GB2057433A - Novel 3,4,5-trimethoxy cinnamoyl piperazine derivatives, processes for preparing the same and their use in therapeutics - Google Patents

Novel 3,4,5-trimethoxy cinnamoyl piperazine derivatives, processes for preparing the same and their use in therapeutics Download PDF

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GB2057433A
GB2057433A GB8025200A GB8025200A GB2057433A GB 2057433 A GB2057433 A GB 2057433A GB 8025200 A GB8025200 A GB 8025200A GB 8025200 A GB8025200 A GB 8025200A GB 2057433 A GB2057433 A GB 2057433A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Abstract

Novel 3,4,5-trimethoxy-cinnamoyl-piperazine derivatives are provided having the general formula: <IMAGE> wherein Ar is a 4-acetyl-2-ethoxy-phenyl group or a benzodioxanyl group having one of a number of possible substituents on the benzene ring, have particular utility in the treatment of cardiovascular disorders and can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Novel 3,4,5-trimethoxy cinnamoyl piperazine derivatives, processes for preparing the same and their use in therapeutics The present invention relates to novel derivatives of 3,4,5-trimethoxy cinnamoyl piperazine, the process for preparing same and their application in therapeutics.
The novel compounds correspond more precisely to the general formula:
in which Ar represents: either the acetyl-4 ethoxy-2 phenyl group of formula:
or a benzodioxannic group of type:
in which R represents: - the methyl-thio-2-ethoxy chain of formula
- an ester group of -COOR1 type in which R, represents an element chosen from the following: methyl, n-propyl, n-butyl, isobutyl, (ethyl-2)n-butyl, n-octyl, cyclopropylmethyl, cyclobutylmethyl.
cyclopentyl methyl, (cyclomethyl-2) ethyl, (cyclopropyl-2) ethyl, cyclopentyl, phenyl or (methyl-3)n-butyl and in the latter case, the corresponding derivative of formula (I) comprising an asymetric carbon is either in the form of a racemic mixture of two enantiomers, or in the form of the levogyrous enantiomer of S configuration; or - a carbamate group of -NH-COOR2 type in which R2 represents the methyl group, a linear or branched alkyl group having 3 to 5 carbon atoms, a cycloalkyl residue having 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 non toxic organic and mineral acids and particularly the salts of hydrochloric, oxalic, maleic acids ...
The process of the invention, for preparing the compounds of formula (I) with the exception of the compound of formula (I) in which Ar represents the group:
and of the compound of formula (I) corresponding to the particular formula:
consists in condensing in an alcoholic medium (methanol, ethanol, butanol. ..)trimethoxy-3,4,5 cinnamoyl piperazine of formula:
with the epoxides of formulae (Ila), (lib). (Illc), and (IIId):
in which R1 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 ora cycloalkyl group having 5 to 6 carbon atoms.
The compounds of formula (Illa), (Illb) and (Illc) are novel and are obtained by condensation of epichlorhydrine or epibromhydrine at reflux in acetonitrile (or acetone), in the presence of potassium carbonate with the compounds of formula (IVa), (IVb) and (IVc):
in which R, and R'2 have the same meanings as in formulae (Illb) and (Illc).
The novel compound of formula (lid) is obtained by condensation of epichlorhydrine at reflux in benzylic alcohol, in the presence of potassium carbonate with the compound of formula (IVd):
The novel compound of formula (IVa) is obtained by a FRIES reaction on acetoxy-1 ethoxy-2 benzene of formula (Va):
which is itself novel and is obtained by action of acetyl chloride on ethoxy-2 phenol.
The compounds of formulae (IVb), (IVc) and (IVd) are novel and are obtained by hydrogenolysis in the presence of palladium on charcoal (5%), in an ethanol medium, of the benzyl group of the compounds of formula (Vb) and (Vc,d):
in which R,, has the same meanings as in formula (IVb) and R"2 represents a methyl group, a linear of branched alkyl group comprising 3 to 5 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms or the phenyl nucleus.
The novel compounds of formula (Vb) are obtained by esterification in two steps, which consist in treating with thionyl chloride the compound of formula:
described in Belgian patent No. 865.990 and then in reacting on the raw compound thus obtained the alcohols of formula (Vll): R1OH (ill) in which R1 has the same meanings as in formula (Vb).
The novel compounds of formula (Vc,d), in which R"2 represents the methyl, isopropyl, n-butyl, isobutyl or phenyl group are obtained by action, in a toluenic medium, of the chloroformiates of formula (VIII): Cl-CO-OR3 (veil) in which R3 represents the methyl, isopropyi, n-butyl, isobutyl or phenyl group with the compound of formula (IX):
described in Belgian patent No. 865.990.
The novel compounds of formula (Vc,d), in which R"2 represents the n-propyl, methyl-3 butyl, cyclopentyl or cyclohexyl group are obtained by condensation of the alcohols of formula (X): R4OH (X) in which R4 represents the n-propyl, methyl-3 butyl, cyclopentyl or cyclohexyi group with isocyanate of formula (Xl):
The novel compound of formula (Xl) is obtained by action of phosgene on the compound of formula (IX).
The process of the invention for the preparation of the compound of formula (I) in which Ar represents the group:
consists in condensing in an ethanol medium, in the presence of potassium carbonate, chloro-1 methylthio-2 ethane with the compound of formula (XIII):
described in Belgian patent No. 865.990.
The process of 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 (Xlil):
obtained by action of sulfonyl paratoluene chloride on the compound of formula (XIV):
This latter is obtained by acid hydrolysis, in an acetone medium, of the compound of formula (XV):
itself obtained by condensing the tosylate of formula (XVI):
described in J. Org. Chem. 42, 1006, (1977) with the compound of formula (IVb) in which R, represents the (methyl-3)n-butyl group.
The preparations below are given by way of examples to illustrate the invention.
EXAMPLE 1 Hydrated (acetyl-4 ethoxy-2) phenoxy-1 [(trimethoxy-3,4,5 cinnamoyl piperazine)-4]-3 propanol-2, oxalate (I) Code number: 1 A solution of 3 g of trimethoxy-3,4,5 cinnamoyl piperazine (II) and 2.7 g of (acetyl-4 ethoxy-2 phenoxy)-1 epoxy-2,3 propane (Illa) (prepared in step 3 of example 3), in 50 ml of ethanol was brought to reflux for 3 hours. Then the solvent was evaporated, the residue dissolved in acetone and an acetone solution of oxalic acid was added and the precipitate obtained was filtered to obtain 5.6 g of product.
Yield: 87% Melting point: 1 600C Empirical formula: C31H40N2O11 + 3/4 H20 Elementary analysis
C ~ C H N Calculated (%) 57.61 6.47 4.34 Obtained (%) 57.57 6.24 4.33 By the same process, but from the corresponding reagents, the compounds of formula (I) were obtained, given in table I below and bearing code numbers 3 to 19, 71 and 73 to 77. TABLE 1
Melting Elementary Analysis Cde Molecular point Yield Number O - Ar Form Emplrical formula weight ( C) (%) (%) C H N 1 # hydrated C31H40N2O11 + 648.16 160 87 Cal. 57.61 6.47 4.34 Oxalate 3/4 H2O Obt. 57.57 6.24 4.33 2 # hydrated C30H41ClN2O9S + 662.19 175 60 Cal. 54.41 6.60 4.23 hydrochloride 7/6 H2O Obt. 54.31 6.37 4.07 3 # " C29h37ClN2O10. + 627.10 163 58 Cal. 55.54 6.27 4.47 H2O Obt. 55.48 6.21 4.41 4 # " C31H41ClN2O10 + 658.13 145 65 Cal. 56.57 6.64 4.26 1/6 H2O Obt. 56.76 6.79 4.42 5 # hydrated C34H44N2O14 + 715.52 150 79 Cal. 57.07 6.37 3.92 Oxalate 3/5 H2O Obt. 57.34 6.47 4.04 TABLE I (Cont.)
