FR2462432A2 - NOVEL DERIVATIVES OF 3,4,5 TRIMETHOXY CINNAMOYL PIPERAZINE, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE THEREOF - Google Patents

Abstract

A. NEW DERIVATIVES OF 3,4,5TRIMETHOXY CINNAMOYLE PIPERAZINE. B. THEY MEET THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH AR REPRESENTS: EITHER THE ACETYL-4 ETHOXY-2 PHENYL GROUP OF FORMULA: (CF DRAWING IN BOPI) OR A BENZODIOXAN GROUP OF THE TYPE: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS: THE METHYLTHIO-2 ETHOXY CHAIN OF FORMULA: -OSCH, AN ESTER GROUP OF THE -COOR TYPE IN WHICH R REPRESENTS A METHYL, N-PROPYL, N-BUTYL, ISOBUTYL, ISOPENTYL, N-OCTYL GROUP , THE CYCLOPENTYL GROUP OR THE PHENYL GROUP, A CARBAMATE GROUP OF THE -NH-COOR TYPE IN WHICH R REPRESENTS THE METHYL GROUP, A LINEAR OR RAMIFIED ALKYL GROUP WITH 3 TO 5ATOMS OF CARBON, A REMAINING CYCLOALKYL OF 5 TO 6B CARBON POSSATOMEDONE , OR A BENZYL GROUP. C. MEDICINES, ESPECIALLY FOR THE TREATMENT OF DISORDERS OF THE CARDIOVASCULAR SYSTEMS.

Description

1 2462432

  This application is an application for a 2nd certificate of addition to main application no 77.11707 and relates to new 3,4,5-trimethoxy cinnamoyl piperazine derivatives of the same structure as those in the application.

  principal, as well as their method of preparation and their therapeutic application.

  These new derivatives correspond more precisely to the general formula

  in which Ar represents either the 4-acetyl-2-ethoxy-2-phenyl group of formula: ## STR5 ## wherein

R OC H

  a benzodioxin group of the type:

0_o

  in which R represents: - the 2-methylthioethoxy chain of formula -O-1 SCH3, - an ester group of -COOR1 type in which R1 represents a methyl, n-propyl, n-butyl, isobutyl, isopentyl, n octyl group, cyclopentyl group or phenyl group; - a carbamate group of the NH-COOR 2 type in which R 2 represents the methyl group, a linear or branched alkyl group having from 3 to 5 carbon atoms, a cycloalkyl residue having from 5 to 6

  carbon atoms, or a benzyl group.

  The present invention also covers the pharmaceutically acceptable salts of the compounds of formula (I), namely the salts of mineral acids

  and non-toxic organic compounds, and in particular the salts of hydrochloric acids, oxa-

lique, maleic ...

  The process according to the invention for the preparation of

  formula (I) with the exception of the compound of formula (I) wherein Ar represents

  In the following: 0 Av0 SCH3 O O consists in condensing in an alcoholic medium (methanol, ethanol, butanol, etc.) 3,4,5-trimethoxy cinnamoyl piperazine of formula: CH30O

CH3 0 <N N - H

CH3 \ N / N-H

3 (It) 4U un3u

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  with the epoxides of formula (Ilia), (IIIb), (IIIc) and (IIId): ## STR5 ##

O - COOR1

(IIIo) OOX NH-COOR '(2Tc) (IId)

0 - NH --COO. (I A

  Where R1 has the nemes -significationsque than in formula (I) and

  F 2 represents a methyl group, a linear or branched alkyl group

  from 3 to 5 carbon atoms or a cycloalkyl group having from 5 to 6

carbon atoms.

  The compounds of formula (IIIa), (IIIb) and (IIIc) are new and are obtained by condensation of epichlorohydrin or epibromhydrin with

  reflux in acetonitrile (or acetone) in the presence of potassium carbonate

  sium with compounds of formula (IVa), (IVb) and (IVc): HO p COCH3 (IVa)

OC2H5

2C5

H0 \ C00R1

  HO. NOT-. COOR'2 (IVc) 0 \ J in which R1 and R'2 have the same meanings as in the formulas

(IIb) and (IIIc).

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

HO - Q \ NH - COO

4 0 0 (IVd) -_ /

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  The compound of formula (IVa) new is obtained by a reaction of FRIES on 1-acetoxy-2-ethoxybenzene of formula (Va)

CH3COO0

  3 w (Va) C2H50 which is itself new and is obtained by 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 half

  ethanol site of the benzyl group of the compounds of formula (Vb) and (Ve, d)

O COOR1

(Wb)

0 0

  In which R 1 has the same meanings as in formula (IVb) and R "'2 represents a methyl group, linear or branched alkyl having from 3 to carbon atoms, a cycloalkyl group; having from 5 to 6 carbon atoms

bone or the phenyl nucleus.

  The new compounds of formula (Vb) are obtained by esterification

  two-step cation, which comprises treating with thionyl chloride the compound of formula:

COOH (VI)

  As described in Belgian Pat. No. 865,990, and then to react with the crude compound thus obtained, the alcohols of formula (VII)

R1 OH (VII)

  in which R1 has the same meanings as in formula (Vb).

  The compounds of formula (Vc, d) new, 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): ## STR2 ##

  wherein R3 represents methyl, isopropyl, n-butyl, isopropyl,

  butyl and phenyl with the compound of formula (IX):

O-O NH2 (IX)

0 \

  is described in Belgian Patent No. 865,990.

  The compounds of formula (Vc, d) new, for which R "2 represents

  The n-propyl, 4-methylbutyl, cyclopentyl and cyclohexyl groups are obtained by condensation of the alcohols of formula (X):

R OH (X)

  wherein R4 represents n-propyl, 4-methylbutyl, cyclohexyl,

  pentyl and cyclohexyl with the isocyanate of formula (XI)

O2 O O N = C = O (XI)

  The compound of formula (XI) new, 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

  mule (I) wherein Ar is the group:

2.- O, SCH

O

0o 0 X-I

  consists in condensing in an ethanolic medium, in the presence of potassium carbonate

  sium, 1-chloro-2-methylthiethane with the compound of formula (XII) ## STR2 ##

CH 3 O \ _-

CE3 - I__] <OH (XII)

0 0 0

CH30

  described in Belgian Patent No. 865,990.

  The following preparations are given by way of example for

to polish the invention.

