H17NOs

279.28

-

96

NMR (CDCl3): 7.4, d; 6.5, d and 4.25, s (6H benzodioxane); 6.85, s (NH);

5.10, m and 1.75, m (COO); 5.95, m (OH)

IR (KBr): 3380 and 1710 cm-1 (NH — COO - ^^)

60

-o

(IVc)

h c15h19no5

293.31

57

77

NMR (CDCl3): 7.4, d; 6.5, d and 4.2, s (6H benzodioxane); 6.85, s (NH); 4.75, m and 1.40, m (COO-Q); 5.70, m (OH)

IR (KBr): 3380 and 1775 cm "1 (NH — COO ^ ~ ^)

61

(IVd)

H

c15h13no5

287.26

-

82

NMR (CDCl3): 7.4, d; 6.5, d and 4.12, s (6H benzodioxane); 7.25, m (COO- ^); 5.70, m (OH)

IR (KBr): 3360 and 1735 cm "'(NH — COO - ^^)

62

-ch3

(ihc)

H

c13h15no6

281.26

134

49

NMR (CDCl3): 7.5, d; 6.6, d and 4.35, s (6H benzodioxane); 6.90, s (NH) and

3.82, s (- COOCH3); 4.20, t; 3.4, m and 2.80, m (5H O / vA) IR (KBr): 3380 and 1730 cm "'(NHCOOCH3) ^

63

-C3H7n

(IIIc)

H

c1sh19no6

309.31

-

66

NMR (CDCl3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 6.95, s (NH);

4.10, t; 1.7, m and 1, t (COOC3H7n); 4.2, t; 3.4, m and 2.80, m (5H q / yOp IR (KBr): 3440 and 1740 cm "1 (NHCOOC3H7n)

64

- <

(IIIc)

-oaÄ

c15h19no6

309.31

-

45

NMR (CDCl3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, m (NH);

5.05, m and 1.25, d (COO—); 4.30, t; 3.40, m and 2.80, m (5H 0A &) IR (KBr): 3310 and 1700 cm "1 (NH — COO—)

65

—C4H9n

(IIIc)

-oaä

c16h21no6

323.33

104

84

NMR (CDCl3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, s (NH);

4.10, t and 1.20, m (COO-C4H9n); 4.20, t; 3.4, m and 2.8, m (5Hn ^ / ° M IR (KBr): 3415 and 1725 cm "1 (NH-COOC4H9n)

Table III (continued)

Code number

AT

Formula rs

Brute formula

Molecular weight

Melting point (° C)

Yield (%)

NMR spectrum and IR spectrum or elementary analysis

66

-ch - <(

(IIIc)

-OAA

Q6h21no6

323.33

-

87

NMR (CDCl3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, s (NH); 4.05, d; 2.05, m and 1.0, d (COO); 4.20, t; 3.4, m and 2.8, m

(5hckj ^)

IR (KBr): 3290 and 1700 cm "1 (NH-COO / S ^)

67

- <VY

(IIIc)

-0 AA

c17h23no6

337.36

-

76

NMR (CDCl3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, s (NH);

4.10, t; 1.6, m and 0.95, d (COO 4.20, t; 3.4, m and 2.8, m (5H On)

V ° 1

IR (KBr): 3290 and 1700 cm "1 (NH-COO / VN)

68

(IIIc)

-o AÄ

c17h21no6

335.35

-

49

NMR (CDCl3): 7.5, d; 6.5, d and 4.3, s (6H benzodioxane); 6.90, s (NH); 5.12, m and 1.8, m (—COO - ^^); 4.20, t; 3.4, m and 2.8, m (5H ^

IR (KBr): 3320 and 1700 cm "1 (NH - COO -Q)

69

-o

(IIIc)

-OAA

C1sH23N06

349.37

113

85

Elementary analysis:

Calculated: C 61.88 H 6.65 N 4.01% Found: C 61.47 H 6.75 N 4.17%

70

(Illd)

-OAA

here ^ noÖ

357.35

110

37

Elementary analysis:

Calculated: C 63.86 H 5.36 N 3.92% Found: C 63.27 H 5.26 N 3.80%

19

646,694

Example 6:

Benzyloxy-5 cyclopentyloxycarbonylamino-8 benzodioxane-1,4 (Vc, d)

Code number: 50

1 "stage: (5-Benzyloxy-1,4-benzodioxane) -y 1-8 isocyanate (XI) In a solution cooled to 0 ° C of 77 g of 8-benzyloxy-5-amino-1,4-benzodioxane (IX) in 500 ml of toluene, 100 g of phosgene are absorbed, then allowed to return to ambient temperature, the solvent is evaporated and the residue is crystallized in hot hexane to obtain 62 g of crude product used as it is in the following stage.