Melting Elementary Analysis Cde Molecular point Yield Number O - Ar Form Emplrical formula weight ( C) (%) (%) C H N 6 # hydrated C32H43ClN2O10 + 672.76 160 82 Cal. 57.13 6.80 4.16 hydrochlorlde 1/2 H2O Obt. 57.18 6.81 4.21 7 # " C33H55ClN2O10 + 687.68 160 75 Cal. 57.82 6.86 4.02 5/4 H2O Obt. 57.63 6.96 4.07 8 # hydrochloride C33H43ClN2O10 663.15 160 57 Cal. 59.77 6.54 4.22 Obt. 59.46 8.68 4.16 9 # hydrated C36H51ClN2O10 + 729.76 106 66 Cal. 59.25 7.25 3.84 hydrochloride Obt. 59.52 7.29 3.81 10 # Oxalate C36H40N2O14 724.70 136 51 Cal. 59.66 5.56 3.87 Obt. 59.60 5.76 4.01 11 # hydrated C89H38ClN2O10 + 851.10 141 64 Cal. 68.49 6.35 6.45 hydrochloride 1.5 H2O Obt. 53.55 6.04 6.43 TABLE I (Cont.)
Melting Elementary Analysis Cde Molecular point Yield Number O - Ar Form Emplrical formula weight ( C) (%) (%) C H N 12 # hydrated C31H42ClN3O10 + 673.75 155 48 Cal. 55.26 6.64 6.24 hydrochloride 1.2 H2O Obt. 55.53 6.46 6.31 13 # " C31H42ClN3O10 + 673.75 164 69 Cal. 55.26 6.64 6.24 1.2 H2O Obt. 55.29 6.42 5.97 14 # " C32H44ClN3O10 + 697.68 156 74 Cal. 55.09 6.86 6.02 1.75 H2O Obt. 55.34 6.63 6.54 15 # " C32H44ClN3O10 + 691.37 175 73 Cal. 55.59 6.82 6.08 7/5 H2O Obt. 55.74 6.68 6.21 16 # " C33H46ClN3O10 + 698.19 176 70 Cal. 56.76 6.93 6.02 H2O Obt. 56.85 7.10 6.15 TABLE (Cont.)
Melting Elementary Analysis Cde Molecular point Yield Number O - Ar Form Emplrical formula weight ( C) (%) (%) C H N 17 # hydrated C33H44ClN3O10 + 699.78 176 58 Cal. 56.64 6.68 6.01 hydrochloride 1.2 H2O Obt. 56.32 6.29 5.95 18 # hydrated C36H47N3O14 + 760.17 182 64 Cal. 56.88 6.44 5.63 Oxalate 4/5 H2O Obt. 57.12 6.38 5.67 19 # hydrated C35H42ClN3O10 + 721.79 171 68 Cal. 58.24 6.20 5.82 hydrochloride 1.2 H2O Obt. 58.28 5.91 5.79 71 # " C34H47ClN2O10. + 703.2 175 40 Cal. 58.07 7.12 3.98 5/3 H2O Obt. 58.34 7.18 4.01 72 # hydrated C38H45ClN2O10 + 687.68 162 37 Cal. 57.63 6.96 4.07 hydrochloride 5/4 H2O Obt. 57.71 6.95 3.92 [&alpha;20 = 7,8* (C = 2,CH3OH) TABLE I (Cont.)
Melting Elementary Analysis Cde Molecular point Yield Number O - Ar Form Emplrical formula weight ( C) (%) (%) C H N 73 # hydrated C32H41ClN2O10 + 673.14 158 52 Cal. 57.09 6.54 4.16 hydrochloride 1.3 H2O Obt. 57.23 6.15 4.01 74 # " C33H43ClN2O10 + 684.17 178 41 Cal. 57.93 6.68 4.09 7/6 H2O Obt. 58.16 6.75 4.11 75 # " C34H45ClN2O10 + 699.69 168 29 Cal. 58.36 6.84 4.00 5/4 H2O Obt. 58.60 6.84 4.04 76 # " C34H15ClN2O10 + 698.79 164 71 Cal. 58.44 6.84 4.01 1/2 H2O Obt. 58.69 6.60 4.03 77 # " C33H43ClN2O10 + 684.77 160 22 Cal. 57.88 6.68 4.09 1.2 H2O Obt. 57.98 6.37 4.09 EXAMPLE 2 Hydrated [(methylthio-2 ethoxy)-4 ethylene dioxy-2,3 phenoxy-1 [(trimethoxy-3,4,5 cinnamoyl) piperazine-4]-3 propanol-2 chlorhydrate (I) Code number: 2 A mixture of 13.3 g of (hydroxy-4 ethylene dioxy-2,3) phenoxy-1 [(trimethoxy-3,4,5 cinnamoyl piperazine-47-3 prnpenol-2(Xll), 3.5 ml of chloro-1 methylthio-2 ethane and 10.3 g of potassium carbonate in 1 50 ml of ethanol was brought to reflux for 1 8 hours. Then it was filtered, the filtrate evaporated, the residue taken up in chloroform and washed in water. The organic phase was dried on sodium sulfate, the solvent was evaporated and the residue chromatographed on a silica column.After elution with pure chloroform and a mixture chloroform (99%) - methanol (1%), 13 g of pure product were obtained which was dissolved in acetone and 4.5 ml of hydrochloric ethanol 6.5 N were added. The precipitate obtained was filtered, dissolved in the minimum of alcohol and diluted with acetone. 9.35 g of product were obtained.
Melting point: 1 750C Empirical formula: C30H41ClN209S + 7/6 H20 Elementary analysis:
C H N Calculated (yO) 54.41 6.60 4.23 Obtained (%) 54.31 6.37 4.07 EXAMPLE 3 (epoxy-2,3 propoxy)-4' ethoxy-3' acetophenone (IIIa) 1st step: acetyloxy-1 ethoxy-2 benzene (Va) To a solution of 30.4 g of ethoxy-2 phenol in 10 ml of tetrahydrofuran and 29 g of triethylamine were added, while cooling. 1 7.3 g of acetyl chloride, then they were left in contact for 24 hours, the precipitate was filtered, the filtrate evaporated and the residue distilled. 27.2 g of product were obtained.
Yield: 69% Bolling point Ebgmm Hg: 115#123 C Empirical formula: C10H12O3 NMR spectrum (CDCl3) # ppm = 7.00,m,(4 benzene protons) = 4.00,q,(-CH2 of O-CH2-CH3) = 2.25,s,(-CH3 of OCOCH3) = 1 .32,t,(-CH3 of 0-CH2-CH3) 2nd step: ethoxy-3' hydroxy-4' acetophenone (IVa) To a solution of 17.6 g of the compound of formula (Va) obtained in the preceding step, in 100 ml of nitrobenzene, were added 24 g of aluminium chloride and it was left for 20 hours under agitation at ambient temperature.Then the reaction mixture was poured into ice and concentrated hydrochloric acid and extracted with ether; the ethereal solution was extracted with a 2N NaOH solution, then the aqueous solution was acidified with concentrated hydrochloric acid and extracted with chloroform. The solvent was evaporated and the residue chromatographed on a silica column and eluted with benzene.