  EXAMPLE 1 (2-Acetyl-2-ethoxy-2-phenoxy) phenoxy-1 (3,4,5-trimethoxy cinnamoyl piperazine) -47-3-2-propanol, oxalate, hydrate (I) Code number: 1 -40 reflux time a solution of 3 g of 3,4,5-trimethoxy-cinnamoyl piperazine (II) and 2.7 g of (4-acetyl-2-ethoxyphenoxy) -1

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  2,3-epoxypropane (IIIa) (prepared in Step 4 of Example 3) in 50 ml of ethanol. The solvent is then evaporated off, the residue is dissolved in acetone and an oxalic acid solution is added and the precipitate obtained is filtered off

to obtain 5.6g of product.

  5. Yield: 87% Melting Point: 160 C Formula: C31H40N2011 + 3/4 H20 Elemental Analysis: Gain Bearing

C H N

  Calculates% 57,61 6,47 4,34 Found% 57,57 6,24 4,33 By the same process, but from the corresponding reagents, the compounds of formula (I) appearing in Table I below and

the code numbers 3 to 19.

TABLE I

PondR - ELEMENTARY ANALYSIS

Number P Point of Render-

  X - fuiArmn of code X - Ar Form Gross formula moldcus merging mer (C) (%) Cal. 57.61 6.47 4.34

  1 _ 02 COCH3 Oxalate C31H40N2011 + 646.16 160 87 -

  3 hydrated 14o2i 0P-2H-hy 3/4 H20 Tr. 57.57 6.24 4.33 2 Chlorh2dra2 2 / - r O, \ SCX Hydrochloride C3OH41ClN2O9S +662,19 175 60 Cal. 5, i 6,60,23>: <3 hydrated

--'-.

  hydrated 7/6 H 2 O 6 O 5 Tr. 54,316.37 4.07 C H-CUHODl 4NO 1 75210+ Cal. 55,546.27 4.47 3? Hydrochloride 29 37 2 10 627.10 163 58 3n Hydrogen H20, Tr. 55.48 6.21 4.41 C H ClN 0+ Cal.56.576.644,26 4 7 n-L. /\V.COOC3H,7 Hydrochloride31 hi 2 10 658,13 1h5 65 Cl 65, hydrated hh2 1/6 HO

2 ......... Tr. 56,766,79 ,.

  C GOON Cal. 57,076.37 3.92 - 0 COOC4H9 n Oxalate C34H44N2014 + 715.52 150 79 - - -. Hydrated 3/5 H20 Tr. 57.3h 6, h7 4, oh Cal. 57.13 6.84 4.16

  6 o COH Hydrochloride 32H3ClN2O10 672.76 160 82 -. -. -

  hydrated C 1H4Ci2010 + 1 / P.2 HO - Tr. 57,186,81 4,21 r ovI M. 4N w TABLE I (Continued) Number oPoidsRende Point-ELEMENTARY ANALYSIS 7 OOChydrochloride 33 552.F10o 687.68 160 75 -ur \ Hydrogen 5/4 Tr. 57.636.96 407 8 HCl C33H43ClN2O150 + 57 16 7 C5 / 43CH2010Cl 97.4 42 ______________ Triggered 59.466.68 4, s15 OO-C1n CH + Cal. 59,257,253,84

  9 | O-J-Hydrochloride 36 512 10 729.76 106 66 -

hydrated4 / 5 H20 Tr. 59,527.29 3.81

ONCal. 59.66 5 .....

  Oxalate 36 40 2 14 724.70 136 51 - -6 - 8 ooU .. Tr. 59,605,764, o1

_. n ,, .. l.

0-I INH-COOCH Cal. 53,496,356,45

  o C0-C8H1n3 Hydrochloride C29H38ClN3010 +651.10141 64.

  hydrated1.5 H20 Tr. 53.556, o46.43 12-O-NH-C3 7n C31H42ClN3O + Cal.55,266, 646.24

0 -COOC-

  102 tC36401.2 H O 673.75 155 48 __ _____., _I'2r. 55.53 6.46 6.31I - 0 <'y.NH-COO- <Cal. 55,264 6,6456.24 1331 C hr rhYdrateC 42CC1N3010 + 3 hydrate31.2 H2O Tr. 55,296,425.97

- 0NH - COC-7

  TABLE I (Continued) Number Weight Point of Rende-ELEMENTARY ANALYSIS Nu X-Ar Code Molecular Form Brutal Formula (C) (%)

4C | H N

  1H-O ON -OOC4H9CHCnO14O NH-COOC 4H9nClohydrochlorideC32H44ClN3010 + 697.68156 74 Cal.55.096,866.02 \ hydrated61.75 H2 OTr. 55.346.63 6.54 ClHhCl3 + Cal. 55,596,826,08

  - O9 NH-COOt "32 443 10 691,37 175 73 - - -

17/5 HO0

  qpy 2 Tr. 55.746.68 6.21 1 6 0 - / 7 - \\ O NH-COOI_1IC33H46 ClN301O + 11 Cal. 56,766,936,02

  16-0- <Q> - NH-C00-N.-S33 h631 698.19 176 70- -

  o v 2 Tr. 56.857.10 6.15 Cal.56.646.686,01 0NH-cQ 32H44Cl3013 0+ + 17-1O t2NH COO-t 33 4h3 10+ 699.78 176 58

1 9,372H70 7

  _______h_2 Tr. 56,326,29 5,95 18 | - OtNHI-COO0 t | hydrate | C36H4 N304 + Cal. 156886,445.53 18 Oxalydateh / 5H 20 760,17 182 6h Tr.571 6.88 ONC0C35H42ClN3010 + Cal.58.246.20 5.82 9 -0 NHO hydrate 2 25.2 5.7 721, 791718 5.915, 79

T. 56, 8 _, 16, 1 5 ==

1.2 H O ..- __ _ _

  __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ . __ __ __ _, __ _ 2 __ __ _, 2 _ __ __ _5, _ __ _5 _

o'j -t: r <M

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  EXAMPLE 2: 2- (2-Methylthioethoxy) ethylene 2,3-dioxyphenoxy / -1 (3,4,5-trimethoxy cinnamoyl) piperazine-47-3 2-propanol hydrochloride, hydrated (t) Code number A mixture of 13.3 g of (4-hydroxy-ethylene-2,3-dioxy) -phenoxy-1 (4-trimethoxy-3,4,5-cinnamoyl-4-piperyl) -2-propanol-2 was refluxed for 18 hours ( XII), 3.5 ml of 1-chloro-2-methylthiethane and 10.3 g of

  potassium carbonate in 150ml of ethanol. Then we filter, evaporate the

  The residue is taken up in chloroform and washed with water. We dry the phase

  on sodium sulphate, the solvent is evaporated and the chromatography

  sidu on a silica column. Eluted by pure chloroform mixtures and

  chloroform 99% - methanol 1%, 13 g of pure product is obtained which is dis-

  in acetone and 4.5 ml of 6.5N hydrochloric ethanol. The precipitate obtained is filtered, dissolved in the minimum amount of alcohol and diluted by

  acetone. 9.35 g of product are obtained.