2nd stage: Benzyloxy-5 cyclopentyloxycarbonylamino-8 benzodioxane-1,4 (Vc, d)

Code number: 50

To a solution of 9 g of the compound of formula (XI) obtained in the preceding stage, in 200 ml of tetrahydrofuran and 10 ml of triethylamine, 5.3 g of cyclopentanol is added and the mixture is brought to reflux for 48 h. The solvent is evaporated, the residue is taken up in chloroform, washed with water, dried over sodium sulfate, the solvent is evaporated and the residue is crystallized from hot hexane. 9 g of crude product used are obtained in the synthesis of the corresponding compound of formula (IVc), bearing the code number 59 appearing in Table III.

Yield: 78%

NMR spectrum (CDCl3): S ppm = 7.4, d; 6.5, d and 4.3, s

(6 benzodioxane protons); 7.4, m and 5.05, s (5 protons CH2- ^ J ^);

5.10, m and 1.75, m (9 protons -O

IR spectrum (KBr): carbamate bands from 3415 to 1710 cm 1 By the same process, but from the corresponding reagents, the compounds of formula (Vc, d) appearing in Table III and of code numbers 45 are obtained, 49 and 51.

Example 7:

Benzyloxycarbonylamino-5 (2,3-epoxy propoxy) -5 benzodioxane-1,4 (Illd)

Code number: 70

A suspension of 10 g of the compound of formula (IVd), of code number 61, obtained according to the protocol described in the 2nd stage of Example 5, of 20 ml of epibromohydrin, of 10 g of benzyl alcohol and 15 g of potassium carbonate in 200 ml of acetonitrile. Then filtered, the filtrate is evaporated and the residue is taken up in chloroform, washed with water, dried over sodium sulfate and the solvent is evaporated. The residue is crystallized from ethyl acetate.

Efficiency: 75%

Melting point: 110 ° C Raw formula: CI9H19N06

Elementary analysis:

Calculated: C 63.86 H 5.36 N 3.92%

Found: C 63.27 H 5.26 N 3.80%

Example 8:

[(Methyl-3) n-butyloxycarbonyl-8 benzodioxane-1,4 5-yl] oxy-3 [(trimethoxy-3,4,5 cinnamoyl) -4piperazine-1 yl] -l propanol-2 [S (-) ] hydrochloride hydrate (la)

Code number: 72

1 "stage: [Methyl-3) n-butyloxycarbonyl-8 benzo-dioxane-1,4,5-yl] oxymethyl-4 dioxolane-1,3 [S] (XV)

A suspension of 14.5 g of the compound of formula (IVb) of code number 32, of 17.5 g of the compound of formula (XVI) and of 38 g of potassium carbonate in 300 ml are brought to reflux for 12 h. of dimethylformamide, then filtered, the filtrate is evaporated and the residue is chromatographed on a silica column. By elution with ethyl acetate (5 to 20%) / hexane (95 to 80%) mixtures, 8 g of the desired product are obtained.

Yield: 30%

Melting point: 85 ° C Raw formula: C29H2S07 [afe0 = —13.2 ° (C = 1, ethanol)

NMR spectrum (CDCl3): 8 ppm = 7.4, d; 6.5, d and 4.35, s (6 benzodioxin protons); 4.25, t (COOCH2 -); 4.12, m

(O — CH2 — CH — CH2); 1.65, m (-CH2-CHO;

i i

'• 4-d (cü; x2:} ° -95'd (^ ch;)

2nd stage: [(Methyl-3) n-butyloxycarbonyl-8 benzodioxane-1,4 5-ylJoxy-3 propanediol-1,2 [S] (XIV)

A solution of 7 g of the compound of formula (XV) above in 100 ml of acetone and 36 ml of hydrochloric acid IN is brought to reflux for 3 h, then the acetone is evaporated, the residue is taken up in methylene chloride , neutralizes with sodium bicarbonate, decant the organic phase, wash it with water, dry over magnesium sulfate, filter, evaporate the solvent and recrystallize the residue from ethyl acetate.