50% of the expected product (IVa) was obtained.
Melting point: 660C Empirical formula: CaOHr203 NMR spectrum (CDCI3): 8 ppm = 7.50,m, and 6.95,d,(3 benzene protons) = 6.72,s,(OH) = 4.1 O,q,(-CH2 of -O-CH2-CH3) = 2.55,s,(-COCH3) = 1 .20,t,(-CH3 of-O-CH2-CH3) then 50% of its isomer ethoxy-4', hydroxy-3' acetophenone, Melting point: 100 C NMR spectrum (CDCI3): 8 ppm = 7.9,m, and 6.90,d,(3 benzene protons) = 6.55,s,(OH) = 4.10,q,(-CH2 of O-CH2-CH3) = 2.50,s,(CH3CO-) = 1.40,t,(-CH3 of O-CH2-CH3) (the structure attributed to the two isomers was confirmed by an NMR study of the influence of complexing with Europium salts [EU (CIO4)3] on the chemical shift of aromatic protons (solvent CD3OD).
3rd step: (epoxy-2,3 propoxy)-4' ethoxy-3' acetophenone (Illa) A mixture of 6.2 g of the compound of formula (IVa) obtained in the preceding step, 5 g of epibromhydrine and 14 g of sodium carbonate in 70 ml of acetonitrile was brought to reflux for 5 hours.
Then it was filtered, the filtrate evaporated, the residue taken up in a mixture of water and chloroform, the organic phase dried on sodium sulfate and the solvent evaporated. 6.5 g of product were obtained.
Yield; 76% Melting point: 900C Empirical formula: Ct4H1604 NMR spectrum (CDCl3): 8 ppm = 7.5,m, and 6.95,d,(3 aromatic protons) = 4.20,m; 3.4,m, and 2.8m, (5 protons
J NMR spectrum (CDCI3): 8 ppm = 4.1 0,q, and 1 .40,t,(O-CH2-CH3) = 2.50,s,(COCH3) EXAMPLE 4 (epoxy-2,3 propoxy)-5 methoxycarbonyl-8 benzodioxanne-1,4 (ill) Code number: 36 1st step: benzyloxy-5 methoxycarbonyl-8 benzodioxanne-1,4 (Vb) Code No. 20 To a toluene solution of 28 g of (benzyloxy-5 benzodioxanne-1 ,4)yl-8 carboxylic acid were added 50 ml of thionyl chloride and the mixture was brought to 70-800C for two hours.Then the solvents were evaporated, the residue dissolved in 200 ml of tetrahydrofuran and 8 ml of methyl alcohol and 38 ml of triethylamine were added. The mixture was brought up to 600C for 3 hours, then the precipitate formed was filtered, the filtrate was evaporated and the residue was chromatographed on a silica column and eluted with methylene chloride. 20 g of product were obtained.
Yield: 74% Melting point: 1 000C Empirical formula: C17H16O5 The product is used raw in the synthesis of the compound of formula (IVb) corresponding to the compound of code number 28 appearing in table II below.
By the same process, but from the corresponding reagents, the compounds of formula (Vb) appearing in table Il hereafter and bearing code numbers 21 to 27 and 78 to 83 were obtained.
2nd step: hydroxy-5 methoxy carbonyl-8 benzodioxanne-1,4 (IVb) Code number: 28 A solution of 20 g of the compound of formula (Vb), having code number 20 and obtained in the preceding step, in 200 ml of ethanol was hydrngenolyzed under pressure and at ordinary temperature in the presence of 2 g of palladium on charcoal (5%). Then it was filtered and the solvent evaporated to obtain 13 g of product.
Melting point: 1 530C Empirical formula: C,OH,005 (used in the raw state in the synthesis of the corresponding compound of formula (Illb) of code number 36 and appearing in table II below).
By the same process, but from the corresponding reagents, the compounds of formula (IVb) were obtained which appear in table II below under code numbers 29 to 35 and 84 to 89.
3rd step: (epoxy-2,3 propoxy)-5 methoxy carbonyl-8 benzodioxanne-1,4 (Illb) Code number: 36 A mixture of 13 g of the compound of formula (IVb) obtained in the preceding step, 25.5 ml of epibromhydrine and 25.5 g of potassium carbonate in 250 ml of acetonitrile was brought to reflux for 4 hours. Then it was filtered, the filtrate evaporated, the residue taken up in methylene chloride, washed with water, then with a 1 N NaOH solution, dried on sodium sulfate and the solvent evaporated. The residue was re-crystallised in ethyl acetate to obtain 11.4 g of product.
Yield: 69% Melting point: 1220C Empirical formula: C,3H,406 By the same process, but from the corresponding reagents, the compounds of formula (Illb) were obtained which are given in table li below under code numbers 37 to 43 and 90 to 95.
TABLE II
Melting Empirical Molscular point Yield Code R1 R5 formula weight ( C) (%) N R M SPECTRUM NMR (CDCl3) : 7.3, d; 6.5, d, and 4.3. s, (6 ben20 (Vb) CH3 # C17H16O5 300.70 100 74 zodioxanne protons) 7.4, m, and 5.2, s, (7 protons-O | #)~ 3.8, s, (COOCH3) NMR (CDCl3) : 7.3, d; 6.5, d, and 4.3 s, (6 ben21 " C3H7n " C19H20O5 328.35 101 66 zodioxanne protons) 7.6, m, and 5.2, s, (7 protons #) 4.3, m; 1.7, m, and 1.00, t, (7 pr. COOC3H7n) 22 " C4H9n " C20H22O5 342.38 < 50 70 NMR (CDCl3) : 7.3, d; 6.5, d, and 4.3, s, (6 ben zodioxanne protons) 7.5, m, and 5.2, s, (7 protons #) 4.3, m, and of 0.8 to 1.6, m, (9 pr.
COOC4H9n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben23 " # " C20H22O5 342.38 63 60 zodioxanne protons) 7.4, m and 5.2, 2, (7 protons #) 4.1, d; 2. m and 1. d ; 9 pr. #) TABLE (Cont.)
Melting Empirical Molscular point Yield Code R1 R5 formula weight ( C) (%) N R M SPECTRUM NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben24 (Vb) # # C21H24O5 356.40 < 50 64 zodioxanne protons) 7.4, m; 5.2, s, (7 protons #) 4.3, m; 1.7, m; and 0.9, d, (11 pr. #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben25 " # " C21H22O5 354.39 87 38 zodioxanne protons) 7.4, m, and 5.2, s, (7 protons #) 5.2, m, and 1,8, m, ( 9 pr. #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben26 " -C5H17n # C24H30O5 398.48 huile 79 zodioxanne protons) 7.5, m, and 5.2, s, (7 protons #) 4.3, m, and of 0.8 to 1.6, s, (17 protons -COO-C8-H17n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben27 " # " C22H18O5 362,36 144 28 zodioxanne protons) 7.4, m, and 5.2, s, (7 protons #) 7.4, m, (5 protons. #) TABLE II (Cont.)