  M.p. Go)

  To a solution of 30.4 g of 6-ethoxy-phenol in 10 ml of tetrahydro-

  furan and 29 g of triethylamine, 17.3 g of chlo-

  acetyl chloride, then left in contact for 24 hours, filtered the precipitate,

  pore the filtrate and distil the residue. 27.2 g of product are obtained Yield: 69% Boiling point Eb 9 mm: 115 - 123 C Formula crude 12 12

: 0 C01203

  NMR Spectrum (CDCl3): mp = 7.00, m, (4 benzene protons) = 4.00, q, (CH2 from O-CH2-CH3) = 2.25, s, (-CH3 from OCOCH3) = 1.32, t, (-CH3 of O-CH2-CH3) 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 100ml of nitrobenzene, 24g of aluminum chloride is added

C H

  Calculated% 54.41 6.60 4.23 Found% 54.31 6.37 4.07

  and allowed to stir for 20 hours at room temperature. Then we pour the mixture

  reaction in ice and concentrated hydrochloric acid and extracted with ether; the ethereal solution is extracted with a 2N sodium hydroxide solution and the aqueous solution is then acidified with concentrated hydrochloric acid and extracted with chloroform. The solvent is evaporated and the residue is chromatographed on a silica column eluted with 100% benzene. 50% of the expected compound (IVa) is obtained,

Melting point: 66 C -

Gross formula: C10H1203

  10. NMR Spectrum (CDCl 3): o ppm = 7.50, m, and 6.95, d, (3 protons ben-

  zeneric) = 6.72, s, (-OH) = 4.10, q, (-CH 2 of -O-CH 2 -CH 3) = 2.55, s, (COCH 3) = 1.20, t, ( -CH3 -O-CH2-CH3) then 50% of its isomer ethoxy4 ', 3-hydroxy-acetophenone, m.p .: 100 C

  NMR Spectrum (CDCl 3): Jppm = 7.9, m, and 6.90, d, (3 protons ben-

  zeneric) = 6.55, s, (OH) = 4.10, q, (-CH2 of O-CH2-CH3) = 2.50, s, (CH3CO-) = 1.4o, t, (- CH3 of O-CH2-CH3) (the structural assignment of both isomers was confirmed by NMR study of the influence of complexation with Europium / EU (Cl04) 3 /

  on the chemical displacement of aromatic protons (solvent CD3OD).

  3rd stage: (2,3-epoxy-propoxy) -4'-ethoxy-3'-acetophenone (IIIa) A mixture of 6.2 g of compound of formula (IVa) obtained in the previous stage, of 5 g, is refluxed for 5 hours. epibromhydrin 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 sulphate and the solvent is evaporated off. We obtain

6.5g of product.

  Yield: 76% 35. Melting point: 900 C Crude formula C H O

14 16 4

  Spectrum of EMN (CDCl 3) - ppm = 7.5, m, and 6.95, d, (3 protons aro-

matic)

= 4.20, m, 3.4, m, and 2.8, m,

4o tones O0 / 0

112462432

  NMR Spectrum (CDCl3): Sppm = 4.10, q, and 1.40, t, (O-CH-CH3 = 2.50, s, COCH3 EXAMPLE 4: (2,3-epoxypropoxy) -5-methoxycarbonyl -8 benzodioxane-1, 4 (IIIb) Code number: 37 l1er stage: 5-benzyloxy-8-methoxycarbonyl-1,4-benzodioxane (Vb) Code number: 20

  To a toluene solution of 28 g of (benzyloxy-5-benzodioxane)

  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 hours. Then the solvents are evaporated, the residue is dissolved in 200 ml of tetrahydrofuran and 8 ml of methyl alcohol and 38 ml of triethylamine are added. The mixture is heated for 3 hours at 60 ° C. and the precipitate formed is filtered off, the filtrate is evaporated and the residue is chromatographed on a silica column, eluted with 100% methylene chloride. We get 20g

of product.

  15. Yield: 74% Melting point: 100 C Formula crude: C17H1605 The product is used crude in the synthesis of the compound of formula (IVb) corresponding to the compound of code number 28 in the table

II below.

  By the same process, but from corresponding reagents, the compounds of formula (Vb) appearing in Table II below are obtained.

  and bearing code numbers 21 to 27.

  2nd stage: 5-hydroxy-8-methoxycarbonyl-1,4-benzodioxan (IVb) Code number: 28 Hydrogenolysis under pressure and ordinary temperature, in the presence

  2 g of 5% palladium on carbon, a solution of 20 g of the compound of formula

  the code number (Vb) obtained in the preceding stage in 200 ml of ethanol.

  Then filtered, evaporated the solvent and 13g of crude product.

  Melting point: 153 ° C Formula: C10H1005 (crude employee in the synthesis of the corresponding compound of formula (IIIb)

  code number 36 and shown in Table II below).

  By the same method, but from the corresponding reagents, the compounds of formula (IVb) appearing in Table II below are obtained.

  and bearing the code numbers 29 to 35.

  3rd stage: (2,3-epoxy-propoxy) -5-methoxy-8-carbonylbenzodioxane

  1.4 (IIIb) 4o Code number: 36 A mixture of 13 g of the compound of formula (IVb) obtained in the preceding stage, 25.5 ml of epibromohydrin and 5 g of potassium carbonate is refluxed for 4 hours. in 250ml of acetonitrile. Then filtered, the filtrate is evaporated, the residue is taken up in methylene chloride, washed with water and then with 1N sodium hydroxide solution, dried over sodium sulfate and the solvent evaporated. The residue is recrystallized from ethyl acetate and

gets 11.4g of product.

  Yield: 69% Melting point: 122 ° C. 10. Formula crude: C13 H1406 By the same method, but starting from the corresponding reagents, the compounds of formula (IIIb), - appearing in Table II below, are obtained

  and bearing code numbers 37 to 43.