Yield: 92%

Melting point: 100 ° C Crude formula: C2 <jH2407 Md = + 4.8 ° (C = 4, methanol)

NMR spectrum (DMSO): 5 ppm = 7.35, d; 6.6, d and 4.22, s (6 benzodioxin protons); 4.10, t (—COO — CH2—); 4.9, d and

4.6, t (OH OH); 3.95, m and 3.45, m (OCH2 - CH - CH2);

i i

/ \ O o l, 52, m (—CH2 —CHO; 0.95, d (- <^ M

3rd stage: [(Methyl-3) n-butyloxycarbonyl-8 benzodioxane-1,4 5-yl] oxy-3 [(trimethoxy-3,4,5 cinnamoyl) -4 piperazine-1 yl] -l propanol-2 [S (-)] hydrochloride hydrate (la)

Code number: 72

2.4 g of tosyl chloride are slowly added to a solution cooled to 0 ° C. of 5.7 g of the diol of formula (XIV) above in 10 ml of pyridine and 100 ml of benzene. It is then left in contact for 45 hours at room temperature, then diluted with benzene and ether, washed with a solution of IN hydrochloric acid, then with water, then dried over magnesium sulphate, filtered and evaporates the solvents. 7.3 g (95%) of tosylate of formula (XIII) are thus obtained, which is dissolved in 50 ml of acetonitrile and added to a suspension of 3.67 g of the compound of formula (II) and 5 g of potassium carbonate in 50 ml of acetonitrile. The mixture is refluxed for 15 h under a stream of nitrogen, then filtered, the filtrate is evaporated, the residue is taken up in methylene chloride, washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated. 8 g (98%) of the desired compound are obtained which are dissolved in 100 ml of methyl ethyl ketone, then a stream of gaseous hydrochloric acid is passed through and the precipitate formed (3 g) is filtered.

Yield: 37%

Melting point: 162 ° C Crude formula: C33H45ClN2O10 + fs H20 Md = —7.8 ° (C = 2, methanol)

Elementary analysis:

Calculated: C 57.63 H 6.96 N 4.07%

Found: C 57.71 H 6.95 N 3.92%

The compounds of formula (I) have been studied in laboratory animals and have shown antianginal activity.

This antianginal activity is demonstrated in the anesthetized dog (sodium pentobarbital 30 mg / kg / i.v.).

Oxygen consumption in the left ventricle is

5

10

15

20

25

30

35

40

45

50

55

60

65

646,694

20

estimated by the product of the coronary venous flow by the coronary arteriovenous difference in oxygen (volume%).

The coronary venous flow is measured at the level of the coronary venous sinus by means of a modified Morawitz cannula, introduced under radioscopic control. s

Coronary arterial and venous oxygenation is measured using a blood gas analyzer (IL Meter 213).

Cardiac effort is estimated according to the Katz index, by the product of average blood pressure and heart rate.

The heart rate is evaluated from the electrocardiogram recorded in lead D2.

Systematic blood pressure is measured at the femoral artery with a pressure sensor (Sanborn 267-BC).

The results obtained by injecting the compounds of formula (I) and the following reference compounds: Lidoflazine and Amiodarone, are reported in Table IV. It should be noted that the test compounds are injected intravenously as a slow infusion.

Table IV

Antianginal activity

Tested compounds (code number)

DLS0 toxicity (mg / kg / i.v.)

Dose (mg / kg / i.V.)

Decrease in consumption of 02

Decreased cardiac effort

(%)

time (min)

(%)

time (min)

1

400 (10%)

2.5

57

45

47

40

2

320

1.25

65

45

27

60

3

400 (0%)

0.15

71

30

24

20

4

400 (0%)

0.15

60

40

18

25

5

-

0.15

45

> 30

15

30

6

220

0.15

64

15

25

45

7

200 (0%)

0.15

60

> 30

39

> 45

8

2000

0.15

41

15 to 60

21

25

(p.o.: 0%)

9

2000

(p.o.: 0%)

0.31

62

45

26

30

10

-

0.31

69

> 30

18

23

11

400 (0%)

0.15

30

30

16

30

12

200 (0%)

0.15

47

25

18

15

13

2000

(p.o .: 0%)

0.15

49

60

18

30

14

200 (0%)

0.31

38

> 30

25

> 45

15

100 (0%)

0.15

42

30

18

> 30

16

2000

{p.o .: 0%)

0.31

62

> 45

40

> 60

17

132

0.15

43

> 30

17

45

18

-

0.15

40

35

24

> 45

19

2000

(p.o.: 0%)

0.31

24

15

26

30

71

> 2000 (p.o.)

0.15

29

60

39

60

72

> 1000 (p.o.)

0.15

36

60

42

60

73

> 2000 (p.o.)