Melting Empirical Molscular point Yield Code R1 R5 formula weight ( C) (%) N R M SPECTRUM NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben28 (IVb) -CH3 H C10H10O5 210.18 153 93 zodioxanne protons) 10.00, s, (OH) 3.8, s, (COOCH3) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben29 " -C3H7n " C12H14O5 238.23 73 98 zodioxanne protons) 6.8, s, (-OH) 4.3, t; 1.8, m; and 1.00, t, (7 pr.
COOC@H7n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben30 " -C4H9n " C13H16O5 252.26 79 98 zodioxanne protons) 7. s, (OH) (9 protons COOC4H9n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben31 " # " C13H16O5 252.26 66 96 zodioxanne protons) 67.95, S, (OH) 4.2, d; 2, m, and 1. d, (9 pr. #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben32 " # " C14H18O5 266.28 69 98 zodioxanne protons) 4.3, m; 1.7, m, and 0.9, d, (11 pr. # TABLE II (Cont.)
Melting Empirical Molscular point Yield Code R1 R5 formula weight ( C) (%) N R M SPECTRUM NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben33 (IVb) # H C14H16O5 264.27 95 95 zodioxanne protons) 6.8, m, (-OH) 5.4, m, and 1.8, m, (9 protons #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben34 " C8H17n " C17H24O5 308.36 63 98 zodioxanne protons) 4.3, m and of 0.8 to 1.8, m, (17 protons COO-C8H17n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben35 " # " C15H12O5 272.25 156 93 zodioxanne protons) 7.25, m, (5 protons #) 6.15, s, (OH) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben36 (IIIb) CH3 # C13H14O6 266.24 122 69 zodioxanne protons) 4.3, m; 3.4, m, and 2.8, m, (5 protons #) 3.8, s, (COOCH3) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben37 " C3H7n " C15H18O6 294.29 100 85 zodioxanne protons) 4.3, m; 3.4, m, and 2.8, m, (5 pr. #) 4.3, t; 2.8, m, and 1.00, t.
(7 pr. COO-C3H7n) TABLE II (Cont.)
Melting Empirical Molscular point Yield Code R1 R5 formula weight ( C) (%) N R M SPECTRUM NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben38 (III)b C4H9n # C16H20O6 308.32 105 85 zodioxanne protons) 4.3, m; 3,4, m, and 2.8, m, (5 protons #) 4.3, m, and 0.8 to 1.7, m, (9 pr. COOC4H@n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben39 " # " C16H20O6 308.32 110 83 zodioxanne protons) 4.2, m; 3.4, m, and 2.8, m, (5 protons #) 4.3, d; 2. m, and 1.00, d, (9 pr. #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben40 " # # C17H22O6 322.35 91 82 zodioxanne protons) 4.2, m; 3.4, m and 2.8, m, (5 pr. #) 4.2, m; 1.7, m, and 0.9, d, (11 pr. #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben41 " # " C17H20O6 320.38 85 98 zodioxanne protons) 4.3, m; 3.4, m, and 2.8, m, (5 pr. #) 5.3, m; 1.8, (9 protons #) TABLE II (Cont.)
Melting Empirical Molscular point Yield Code R1 R5 formula Weight ( C) (%) N R M SPECTRUM NMR (CDCl3) : 7.3, d; 6.5, d, and 4,3, s, (6 ben42 (IIIb) C3H17n # C20H2@O6 364.42 95 85 zodioxanne protons) 4.3, m; 3.4, m and 2.8, m, (5 pr. #) 4.3, m, and of 0.8 to 1.5, m, (17 pr. COO-C6H17n) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,4, s, (6 ben43 " # " C13H16O6 328.37 104 71 zodioxanne protons) (5 protons #) 7.15, m, 4.3, m; 3.4, m, and 2.8, m, (5 pr. #) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,22, s, (6 ben78 (Vb) # # C23H26O5 370.43 liquid 9 zodioxanne protons); 7.18, s and 5.05, s (5 protons-CH2-#); 4.1, d, COOCH2-; 1.4, m 0.95, m (#) NMR (CDCl3) : 7.3, d; 6.5, d, and 4,75, s, (6 ben79 " # " C20H20O5 340.36 95 95 zodioxanne protons); 7.18, s and 5.22, s (5 protons -CH2-#); 4.1, d, (COOCH2-); and 0.9, m, (#) TABLE II (Cont.)
Melting Code Empirical Molscular point Yield N R M SPECTRUM Number R1 R5 formula Weight ( C) (%) OR ELEMENTARY ANALYSIS Elementary analysis : % C H 80 (Vb) # # C21H22O5 354.38 76 99 Cal. 71.17 6.26 Obt. 70,93 Elementary analysis : % C H 81 " # # C22H24O5 388.41 62 76 Cal. 71.72 6.57 Obt. 71.60 6.53 NMR (DMSO); 7.3, d, 6.70, d, and 4.22, s, (6 ben82 " # " C22H24O5 368.41 gum 94 zodioxanne protons); 7.4, s, and 6.18, s, (5 protons -CH2-#); 4.1, d, (COOCH2-); and 1.5, m, (#) NMR (CDCl3); 7.4, d, 6.7, d, and 4.2, s, (8 ben83 " # " C21H24O5 254.39 gum 72 zodioxanne protons); 7.35, s; and 5.2, s, (5 protons -CH2-#); 4.15, t, (COOCH2-); 1.9, m, 1.5, q, and 0.9, m NMR (CDCl3); 9.5, s, (OH); 7.38, d, 6.5, d and 84 (IVb) # -H C15H20O5 280.31 80 70 4.25, s (6 benzodioxanne protons); 4.1, d.
(COOCH2-); 1.4, m, and 0.95, m, (#) TABLE II (Cont.)
Melting Code Empirical Molscular point Yield N R M SPECTRUM Number R1 R5 formula Weight ( C) (%) OR ELEMENTARY ANALYSIS Elementary analysis : % C H 85 (IVb) # -H C13H14O5 250.24 70 82 Cal. 62.39 5.64 Obt. 62.09 5.69 NMR (CMSO); 10.0, s, (OH); 7.25, d, 6.5, d, and 86 " # " C14H16O5 264.27 84 98 4.25, s, (6 benzodioxanne prot.); 4.08, d, (COOCH2-); 2.5, m, and 1.95, m, (#) Elementaryanalysis: % C H 87 " # " C15H18O6 278.29 75 99 Cal. 64.73 6.52 Obt. 64.84 6.42 NMR (DMSO); 10.0, s, (OH); 7.22, d, 6.5, d, and 88 " # " C15H18O5 278.29 gum 99 4.85, s, (6 benzodioxanne protons); 4.05, d, (COOCH2-); 2.3, m, and 1.5, m, (#) NMR (CDCl3); 7,4, s, (OH); 7.4, d, 6.7, d and 89 " # " C14H16O5 264.27 gum 98 4.2, s, (6 benzodioxanne protons); 4.25, t.
(COOCH2-); 1., q, and 0.9, m, # TABLE II (Cont.)
Melting Code Empirical Molscular point Yield N R M SPECTRUM Number R1 R5 formula Weight ( C) (%) OR ELEMENTARY ANALYSIS NMR (CDCl3); 7.42, d, 8.5, d, and 4.28, 9, (6 90 (III) # # C18H24O6 336.37 110 72 benzodioxanne protons); 4.2, m, 3.4, m, and 2.8, m. (#) 4.2, d, (COOCH2); 1.5, m and 0.9, m (#) Elementary analysis : % C H 91 " # " C16H18O6 306.30 128 65 Cal. 62.74 5.92 Obt. 62.45 5.93 Elementary analysis: % C H 92 " # " C17H20O6 320.25 114 68 Cal. 63.74 6.20 Obt. 63.57 6.15 Elementary analysis : % C H 93 " # " C18H22O6 334.35 87 82 Cal. 64.66 6.63 Obt. 64.40 6.66 TABLE II (Cont.)