TABLE II R10C0 OR5

  Number R. R. Formula Weight Point of Render-

  R-5 Molecule-fusion fuze Rough-field (M) (o) C (%)

  NMR (CDCl3) 7.3, d; 6.5, d, and 4.3, s, (6

  (Vb) CH3-CH2-C17H1605 300.70 100 74 benzodioxan tones) 7.4, m, and 5.2, s, (7 protons-O-CH2 <) 3.8, s, (COOCH3) -NMR ( CDCl): 7.3, d; 6.5, d, and 4.3, s, (6 pro 21 if 337 2 n C3H7n CH19H2005 328.35 101 66 benzodioxan tones) 7, 6, m, and 5.2, s, (7 protons -CH 4 , 3, m; 1.7, m, and 1.00, t, (7 pr.C00C H7) NMR (CDCl3: 7.3, d; 6.5, d, and 4.3, s, (6 pro benzodioxanne tones)

  C4Hg C20H2O5 342.38 <50 70 7.5, m, and 5.2, s, (7 protons-O-CH -).

  h. 9n20 22 hr 3, m, and from 0.8 to 1.6, m, (9pr.COOC4H-) I 4 n

  CHCH NMR (CDCl3): 7.3, d; 6.5, d, and 4.3, s, (6pro-

/ C CH 3-tonesbenzodioxane)

/ CH OC32,3

  23 CH 0 342.38 63 60 7.4, m and 5.2, S, (7 protons-O-CH-Q), 233 CH3, n, 3423630.1, d, 2, m and 1, d, (9 hours COO)

  NMR (CDCl3): 7.3, d; 6.5, d and 4.3, s (6

  CH 21H2405 356.40 <50.64 7.4, m; 5.2, s, (7protons-O-CH 2

  2 // CH3 4.3, m; 1.7, m; and 0.9, d, (11pr, C-eOOn) -

  NMR (CDCl3): 7.4, d; 6.5, d, and 4.3, s, (6pro-.

  C21H220 35h, 87387, and, 2s, 7prtons benzodioxane)

  C 1 H 2 O 5 354.39 87 38 7.4, m, and 5.2, s, (9 pr-o) -O-C-

  ..2 22i 5.2, m, and 1.8, m, (p.2 \ = w ru o .. Wt> TABLE II (Continued) .. DTD: Weight Point of Rend-

  H number R. R. Molecular formula R M N SPECTRA of code 1 gross (oC) (%) o

  ________-. NMR (CDCl3): 7.3, d; 6.5, d, and 4.3, s, (6

  26 (Vb) -C8H17n -CH C24 305 398.48 oil 79 tones benzodioxane 28617n -CH 2 C24H3005 7.5, m, and 5.2, s, (7 protons -O-CH- /) 4 3.m and from 0.8 to 1.6, s, (17 protons

  __________________ = O0-δ8-H1 __ _ _ _ _ _ _ _ _ _ _ _

  NMR (CDCl3): 7.6, d; 6.6, d, and 4.3, s (6 pro-

  27 C H 0 362.36 144 28 tones benzodioxane) 22 18 5 7.4, m, and 5.2, s, (7 protons -O-CH2- () 7.4, m, (5 protons C00-)

  NMR (CDCl3): 7.3, d; 6.5, d, and 4.3, s (6 pro-

  Benzodioxan tones) 28 (IVb-CH 3 H C 10 H 10 5 210.18 153 93 10.00, s, (OH) 3.8, s, (COOCH 3)

_. .

  NMR (cD1c) 7.5, d; 6.6, d, and 4.3, s, (6

3benzodioxan tones)

29 -CH "C

  2 "3 7n C12 14 5 238.23 73 98 6.8, s, (-OH) 4.3, t; 1.8, m; and 1.00, t, (7pr COOC3H7) 3 7n

  NMR (CDCl3): 7.5, d; 6.6, d, and 4.3, s, (6

  B. Benzodioxan H) tones "CH 9 n" C 13 H 16 O 2 99 49. C 13 H 1605 252.26 79 98 7, s, (OH); 4.3, m, and 0.9 to 1.8, m, (9.protons COOC4H9n)

  _ CHCH. NMR (CDCl3): 7.4, d; 6.6, d, and 4.3, s, (6

  31 n / 2. 3 benzodioxane CH) 31 y C13 H1605 252.26 66) 96,695, s, (OH) CH3 4.2, d; 2, m, and 1, d, (9 protons COO0 /)

  3CH NMRN (CDCl3): 7.5, d; 6.6, d and 4.3, s, (6

  32% benzodioxane) XH2 + 14 18 5 266.28 69 98 4.3, m, 1.7, m, and 0.9, d, (11 protons

c_ 3jr coo.vk).

N 4> - 0. wu tg TABLE II (Continued)

I! Weight Point of Rende-

  R number R R Molecular formula R M N SPECTRA code q gross (C) (%) o

  NMR (CDCl3): 7.4, d; 6.6, d and 4.3, s, (6

  Benzodioxan tones) 33 (IVb) H C14H1605 264.27 95 95 6.8, m, (-OH), 4, m, and 1.8, m, (9 protons -)

  NMR (CDCl3): 7.5, d; 6.5, d, and 4.3, m, (6

  34 C H C H O 308.36 63 98 tones benzodioxane) 8 17n 17 24 5 4.3, m and from 0.8 to 1.8, m, (17 protons

COO-C8H17)

8 17n

  NMR (CDCl3): 7.65, d; 6.6, d, and 4.3, s, (6

  benzodioxan tones) "15H1205 272.25 156 93 7.25, m, (5 protons -COO 7.25, m, (5 protons -COO) 6.15, s, (OH)

  NMR (CDCl3): 7.5, d; 6.6, d, and 4.35s,

  benzodioxane tones) 36 ITb) CH3CH2 \ kC 13H, 4406 266.24 122 69 4.3, m; 3, 4, m, and 2.8, m, (5 protons 0 / V)

__, ___ 3.8, s, (COOCH3).

  NMR (CDCI1: 7.4, d, 6.7, d, and 4.3, s, (6 products 3-benzodioxan) 37 n 3H7-C15H1806294.29 100, 4.3, m, 3, h, m, and 2.8, m, (5 pr.OCH /) O 3 n 7 CH 2 C, 24.3, t, 2.8, m, and 1.00, t, (7pr CO-C 3H 7)

i ...... -

  NMR (CDCl3): 7.5, d; 6.5, d, and 4.3, s, (6

  benzodioxane tones) 38 C4H9n n 16 H2006 308.32 105 85 4.3, m; 3.4, m, and 2.8, m, (5 protons 040-) 4.3, m, and 0.8 to 1.7, m, (9 pr COOC4H) |

  CHCH32N (NMR (CDCl3): 7.4, d; 6.5, d, and 4.35, s (6

* 39 C C6206 3308.32 110 83 benzodioxan tones) protons O 39 CH C1H2006 308, 32 110 83 432, m; 3.4, m, and 2.8, m, (9 prt.COOZ / N () CH3 4.3, d, 2, m, and 1.00, d, (9) COOn 00 rg3 rca TABLE II (Continued)

Weight Point of Rende-

  Number a) R R Molecular Formula SPECTRUM OF R M N raw code (C) (%)

  ECHRMN (CDCl3): 7.4, d; 6.5, d, and 4.38, s, (6

  (IIIb 22 CH2 C17H2O6322,35 91 82 Benzodioxan tones) pr.