0.15

18

15

10

15

74

> 2000 (p.o.)

0.31

72

60

40

45

75

> 2000 (p.o.)

0.31

54

45

39

30

76

> 2000 (p.o.)

0.15

30

30

11

45

77

> 2000 (p.o.)

0.15

28

60

27

60

Lidoflazine

25

1.5

48

30

40

15

Amiodarone

180

10

11

15

22

15

It appears from the preceding results that the difference between the therapeutic doses and the toxic doses is large enough to allow the use of the compounds of formula (I) in the treatment of disorders of the cardiovascular systems, in particular as anti-gororous.

They will be administered intravenously in the form of injectable ampoules containing 60 to 120 mg of active principle or orally in the form of tablets, dragees or capsules containing 20 to 200 mg of active principle (1 to 3 per day).

R

3 sheets of drawings

Claims (7)

646,694 1. Derivatives of 3,4,5-trimethoxycinnamoylpiperazine, characterized in that they correspond to the general formula: in which Ar represents: - or the 4-acetyl-2-ethoxyphenyl group of formula: ^^ c ° ck3 0C2H5 - or a benzodioxane group of the type: o. 0 in which R represents: - the methylthio-2-ethoxy sequence of formula - O / S / SCH3; - an ester group of the type - COORj, in which R represents an element chosen from the following: methyl, n-propyl, n-butyl, isobutyl, (2-ethyl) -n-butyl, n-octyl, cyclopropylmethyl, cyclo - 2. Medicament used in particular for the treatment of disorders of the cardiovascular system, characterized in that it consists of or contains at least one of the compounds according to claim 1. 20 3. Process for the preparation of the compounds of formula (I), with the exception of that for which Ar represents the unit: o A / SCH, 25 O 0 \ _y and the one corresponding to the particular formula: characterized in that it consists in condensing the 3,4,5-cinnamoylpiperazine trimethoxy in the alcoholic medium of formula: 35 / \ NOT ? —H (II) 40 2 4. Process for the preparation of the compound of formula (I), in which Ar represents the group: O- ^ VSCH, > = r 3 O 0 with the epoxides of formulas (Illa), (Illb), (IIIc) and (Illd): characterized in that it consists in condensing in an ethanolic medium, in the presence of potassium carbonate, 1-chloro-2-methylthioethane 45 with the compound of formula (XII): (Illa) 0C2H5 (xn) he oh 50 (IHb) 5. Process for the preparation of the compound of formula: 0 KH ~ C00R'2 \ f 55 ch, 0 ch. (IIIC) oh xj CHjO / [sî-dd (the) ° - € Vm (nest) 60 characterized in that it consists in condensing the compound of formula (II) defined in claim 3 with the compound of formula (XIII): in which Ri has the same meanings as in formula (I) and R'2 represents a methyl group, a linear or branched alkyl group having from 3 to 5 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms . 65 TsO C00 > \ TO (XIII) 646,694 5 butylmethyl, cyclopentylmethyl, (cyclobutyl-2) -ethyl, (cyclo-propyl-2) -ethyl, cyclopentyl, phenyl or (methyl-3) -n-butyl and, in the latter case, the derivative of formula (I) corresponding having an asymmetric carbon is either in the form of a racemic mixture of two enantiomers, or in the form of io the levorotatory enantiomer of S conformation, or - a carbamate group of the —NH — COOR2 type, in which R2 represents the methyl group, a linear or branched alkyl group having from 3 to 5 carbon atoms, a cyclo-alkyl residue having 5 or 6 carbon atoms, or a group 15 benzyl, as well as their pharmaceutically acceptable salts. 6. Composed of formulas: x; 7 N \ _ COCH „ (Illa) 0C2H5 0 / \ 0 / V isobutyl, (2-ethyl) -n-butyl, n-octyl, cyclopropylmethyl, cyclo-butylmethyl, cyclopentylmethyl, (cyclobutyl-2) -ethyl, (cyclo-propyl-2) -ethyl, cyclopentyl, phenyl or (methyl-3 ) -n-butyl and, in the latter case, the corresponding derivative of formula (I) comprising an asymmetric carbon is either in the form of a racemic mixture of two enantiomers, or in the form of the levorotatory enantiomer of conformation S , or - a carbamate group of the type - NH — COOR2, in which R2 represents the methyl group, a linear or branched alkyl group having 3 to 5 carbon atoms, a cyclo-alkyl residue having 5 or 6 carbon atoms, or a benzyl group.