Melting Code Empirical Molscular point Yield N R M SPECTRUM Number R1 R5 formula Weight ( C) (%) OR ELEMENTARY ANALYSIS Elementary analysis : % C H 94 (III) # # C18H22O6 334.35 102 70 Cal. 64.56 6.63 Obt. 64.55 6.71 Elementary analysis : % C H 95 (III) # # C17H20O6 320.33 100 71 Cal. 63.74 6.29 Obt. 63.57 6.36 EXAMPLE 5 (epoxy-2,3 propoxy)-5 methoxycarbonylamino-8 benzodioxanne-1,4 (Illc) Code number: 62 1st step: benzyloxy-5 methoxyca rbonyla mino-8 benzodioxanne-1,4 (Vc,d) Code number: 44 To a solution, cooled to OOC, of 25 g of amino-5 benzyloxy-8 benzodioxanne-1,4 (IX) in 250 ml of tetrahydrofuran and 17.6 ml of triethylamine was slowly added 1 ml of methyl chloroformiate, then it was left under agitation for 7 hours. It was filtered, and washed with a dilute solution of hydrochloric acid, with water, with a solution of bicarbonate of sodium and with water. The solvent was evaporated and the residue re-crystallised in ethyl acetate. 17.8 g of product were obtained.
Yield: 58% Melting point: 1000C Empirical formula: C17Hl7NO5 NMR spectrum (CDCl3): S ppm = 7.4,d,; 6.5,d, and 4.3,s(6 benzene protons) = 6.82,s,(NH-COO-) = 7.4,m, and 5.18,s,
= 3.76,s,(COOCH3) 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) were obtained which appear in table Ill hereafter under code numbers 46, 47, 48 and 52.
2nd step: hydroxy-5 methoxyca rbonyla mino-8 benzodioxanne-1,4 (IVc) Code number: 53 A solution of 1 7.8 g of the compound of formula (Vc,d), code number 44, obtained in the preceding step, in 400.ml of ethanol was hydrogenolyzed under pressure and at ordinary temperature in the presence of 2 g of palladium on charcoal (5%), then it was filtered and the filtrate evaporated to obtain 11.5 g of raw product which was used as it was in the following step.
Yield: 90% Melting point: 150 C NMR spectrum (CDCl3): # ppm =7.95,s,(OH) = 7.30,d; 6.50,d, and 4.3,s,(6 benzene protons) = 7,s,(NH-) = 3.78,s,(COOCH3) 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) under code numbers 54 to 60 were obtained as well as the compound of formula (IVd) appearing in table Ill under code number 61.
3rd step: (epoxy-2,3 propoxy)-5 methoxyca rbonyla mino-8 benzodioxanne-1,4 (Il Ic) Code number: 62 A suspension of 11 g of the compound of formula (IVc), code number 53 obtained in the preceding step, 23 ml of epibromhydrine and 17 g of potassium carbonate in 200 ml of acetonitrile was brought to reflux for 3 hours, then it was filtered, the filtrate evaporated and the residue taken up in chloroform, washed with water and the solvent was evaporated. A raw product (13 g) was obtained which was used as it was in the synthesis of the corresponding compound of formula (I) appearing in table I under the code number 11.
Melting point: 1340C NMR spectrum (CDCI3): S ppm = 7.5,d; 6.6,d and 4.35,s,(6 benzodioxanne protons) = 6.90,s,(-NH-) = 4.20,m; 3.4,m, and 2.80,m, (5 prot ons
) = 3.82,s,(COOCH3) IR spectrum (KBr): bands of carbamate at o 3415 and 1710 cm-1.
By the same process, but from the corresponding reagents, the compounds of formula (Illc) were obtained appearing in table III under code numbers 63 to 69.
EXAMPLE 6 benzyloxy-5 cyclopentyloxyca rbonyla mino-8 benzodioxanne- 1 ,4 (Vc,d) Code number: 50 1st step: (benzyloxy-5 benzodioxanne-l ,4)yl-8 isocyanate (Xl) 100 g of phosgene were absorbed into a solution, cooled to OOC, of 77 g of benzyloxy-8 amino-5 benzodioxanne-1,4 (IX) in 500 ml of toluene. Then it was left to come up to ambient temperature, the solvent was evaporated and the residue was crystallized in hexane. 62 g of raw product were obtained, which was used as it was in the next step.
2nd step: benzyloxy-5 cyclopentyloxyca rbonylamino-8 benzodioxanne-1,4 (Vc,d) Code number: 50 To a solution of 9 g of the compound of formula (Xl), obtained in the preceding step, in 200 ml of tetrahydrofuran and 10 ml of triethylamine, were added 5.3 g of cyclopentanol and it was brought to reflux for 48 hours. The solvent was evaporated, the residue was taken up in chloroform, washed with water, dried on sodium sulfate, the solvent was evaporated and the residue crystallized in hexane. 9 g of product were obtained which were used in the synthesis of the corresponding compound of formula (IVc) appearing in table Ill below under code number 59.
Yield: 78% NMR spectrum (CDCI3): S ppm = 7.4,d; 6.5,d, and 4.3,s,(6 benzodioxanne protons) = 7.4,m, and 5.05,s,
=5.10,m,and 1.75,m, s-9 pr
) IR spectrum (KBr): bands of carbamate at 3415 and 1710 cm-1.
By the same process, but from the corresponding reagents, the compounds of formula (Vc,d) were obtained which appear in table III under code numbers 45, 49 and 51.
EXAMPLE 7 benzyloxycarbonylamino-5 (epoxy-2,3 propoxy)-5 benzodioxanne-1,4 (Illd) Code number: 70 A suspension of 10 g of the compound of formula (IVd), code number 61, obtained in accordance with the procedure described in the 2nd step of example 5,20 ml of epibromhydrine, 10 g of benzyl alcohol and 1 5 g of potassium carbonate in 200 ml of acetonitrile was brought to reflux for 6 hours.
Then it was filtered, the filtrate was evaporated and the residue taken up in chloroform, washed with water, dried on sodium sulfate and the solvent was evaporated. The residue was crystallized in ethyl acetate.
Yield: 75% Melting point: 110 C Empirical formula: C1gHlgNO6 Elementary analysis:
ss ( H N Calculated (%) 63.86 5.36 3.92 Obtained (%) 63.27 5.26 3.80 TABLE III
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3) : 7.4, d; 6.5, d, and 4.3, s, (6 H 44 CH3 (Vc,d) # C17H17NO5 315.31 100 58 benzodioxanne); 6.82, s, (NH-COO-); 7.4, m, and 5.18, s # 3.76, s, (COOCH3) 1R (KBr): 3420 and 1715 cm-1 NMR (CDCl3) : 7.4, d; 6.5, d, and 4.3, s, (6H benzo45 C3H7n " " C19H21NO5 343.37 156 68 dioxanne); 7.4, m, and 5.10, s, # 7, s, (NH); 4.10, t; 1.70, m and 1, t, (COOC3H7n) 1R (KBR): 3420 amd 1720 cm-1 NMR (CDCl3) ; 7.6, d; 6.5, d, and 4.2, s (6H benzo46 # " " C19H21NO5 343.37 124 81 dioxanne); 7.4, m; 5.05, s, # 6.90, s, (NH): 5.02, m; 1.15, d, (COO #) 1R (KBr): 3430 and 1710 cm-1 (NH-COO #) NMR (CDCl3) : 7.5, d; 6.5, d, and 4.3, s, (6H benzo47 C4H9n " " C20H23NO5 357.39 - 65 dioxanne); 7.4, m, and 5.08, s, # 6.90, s, (NH); 4.10, t, and 1.20, m, (COOC4H9n) 1R (KBr): 3420 and 1720 cm-1 (NH-COOC4H9n) TABLE (Cont.)