  4.2, m; 3.4, m, and 2.8, m, (5 pr.OVO) A> CH C 4.2, m; 1.7, m, and 0.9, d, (11 pr 0)

  NMR (CDCl): 7.4; 6.7, d, and 4.3, s, (6

  41., "C17 20f6 320.33 85 98 tones benzodioxane) 4.3, m; 3,4, m, and 2,8, m, (5 pr.O./0), 3, m; 1,8 , (9 protons')

  NMR (CDCl 3): 7.5, d; 6.5, d, and 4.3, s, (6

  42 CH CHO (benzodioxane) tones 42 "C8H17n" C20H2806 364.42 958 or t28m (5p.) C8H iu C20H 28 s6 364.42 95 85 4.3, m, 3.4, m and 2.8, m, (5 pt.) 4,3, m, and from 0,8 to 1,5, m, (17 pr.COO-C H17) ________ _ _ _ __ _ _ _ _ _ 8i17n

  NMR (CDCl): 7.7, d; 6.6, d, and 4.4, s, (6

  3benzodioxane) 43 "", C18H1606 328.31 104 71 7.15, m, (5 protons C00-r) o

  4.3, m; 3.4, m, and 2.8, m, (5 to 0%).

3%) 4Y W%

17 2462432

  EXAMPLE 5 (2,3-epoxy-propoxy) -5-methoxycarbonylamino-8-benzodioxane-1,4 (IIIc) Code number: 62 1st stage: 5-benzyloxy-8-methoxycarbonylamino-1,4-benzodioxane (Vc, d) code: 44 To a solution cooled to 0 ° C. of 25 g of 5-amino-benzyloxy-8-benzodioxan-1,4 (IX) in 250 ml of tetrahydrofuran and 17.6 ml of triethylamine,

  1 ml of methyl chloroformate is slowly added and the mixture is stirred

  7 hours. The mixture is filtered and the filtrate washed with dilute hydrochloric acid solution.

  drique, with water, with a solution of baking soda and water. We evaluate

  pore the solvent and crystallize the residue in ethyl acetate. We obtain

17.8g of product.

  Yield: 58% Melting point: 100 C Formula: C17H17NO5

  15. NMR Spectrum (CDCI): Crppm = 7.4, d; 6.5, d, and 4.3, s, (6

  benzodiazepines) = 6.82, s, (NH-COO-) = 7.4, m, and 5.18, s, (-CH2) = 3.76, s, (COOCH3) 20. IR spectrum (KBr ): carbamate strips at 3420 and 1715 cm-1 By the same method, but from the corresponding reagents,

  obtain the compounds of formula (Vc, d) appearing in Table III and

  both code numbers 46, 47,48 and 52.

  2nd stage: 5-hydroxy-8-methoxycarbonylamino-1,4-benzodioxane (IVc) Code number: 53 Hydrogenolysis under pressure and ordinary temperature, in the presence

  2 g of 5% palladium on charcoal, a solution of 17.8 g of the compound of

  mule (Vc, d) of code number 44 obtained in the previous stage in 400 ml of ethanol

  then filtered, evaporated the filtrate and obtained 11.5 g of crude product em-

  folded as is in the next stage.

  Yield: 90% Melting point: 150 C NMR spectrum (CDCl 3): cf ppm = 7.95, s, (OH)

= 7.30, d; 6.50, d, and 4.3, s, (6

  benzodioxane tones) = 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) having code numbers 54 to 60 are obtained.

182462432

  as well as the compound of formula (IVd) of code number 61 in the

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) of code 53 obtained in the previous stage, 23 ml of epibromnhydrin and 17 g of potassium carbonate in 200 ml of acetonitrile, then filtered, evaporated the filtrate and the residue in chloroform, washed with water and the solvent evaporated. 13 g of crude product employed as such are obtained in the synthesis of the compound of formula (I) corresponding to code number 11 and shown in Table I. Melting point: 134 ° C.

  NMR spectrum (CDCl3): δ ppm = 7.5, d; 6.6, d, and 4.35, s, (6

  benzodioxan tones) = 6.90, s, (-NH-)

= 4.20, m; 3.4, m, and 2.80, m,

O / O tones = 3.82, s, (COOCH3)

  IR spectrum (KBr): carbamate bands at 3380 and 1730 cm.

  By the same method, but from the corresponding reagents, the compounds of formula (IIIc) of code number 63 to 69 appearing

in Table III.

  EXAMPLE 6 5-Benzyloxy-8-cyclopentyloxycarbonylamino-1,4-benzodioxane (Vc, d) Code number: 50 1st stage: 5-benzyloxy-1,4-benzodioxanyl-8-isocyanate (XI) In a solution cooled to 0 ° C. 77g of benzyloxy-8-amino-5

  benzodioxane-1,4 (IX) in 500 ml of toluene is absorbed 100g of phosgene.

  Then allowed to come to room temperature, evaporate the solvent and crystallize

  Read the residue in hot hexane. 62 g of crude product are obtained.

as is in the next 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 pre-

  In 200 ml of tetrahydrofuran and 10 ml of triethylamine, 3 g of cyclopentanol are added and refluxed for 48 hours. The solvent is evaporated, the residue is taken up in chloroform, washed with water and dried over sulphate.

  of sodium, evaporates the solvent and crystallizes the residue in hot hexane.

  9 g of crude product are obtained in the synthesis of the compound of formula

192462432

  (IVc) corresponding to the code number 59 in the table

III below. -

Yield: 78%

  NMR Spectrum (CDCl3): mp = 7.4, d; 6.5, d, and 4.3, s, (6

  benzodioxan tones) = 7.4, m, and 5.05, s, (5 protons 2) = 5.10, m, and 1.75, m, (9 protons

È - (>) -1

  10. IR spectrum (KBr): carbamate bands from 3415 to 1710 cm By the same method, but from the corresponding reagents, the compounds of formula (Vc, d) appearing in Table III and

code numbers 45, 49 and 51.