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3): 7.5, d; 6.5, d, and 4.3, s (6H benzo48 # (Vc,d) # C20H23NO5 357.39 - 47 dioxanne; 7.4, m, and 5.10, s, # 6.90, s, (NH); 3.95, d; 2.05, m and 1.0, d (CCO-CH2#) 1R (KBr): 3420 and 1720 cm-1 (NH~COO-CH2#) NMR (CDCl3) : 7.5, d; 6.5, d, and 4.2, s, (6H benzo49 # " " C21H25NO5 371.42 - 48 dioxanne); 7.4, m, and 5.08, s, # 6.90, s, (NH); 4.12, t; 1.6, m, and 1, d, (#) 1R (KBr): 3420 and 1720 cm-1 (#) NMR (CDCl3) : 7.4, d; 5.6, d and 4.2, s (6H benzo0 50 # " " C21H23NO5 369.40 - 78 dioxanne); 6.85, s (NH); 5.05, m and 1.80, m, (-COO-); 7.4, m and 5.05, s, (#) 1R (KBr) : 3425 and 1710 cm-1 (#) Elementary analysis : % C H N 51 # " " C22H25NO5 383.43 178 78 Claclulated (%) 68.91 6.57 3.75 Obtained (%) 68.71 6.36 3.41 TABLE III (Cont.)
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6H benzo52 # (Vc,d) # C22H19NO5 377.38 - 67 dioxanne) ; 7.4 m, and 4.10, s (#) 7.02, m, (#) 6.85, s, (NH) 1R (KBr): 3415 and 1710 cm-1 (#) NMR (CDCl3) : 7.95, s (OH); 7.30, d; 5.50, d and 53 -CH3 (IVo) H C10H11NO5 225.10 150 90 4.3, s (6H benzodioxanne); 7, s (NH); 3.78, s (-COOCH3) 1R (KBR): 3410 and 1710 cm-1 (NHCOOCH3) NMR (CDCl3): 7.55, s (OH); 7.30, d; 6.50, d and 54 -C3H7n " " C12H15NO5 253.25 - 83 4.3, s (6H benzolioxanne); 6.55, s (NH); 4.10, t; 1.70 m and 1, t, (COOC3H7n) 1R (KBr): 3380 (OH) 3380 and 1710 cm-1 (NH-COOC3H7n) NMR (CDCl3) : 7.4, d; 6.5, d and 4.3, s (6H benzo55 # " " C18H15NO5 253.25 - 99 dioxanne); 6.70, s (NH); 5.0, m and 1.22, d (COO#); 5.6, m (OH) 1R (KBr): 3380 (OH and HN), 1710 (NH-COO#) NMR (CDCl3) : 7.4, d; 6.5, d and 4.3, s (6H benzo56 C4H9n " " C13H17NO5 267.27 - 95 dioxanne); 6.90, s (NH); 4.10, t and 1.20, m, (COOC4H9n); 5.20, m (OH) 1R (KBr): 3360 and 1715 cm-1 (NHCOOC4H9n) TABLE III (Cont.)
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3): 7.4, d; 6.5, d and 4.3, s (6H benzo57 # (IVc) H C13H17NO5 267.27 - 90 dioxanne); 6.90, s (NH); 9.95, d; 2.05, m and 9.95 d, (#) 1R (KBr): 3360 and 1715 cm-1 (#) NMR (CDCl3) : 7.4; 6.5, d and 43., s (6H benzo58 # " " C14H19NO5 281.30 - 98 dioxanne); 6.85, s (NH); 4.15, t; 1.62, m and 0.95, d, (#) 5.28, m (OH) 1R (KBr): 3360 and 1710 cm-1 (#) NMR (CDCl3) : 7.4, d; 6.5, d and 4.25, s (6H benzo59 # " " C14H17NO5 279.28 - 96 dioxanne); 6.85, s (NH); 5.10, m and 1.75, m (#) 5.95, m (OH) 1R (KBr): 3380 and 1710 cm-1 (#) NMR (CDCl3) : 7.4d; 6.5, d and 4.2, s (6H benzo60 # " " C15H15NO5 293.31 57 77 dioxanne); 6.85, s, (NH); 4.75, m and 1.40, m (#) 5.70, m (OH) 1R (KBr); 3380 and 1775 cm-1 (#) TABLE III (Cont.)
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3) : 7.4, d; 6.5, d and 4.12, s (6H benzo61 # (IVd) " C15H13NO5 287.26 - 82 dioxanne); 7.25, m (#) 5.70, m (OH) 1R (KBR): 3360 and 1735 cm-1 (#) NMR (CDCl3) : 7.5, d; 6.6, d and 4.35, s (6H benzo62 -CH3 (IIIc) # C13H15NO6 281.26 134 49 dioxanne); 6.90, s (NH) and 3.82, s (-COOCH3) 4.20, t; 3.4, m and 2.80, m (5H #) 1R (KBr): 3380 and 1730 cm-1 (NHCOOCH3) NMR (CDCl3) : 7.5, d; 6.5, d and 4.3, s (6H benzo63 -C3H7n " " C15H19NO6 309.31 - 66 dioxanne); 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 #) 1R (KBr): 3440 and 1740 cm-1 (NHCOOC3H7n) NMR (CDCl3) : 7.5, d; 6.5, d ande 4.3, s (6H benzo64 # (IIIc) # C15H19NO6 309.31 - 45 dioxanne); 6.90, m (NH); 5.05, m and 1.25, d, (COO#); 4.30, t; 3.40, m and 2.80, m (5H #) 1R (KBr): 33.10 and 1700 cm-1 (NH-COO#) TABLE III (Cont.)
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3) : 7.5, d; 6.5, d and 4.3, s (6H benzo65 -C4H9n (IIIc) " C16H21NO6 323.33 104 84 dioxanne); 6.90, s (NH): 4.10, t and 1.20, m (COO-C4H9n); 4.20, t; 3.4, m and 2.8, m (5 H #) 1R (KBr): 3415 and 1725 cm-1 (NH-COOC4H9n) NMR (CDCl3) : 7.5, d; 6.5, d and 4.3, s (6H benzo66 # " " C16H21NO6 323.33 - 87 dioxanne); 6.90, s (NH); 4.05, d; 2.05, m and 1.0, d, (#) 4.20, t; 3.4, m and 2.8, m (5 H #) 1R (KBr): 2390 and 1700 cm-1 (5 H #) NMR (CDCl3) : 7.5, d; 6.5, d and 4.3, s (6H benzo67 # " " C17H23NO6 337.36 - 76 dioxanne); 6.90, s (NH); 4.10 , t; 1.6, m and 0.95, d, (#) 4.20, t; 3.4, m-and 2.8, m (5 H #) 1R (KBR): 3290 and 1700 cm-1 (#) TABLE III (Cont.)
Melting Code Empirical Molecuiar point Yield Number A Formula R5 formula Weight ( C) (%) C.H.N. OR NMR SPECTRUM AND IR SPECTRUM NMR (CDCl3) : 7.5, d; 6.5, d and 4.3, s (6H benzo68 # (IIIc) " C17H21NO6 335.35 - 49 diosanne); 6.90, s (NH); 5.12, m and 1.8, m, (#) 4.20, t; 3.4, m and 2.8, m (5 H #) 1R (KBr): 3320 and 1700 cm-1 (#) Elementary analysis : C H N 69 # " " C18H23NO6 349.37 113 85 Calculated (%) 61.88 6.65 4.01 Obtained (%) 61.47 6.75 4.17 Elementary analysis : C H N 70 # (IIId) " C19H19NO6 357.35 110 37 Calculated (%) 63.86 5.36 3.92 Obtained (%) 63.27 5.26 3.80 EXAMPLE 8 Hydrated [(methyl-3) n-butyloxycarbonyl-8 benzodioxanne-1,4,5-yl]oxy-3[(trimethoxy-3,4,5 cinnamoyl)-4 piperazione-1 yl]-1 propanol-2[S(-)]chlorhydrate (la) Code number: 72 1st step: [(methyl-3) n-butyloxycarbonyl-8 benzodioxanne-1 ,4,5-yl]oxymethyl-4 dioxolanne-1 3 [S] (XV) A suspension of 14.5 g of the compound of formula (IVb), code number 32, 17.5 g of the compound of formula (XVI) and 38 g of potassium carbonate in 300 ml of dimethylformamide was brought to reflux for 12 hours.Then it was filtered, the filtrate was evaporated and the residue chromatographed on a silica column. After elution with ethyl acetate (5 to 20%)/hexane (95 to 80%) mixtures, 8 g of the desired product were obtained: Yield: 30% Melting point: 85 C Empirical formula: C2gH2gO7 [cy]O = ~13.2 (C = 1, ethanol) NMR spectrum: # ppm = 7.4,d,; 6.5,d, and 4.35,s,(6 benzodioxanne protons) = 4.25,t, (-COO-CH2-)
2nd step: [(methyl-3) n-butyloxycarbonyl-8 benzodioxanne-1 4 5-yl]oxy-3 propanediol-1 ,2 [S] (XIV) A solution of 7 g of the preceding compound of formula (XV) in 100 ml of acetone and 36 ml of 1 N hydrochloric acid was brought to reflux for 3 hours. Then the acetone was evaporated, the residue was taken up in methylene chloride, neutralized with sodium bicarbonate, the organic phase was decanted, it was washed with water, dried on magnesium, sulfate, filtered, the solvent was evaporated and the residue was re-crystallized in ethyl acetate.
Yield: 92: Melting point: 10000 Empirical formula: C26H24O7 [&alpha;]D20 = + 4.8 (C = 4, methanol) NMR spectrum (DMSO): # ppm = 7.35,d; 6.6,d, and 4.22,s,(6 benzodioxanne protons) = 4.10,t, (-COO-CH2-)
3rd step:Hydrated [(methyl-3) n-butyloxyca rbonyl-8 benzodioxanne-1 ,4 5-yI]oxy-3 [(trimethoxy-3 ,4,5 cinnamoyl)-4 piperazine-1 yI]-1 propanol-2 [S(-)jhydrochloride (la) Code number: 72 To a solution, cooled to 0 C, of 5.7 g of diol of formula (XIV), obtained previously, in 10 ml of pyridine and 1 00 ml of benzene was slowly added 2.4 g of tosyl chloride. Then they were left in contact for 45 hours at ambient temperature, diluted with benzene and ether, washed with a 1 N hydrochloric acid solution, then with water, filtered and the solvents were evaporated. Thus 7.3 g (95%) of tosylate offormula (XIII) were obtained, which was 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. It was brought to reflux for 1 5 hours under a nitrogen stream, then filtered, the filtrate was evaporated, the residue was taken up in methylene chloride, washed with water, dried on magnesium sulfate, filtered and the solvent was evaporated. 8 g (98%) of the desired product were obtained which was dissolved in 100 ml of methyl-ethylketone. Then a stream of gaseous hydrochloric acid was passed and the precipitate formed (3 g) was filtered.
Yield: 37% Melting point: 16200 Empirical formula: C33H4sCIN201o + 4/5 H20 []Do = - 7.80 (C = 2,methanol) Elementary analysis:
C H N Calculated (%) 57.63 6.96 4.07 Obtained (%) 57.71 6.95 3.92 The compounds of formula (I) were studied on laboratory animals and showed a anti-heart ischemic activity.
This anti-heart ischemic activity was revealed on anaesthetized dogs (sodic pentobarbital 30 mg/kg/i.v.).
-The oxygen consumption in the left ventricle was estimated by the product of the coronary venous flow multiplied by the coronary arteriovenous different in oxygen (% volume).
The coronary venous flow was measured at the level of the coronary venous sinus by means of a modified Morawitz cannula, introduced under radioscopic control.
The coronary and venous oxygenation was measured by means of a blood-gas analyzer (IL Meter 213).
- The cardiac effort was estimated from the KATZ index, by the product of the average arterial pressure multiplied by the cardiac frequency.
The cardiac frequency was determined from the electrocardiogram recorded in derivation D2.
The systemic arterial pressure was 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 shown in tableau IV below. It should be noted that the compounds tested were injected intravenously with slow perfusion.
TABLE IV
ANTI-HEART ISCHEMIC ACTIVITY Reduction in Reduction in consumption of 03 cardiac effort Tested Toxicity compounds LD 50 Dose in time in time Code No. mg/kg/i.v. mg/kg/i.v. in % | (mn.) in % (mn.) 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 á 60 21 25 (p.o. : 0%) 9 2000 0.31 62 45 26 30 (p.o. : 0%) 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 0.15 49 60 18 30 (p.o. : 0%) 14 200 (0%) 0.31 38 > 30 25 > 45 15 100 (0%) 0.15 42 30 18 > 30 16 2000 0.31 62 > 45 40 > 60 (p.o. : 0%) 17 132 0.15 43 > 30 17 45 18 - 0.15 40 35 24 > 45 19 2000 0.31 24 15 26 30 (p.o. : 0%) 71 > 2000 (po) 0.15 29 60 39 60 72 > 1000 (po) 0.15 36 60 42 60 73 > 2000 (po) 0.15 18 15 10 15 74 ,, 0.31 72 60 40 45 75 ,, 0.31 54 45 39 30 TABLE IV (Cont.)
ANT1+HEART ISCHEMIC ACTIVITY Reduction in Reduction in consumption of O2 cardiac effort Tested Toxicity compounds LD 50 Dose in time in time Code No. mg/kg/i.v. mg/kg/i.v. in % (mn.) in % (mn.) 76 2000 (po) 0.15 30 30 11 45 77 " 0.15 28 60 27 60 Lidoflazine 25 1.5 48 30 40 15 Amiodarone 180 10 11 15 22 15 It follows from the preceding results that the difference between the therapeutic doses and the toxic doses is sufficiently wide to allow the compounds of formula (I) to be used in the treatment of troubles of the cardiovascular systems, particularly as an anti-heart ischemic agent.
They will be administered intravenously in the form of injectable ampoules containing 60 to 1 20 mg of active ingredients or orally in the form of tablets, pills or capsules containing from 20 to 200 mg of active ingredient (1 to 3 per day).