  EXAMPLE 7 Benzyloxycarbonylamino-5 (2,3-epoxypropoxy) -5 benzodioxan-1,4 (IIId) Code number: A suspension of 10 g of the compound of formula (IVd) of code 61 obtained according to the protocol described in the 2nd stage of example 5, 20 ml of epibromohydrin, 10 g of benzyl alcohol

  and 15 g of potassium carbonate in 200 ml of acetonitrile. Then we

  The filtrate is evaporated and the residue is taken up in chloroform, washed with water, dried over sodium sulphate and the solvent evaporated. We crystallize the

residue in ethyl acetate.

  Yield: 75% 25. Melting point: 110 C Crude formula C H19NO6 Elementary analysis: 19196 AAnalysis:

C H N

  Calculated% 63.86 6.36 3.92 Found% 63.27 5.26 3.80 _ i '

TABLE III 550 NH-COO-A

Weight Point of Rende-

  Number A For- R Molecular formula C.H.N. or SPECTRUM OF R M N and SPECTRUM l R code mule 5 crude (C) (%) NMR (CDCl3): 7.4, d; 6.5, d, and 4.3, s, (6H 44 CH (Vcd) CH 7 -CH 315.31 100 58benzodioxan) - 6.82, s, (NH-COO -); 7.4 m, and CH3 (Vcd) CH2 17 175 315.31 100 58 5.18, s (-CH2-C); 3.76, s, (COOCH) IR (KBr): 3420 and 1715 cm-1

  NMR (CDCl): 7.4, d; 6.5, d, and 4.3, S, (6H benzo

  C3 H7n C19H21NO 343.37 156 68 dioxaline); 7.4, m, and 5.10, s, (CH 2 -5 CH, .19H21N5 343.37 156 68, s, (NH); 4.10, t; 1.70, m and 1, t (C00C H7n) IR (KBr): 3420 and 1720 cm-1 / m.

  NMR (CDCl3): 7.6, d; 6.5, d, and 4.2, s (6H benzo

  46, 7.45, s, (-CH2-); 6.90, s, (NH): 5.02, m.p. mp; 1.15, d, (C00-) IR (KBr): 3430 and 1710 cm-1 (NH-C00-) NMR (CDCl3): 7.5, d, 6.5, d, and 4.3, s, (6H benzene, 47 CH, 2023NO 357.39, dioxane), 7.4, m, and 5.08, s, (CH 2) 4 n = 6.90, s, ( NH); 4.10, t, and 1.20, m, (COOC4Hn IR (KBr): 3420 and 1720 cm-1 (NH-COC4H);

  NMR (CDCl3): 7.5, d; 6.5, d, and 4.3, s (6H benzo

  48 CH2 C20H 235 357.39 dioxane; 7.4, m, and 5.10, s, (CH 2 -), 6.90 s, CNH), 3.95, d, 2.05, m and 1.0, d (COO-CH 2 - IR (KBr): 3420 and 1720 cm-1 (NH-COO-CH 2 -)

  9RMN (CDCl 3): 7.5, d, 6.5, d, and 4.2, s, (6H benzoyl);

  CH 2 H 25 NO 5 371.42 - 48 dioxane) 7.4, m, and 5.08, s, (CH 2 -), 6.90, 2, 371.42s, (NH); , t, 1.6, m, and 1, d, (COOCH 2 /): (KBr): 3420 and 1720 cm-1 (NH-COO), where N o s 4> rla Wu TABLE III (Continued)

,. -....

Weight Point of Rende-

  Number A For- R5 Molecular formula C.H.N. or SPECTRUM OF R M N and SPECTRUM I R of gross mule code (C) (%)

  NMR (CDCl3): 7.4, d; 6.5, d and 4.2, s (6H benzo

  (Vc, d) 2CH 21N235 369.40 78 - dioxane), 6.85, s (NH), 5.05, m and 1.80, m, (COO -), 7.4, m and 5.05 , s (CH2-Y) IR (KBr): 3425 and 1710 cm-1 (NH-COO-) Elemental analysis: CHN

51 "" C22H25CHNO5 383.43 178 78 '

  51 0. n 22H25N5 383.43 178 78 Calculated (%) 68.91 6.57 3.75 Found (%) 68, 71 6.36 3.41

  NMR (CDCl3): 7.4, d: 6.5, d and 4.3, s (6H benzo

  52 C22H19NO5 377.38 - 67 dioxane): 7.4m, and 5.10, s (CH2-5): 7.02, 52 "C22H19NO5377.38 - 67m, (COO-5 22m (ccm D): 6.85, s, (NH) IR (KBr): 3415 and 1710 cm-1 (NH-COO-) NMR (CDCl3): 7.95, s (OH), 7.30, d; , 50, d and 4.3, s (6H benzodioxane); 7, s (NH); 3.78, s (-C00CH3) 53 -CH3 (IVc) H C10H11 NO5 225.10 150 90 IR (KBr) : 3410 and 1710 cm-1 (NHCOOCH3) NMR (CDCl3): 7.55, s (OH), 7.30, d: 6.50, d and 4.3, s 54 -C HCH NO 253.25 - 83 (6H benzodioxane); 6.55, s (NH); 4.10, t; 1.70 53 -7n nn 12 15 5 83 met 1, t, (COOC3Hn) IR (KBr): 3360 (OHI 3380 and 1710cm); -1 (NH-COOC3H7_

  NMR (CDCl 3): 7.4, d; 6.5, d and 4.3, s (6H benzo);

  CH 1212 155 253.25 _99 dioxane), 6.70 s (NH), 5.0, m and 1.22, d C12H15NO5 253.25 - (COO --- <), 5.6, m (OH R (KBr): 3380 (OH and HN), 1710 (NH-COO -)

  NMR (CDCl3): 7.4, d, 6.5, d and 4.3, s (6H benzo

  C4H C12H17N5 267.27 95 dioxane), 6.90, s (NH); 4.10, t and 1.20, m, 56 C4H9n- C13Hq7NO5; 7.27-95 (COOC4H9n); 5.20, m (OH) IR (KBr): 3360 and 1715 cm-1 (NHCOOC4H9n), m.p.

Weight Point of Rende-

  Number A For- R5 Molecular formula C.H.N. or SPECTRUM OF R M N and SPECTER I R of gross mule code (on) (%)

  NMR (CDCl 3): 7.4, d; b, 5, d and 4.3, s (6H benzo);

  57 -CH 2 (IVc) Hc 13 H 17 N 5 267.27 90 dioxane), 6.90, s (NH), 9.95, d, 2.05, m and 9, 95 57 - CH - Ic O 2672 od (OY)

(I2 H 13H17N0526,7-9

  d ((COO 3)) IR (KBr): 3360 and 1715 cm-1 (NHCOO / Y) NMR (CDCl 3): 7.4, 6.5, d and 4.3, s (6H benzodioxan 58CH , CHNO 2, 281.30 98 (e); 6.85, s (NH); 4.15, t; 1.62, m and 0.95, d, 21y 1h 19 (COO0 3, wt); IR (KBr): 3360 and 1710 cm-1 (NHCOO).

  ___N (CDCl3): 7.4, d, 6.5, d and 4.25, s (6H benzo)

  59-N, t 1475 298 (6dxxan)), 6.85, s (NH), 5.10, m and 1.75, m 59 ° C 4H17HNO5279.28 96 (COO-Q), 5.95, m (OH); IR (KBr): 3380 and 1710 cm-1 (NH-COO-) NMR (CDCl3): 7.4d, 6.5, d and 4.2, s (6H benzidiox N 293.31); , 85, s, (NH); 4.75, m and 1.40, m C15H19N5 7 (COO-Q); 5.70, m (OH) ________________________ (KBr): 3380 and 1775 cm-1 ( NH-CO0 ')

  NMR (CDCl 3): 7.4, d, 6.5, d and 4.12, s (6H benzoyl);

  dioxane), 7.25, m (COOOC), 5.70 (OH) 61 (IVd) C15H1NO287.26, 82) IR (KBr): 3360 and 1735 cm- (NH-CO)

  NMR (CDCl 3): 7.5, d, 6.6, d and 4.35, s (6H benzo)

  2 -0 HCl (5NO6) -81s, 2 C34H NO dioxane) 6.90, s (NH) and 3.82, s (COOCH3) 62 -CH3 (IIIc) 13 15 6 281.26 134 49 4.20, t; 3.4, m and 2.80, m (5H O COCH) TIR (KBr): 3380 and 1730 cm-1 (NHCOOCH3),, 1 ......... ..-., _, liÀ .. .. ... ,,, _

  NMR (CDCl 3): 7.5, d, 6.5, d and 4.3, s (6H benzo

  63 (CH 2 HCl, dioxane), 6.95, s (NH), 4.10, t, 1.7, m and 1, t, -C 3 H 7 n, 19, 309, 31-66 (COOC 3 H 7); 2, t; 3.4, m and 2.80, m (5H O and <- - - ___________________ IR (KBr): 34h0 and 1740 cm-1 (NHCOOC3H7n) iiiiiii.-1,. TABLE III (continued)

Weight Point of Rende-

  Number A For- R5 Molecular formula C.H.N. or SPECTRUM OF R M N and SPECTRUM I R of gross mule code (C) (%)

  NMR (CDCl 3): 7.5, d, 6.5, d and 4.3, s (6H benzo

  (NH 4) 309.31 dioxane), 6.90, m (NH), 5.05, m and 1.25, d, 64 (III) -O 2 C 15 H 19 O 6 - (COO-) 4 , 30, t; 3.40, m and 2.80, m (5H O0 IR (KBr): 3310 and 1700 cm-1 (NH-COO--)

  NMR (CDCl 3): 7.5, d, 6.5, d and 4.3, s (6H benzo

  323.33 dioxane), 6.90, s (NH): 4.10, t and 1.20, m.p. H9 nn 16 21 6 323.33 (84) (CO-C4H9n); 20, t; 3.4, m and 2.8, m (5H nm) R (KBr): 3415 and 1725 cmn-1 (NH-COOC4H9n)

  NMR (CDCl3): 7.5, d, 6.5, d and 4.3, s (6H benzo)

  66.9 ° C, NH 3 O 3, 32.0.33 dioxane), 6.90, s (NH), 4.05, d, 2.05, m and 1.0, <2 16 21 6, R d (COO / y): 4.20, t, 3.4, m and 2.8, m (5H 0 IR (KBr): 3290 and 1700 cm-1 (NH-COO) 0

  NMR (CDCl 3): 7.5, d, 6.5, d and 4.3, s (6H benzo

  67-CH 2 CH NO 73 337.36 76 dioxane), 6.90, s (NH), 4.10, t, 1.6, m and 0.95, 12.2 (3, 1736, d, (COO 4.20, t; 3.4, met2.8, m (5H0O) IR (KBr): 3290 and 1700 cwr1 (NH-COO0) 90

  6 IRMN (CDCl3): 7.5, d, 6.5, d and 4.3, s (6H benzoate)

  68 Hf 17 H 21 NO 3 635.35 - 49 dioxane), 6.90, s (NH), 5.12, m and 1.8, m, (-Coo -), 4, 20, t; m (5H 0) IR (KBr): 3320 and 1700 cm-1 (NH-COO-) Elemental analysis CHN 69 0 - 18H23NO6 349.37 113 Calcd. (%) 61.88 6.65 4.11 Found (%) 61.47 6.75 4.17-CH 1 (1H) 57.3 Elemental analysis CHN 702 NO23 (Id) 91 357.35 110 37 6Calculated (%) 63.86 5.36 3.92% C19 196 Found (%) 63.27 5.26 3.80

- - -...

Po rla 4- 01% O% 41. U4

2462432

  The compounds of formula (I) have been studied in laboratory animals.

  and showed antiangorous activity.

  This antiangorous activity is highlighted in dogs

  anesthetized (sodium pentobarbital 30mg / kg / i.v.).

  - The oxygen consumption in the left ventricle is estimated by the product of the coronary venous flow by the arteriovenous difference

coronary oxygen (volume%).

  Coronary venous flow is measured at the level of the venous sinus

  coronary artery with a modified Morawitz cannula, introduced under

radioscopic trellis.

  Arterial and venous oxygenation is measured by means of

  a blood gas analyzer (IL Meter 213).

  - The cardiac effort is estimated according to the KATZ index, by the

  lowers the average arterial pressure by the heart rate.

  Heart rate is assessed from the electrocardiogram-

saved me in derivation D2.

  Systemic arterial pressure is measured at the femoral artery

  with a pressure sensor (SAiBORN 267-BC).

  The results obtained by injecting the compounds of formula (I) and

  the following reference compounds: LIDOFLAZINE and AMIODARONE, are

  in the following Table IV. It should be noted that the compounds tested are

  injected intravenously as a slow infusion.

TABLE IV

  Compounds Decreased Decrease of Tested Toxicity Dose 02 Consumption of Heart Effort LD 50 Number

mg / kg / i.v. mg / kg / i.v.