Claims (1)

1. A 3,4,5-trimethoxy cinnamoyl piperazine derivative having the formula:
in which Ar represents: either a 4-acetyl-2 ethoxy phenyl group of formula:
or a benzodioxannic group of type:
in which R represents: - a methyl-thio-2-ethoxy chain of formula
an ester group ofCOOR1 type in which R1 represents an element chosen from the following:: methyl, n-propyl, n-butyl, isobutyl, (ethyl-2)n-butyl, n-octyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl methyl, (cyclo-2-methyl) ethyl, (2-cyclopropyl) ethyl, cyclopentyl, phenyl or (3-methyl)n-butyl and in the latter case, the corresponding derivative of formula (I) comprising an asymetric carbon is either in the form of a racemic mixture of two enantiometers, or in the form of the levogyrous enantiometer of S configuration; or - - a carbamate group of-NH-OOOR2 type in which R2 represents a methyl group, a linear or branched alkyl group having 3 to 5 carbon atoms, a cycloalkyl residue having 5 to 6 carbon atoms, or a benzyl group, or a pharmaceutically acceptable salt thereof.
2. Any one of the compounds numbered 1 to 19 and 71 to 77 herein.
3. A 3,4,5-trimethoxy cinnamoyl piperazine derivative according to claim 1 substantially as herein described with reference to any one of the Examples.
4. A process for preparing the compounds of formula (I) with the exception of the compound of formula (I) in which Ar represents the group:
and of the compound of formula (I) corresponding to the particular formula:
characterized in that it consists in condensing in an alcoholic medium a 3,4,5-trimethoxy cinnamoyl piperazine of formula:
with the epoxides of formula (Illa), (IlIb), (Illc), and (Illd):
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 to 6 carbon atoms.
5. A process according to claim 4, substantially as herein described with reference to any one of the Examples.
6. A process for preparing the compound of formula (I) in which Ar represents the group:
characterised in that it consists in condensing in an ethanbl medium; in the presence of potassium carbonate, 1 -chloro-2-metylthio ethane with the compound of formula (XII):
7. A process according to claim 6, substantially as herein described and exemplified.
8. A process for preparing the compound of formula:
characterised in that it consists in condensing, in the presence of potassium carbonate, the compound of formula (II) defind in claim 4, with the compound of formula (XIII):
9. A process according to claim 8, substantially as herein described and exemplified.
10. A compound according to any one of claims 1 to 3 for use in the treatment of disorders of the cardiovascular system.
1 A pharmaceutical composition comprising a compound according to claim 10 as an active ingredient together with a pharmaceutically acceptable carrier.
12. As synthesis intermediates, the compounds of formulae (Illa), (Illb), (Illc), (Illd), (XIII) and those of formulae:
New claims or amendments to claims filed on 13th January, 1981.
Superseded claims 1.
New or amended claims:-
1. A 3,4,5-trimethoxy cinnamoyl piperazine derivative having the formula:
in which Ar represents: either a 4-acetyl-2 ethoxy phenyl group of formula:
or a benzodioxannic group of type:
in which R represents: - a methyl-thio-2-ethoxy chain of formula
an ester group of -COOR1 type in which R1 represents an element chosen from the following: : methyl, n-propyl, n-butyl, isobutyl, (ethyl-2)n-butyl, n-octyl, cyclopropyl methyl, cyclobutylmethyl, cyclopentyl methyl, 2-cyclobutyl ethyl, (2-cyclopropyl) ethyl, cyclopentyl, phenyl or (3-methyl)n-butyl and in the latter case, the corresponding derivative of formula (I) comprising an asymetric carbon is either in the form of a racemic mixture of two enantiometervs, or in the form of the levogyrous enantiometer of S configuration; or - a carbamate group of -NH-000R2 type in which R2 represents a methyl group, a linear or branched alkyl group having 3 to 5 carbon atoms, a cycloalkyl residue having 5 to 6 carbon atoms, or a benzyl group, or a pharmaceutically acceptable salt thereof.
GB8025200A 1979-08-03 1980-08-01 3,4,5-trimethoxy cinnamoyl piperazine derivatives processes for preparing the same and their use in therapeutics Expired GB2057433B (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4499100A (en) * 1983-05-18 1985-02-12 Syntex (U.S.A.) Inc. Benzodioxanyl-hydroxyethyleneamino-piperidinyl acetanilides, ketones, esters and carbamates which effect immunity and calcium entry and β-blockade
US4558129A (en) * 1983-05-18 1985-12-10 Syntex (U.S.A.) Inc. Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and β-blockade
US4567264A (en) * 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
EP0943613A1 (en) * 1996-11-19 1999-09-22 Kyowa Hakko Kogyo Kabushiki Kaisha Oxygenic heterocyclic compounds
US6514996B2 (en) 1995-05-19 2003-02-04 Kyowa Hakko Kogyo Co., Ltd. Derivatives of benzofuran or benzodioxole

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2507604A2 (en) * 1977-04-19 1982-12-17 Delalande Sa Tri:methoxy cinnamoyl piperazine(s) - for treatment of cardiovascular disorders
US4997836A (en) * 1988-11-11 1991-03-05 Takeda Chemical Industries, Ltd. Trisubstituted piperazine compounds, their production and use
WO2008144933A1 (en) * 2007-05-29 2008-12-04 Université de Montréal Cinnamoyl inhibitors of transglutaminase

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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FR2387971A1 (en) * 1977-04-19 1978-11-17 Delalande Sa NEW TRIMETHOXY CINNAMOYLES PIPERAZINES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4499100A (en) * 1983-05-18 1985-02-12 Syntex (U.S.A.) Inc. Benzodioxanyl-hydroxyethyleneamino-piperidinyl acetanilides, ketones, esters and carbamates which effect immunity and calcium entry and β-blockade
US4558129A (en) * 1983-05-18 1985-12-10 Syntex (U.S.A.) Inc. Benzodioxanyl-hydroxyethylene-piperazinyl acetanilides which effect calcium entry and β-blockade
US4567264A (en) * 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
US6514996B2 (en) 1995-05-19 2003-02-04 Kyowa Hakko Kogyo Co., Ltd. Derivatives of benzofuran or benzodioxole
US6716987B1 (en) 1995-05-19 2004-04-06 Kyowa Hakko Kogyo Co., Ltd. Derivatives of benzofuran or benzodioxazole compounds
EP0943613A1 (en) * 1996-11-19 1999-09-22 Kyowa Hakko Kogyo Kabushiki Kaisha Oxygenic heterocyclic compounds
EP0943613A4 (en) * 1996-11-19 2002-07-10 Kyowa Hakko Kogyo Kk Oxygenic heterocyclic compounds

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FR2462432A2 (en) 1981-02-13
SE8005300L (en) 1981-02-04
ES493931A0 (en) 1981-10-01
ES8301944A1 (en) 1982-12-16
JPS634827B2 (en) 1988-02-01
JPS5626885A (en) 1981-03-16
CH646694A5 (en) 1984-12-14
AU6100380A (en) 1981-02-05
BE884602R (en) 1981-02-02
FR2462432B2 (en) 1983-05-27
CA1155121A (en) 1983-10-11
LU82677A1 (en) 1982-05-10
NL8004434A (en) 1981-02-05
ES499814A0 (en) 1982-12-16
GR68073B (en) 1981-10-29
ZA804709B (en) 1981-10-28

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