  Code.in% time in% in time (rn.) (Min.) 400oo (10%) 400oo (0%) 400oo (0%) (0%) (in: 0%) (in: 0%) 400oo (0%) (0%) (in: 0%) (0%) (0%) (in: 0%) (in: 0%) 2.5 1.25 0.15 0.15 0.15 0 , 0.15 0.35 0.31 0.31 0.15 0, 0.15 0.31 0.15 0.31 0.15 0.15 0.31 hr> 30> 30 to 60> 30 > 30> 45> 30 4o 4o> 45> 45> 30> 60> 45

LIDOFLAZINE 25 1.5 48 30 40 15

AMIODARONE 180 10 to 15 22 15 - i

2462432

  From the above results it can be seen that the difference between therapeutic and toxic doses is sufficiently large to allow the use of the compounds of formula (I) in the treatment of

  cardiovascular systems, especially as antiangorous.

  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 from 20 to 200 mg of principle.

active. (1 to 3 per day).

27 2462432

Claims (12)

  1. As new industrial products, the compounds corresponding to the general formula (I): ## STR3 ## in which -Ar represents: A is the 4-acetyl-2-ethoxyphSnyl group of formula: ## STR2 ## CH 0 O- OH (1)   a benzodioxin group of the type: R CH 0 0   Wherein Ar represents: either the acmethylthioxy-2-thythyloxy group of the formula -O / 7SCOCH, OC 3   is a benzodioxanic group of the type c2H5 where R represents the 2-methylthio-6eoxy sequence of formula -OOtV-SCH, a -COOR1 ester group in which R1 represents a methyl, n-propyl group, n-butyl, isobutyl, isopentyl, n-octyl, the cyclopentyl group or the phenyl group, a carbamate group of the -NHCOOR 2 type in which R 2 represents the methyl group, a linear or branched alkyl group having from 3 to 5 atoms of carbon, a cycloalkyl residue having from 5 to 6 carbon atoms, or a benzyl group,   and their pharmaceutically acceptable salts.   2. Medicines, particularly for the treatment of systemic disorders   cardiovascular systems, characterized in that it comprises as a principle   at least one compound according to claim 1.   3. Process for the preparation of the compounds according to claim 1, with the exception of the compounds of formula I, wherein Ar represents the unit: ## STR3 ## 3 0O 0 \ -J   characterized in that it consists in condensing in alcoholic medium, the trimer-   3,4,5-thoxy cinnamoyl piperazine of formula (II): CH 3 C0 N NH (II) 3 \ (II) ho 28 2462432   with the epoxides of formulas (IIIa), (IIIb), (IIIc) and (IIId): O * / \ <COCH3 (IIIa) OC2 H5 O '<COO1 (IIIb) 0 O COOR1 o NH-COOR2 (III) AY (IIId) È - NH -000 ..   in which R has the same meanings as in formula (I) and i   R'2 represents a methyl group, a linear or branched alkyl group possessing   from 3 to 5 carbon atoms or a cycloalkyl group having from 5 to 6 carbon atoms.   4. Process for the preparation of the compounds according to claim 1, corresponding to formula (I) in which Ar represents the unit: O SCH3   characterized in that it consists in condensing in an ethanolic medium, in pre-   Potassium carbonate, 1-chloro-2-methylthiethane with the compound of formula (XII): CH 2 O C3 N N O 0 OH CH OO CH30 OH (XII) O O O 00 0 CH30 \ OJ   5. Process according to claim 3, characterized in that the compounds   poses of formulas (IIIa), (IIIb) and (IIIc) are obtained by condensation of epichlorohydrin or epibromohydrin under reflux in acetonitrile (or acetone), in the presence of potassium carbonate with the compounds of formula (IVa), (Ib) and (IVc): 4o 292462432   HO Qp COCH3 (IVa) OC2H5 COOR1 HO (IVb) HO _Q NH-COOR'2 (IVc) O2   in which R 1 and R 'have the same meanings as in formulas i 2 (IIIb) and (IIIc).   6. Method according to claim 3, characterized in that the com-   of formula (IIId) is obtained by condensation of pichlorhydrin with   flow in benzyl alcohol, in the presence of potassium carbonate with the compound of formula (IVd): HO NH - COO at p-J (IVd)   7. Method according to claim 5, characterized in that the com-   layer of formula (IVa) is obtained by a reaction of FRIES on acetoxy-2-ethoxy-benzene of formula (Va): CH3CO- (Va) C2H50   8. Process according to claims 5 and 6, characterized in that   the compounds of formula (IVb), (IVc) and (IVd) are obtained by hydrogenolysis in the presence of 5% palladium on carbon, in an ethanolic medium of the benzyl group of the compounds of formula (Vb) and (Vc, d): COOR (Vb) 0 0 4o 2462432   Embedded image in which R 1 has the same meanings as in formula (IVb) and R "2 represents a linear or branched alkyl group comprising 3 to 8 carbon atoms, a cycloalkyl group comprising from 5 to 6 carbon atoms bone or the phenyl nucleus.   9. Process according to claim 8, characterized in that the compound of formula (Vb) is obtained by a two-step esterification which consists in treating with thionyl chloride the compound of formula (VI): O QN COOH (VI)   then to react on the crude compound thus obtained the alcohols of formula   R 1 OH (VII) in which R 1 has the same meanings as in formula (Vb).   10. Method according to claim 8, characterized in that the com-   layer of formula (Vc, d) in which R "2 represents methyl, isopropyl and   propyl, n-butyl, isobutyl and phenyl are obtained by the action in toluene medium of chloroformates of formula (VIII): Cl-CO-OR3 (VIII)   wherein R3 represents methyl, isopropyl, n-butyl, isopropyl,   butyl and phenyl with the compound of formula (IX): O <NH2 (IX) 0 0 \! J   11. The method of claim 8, characterized in that the com-   embedded image of formula (Vc, d) in which R "represents n-propyl, 4-methyl-butyl, cyclopentyl and cyclohexyl groups, are obtained by condensation of the alcohols of formula (X): R OH (x) h   wherein R4 is n-propyl, methyl-4 butyl, cyclopentyl   tyl and cyclohexyl with the isocyanate of formula (XI): N = C = O (XI) ho O 31 2462432   12. As intermediaries necessary for the preparation of   poses of formula (I), the compounds of formula (IIIa), (IIIb), (IIIc), (IIId),   (IVa), (IVb), (IVc), (IVd), (Vb), (Vc, d) and (XI).