NL8004434A - NEW 3,4,5-TRIMETHOXY-CINNAMOYLPIPERAZINE COMPOUNDS, METHOD FOR THEIR PREPARATION AND USE AS MEDICINES. - Google Patents

Description

1 »- ε · \ * ^ 803264 / vdV / AR / hh

Short designation: New 3,4,5-trimethoxy-cinnamoyl-piperazine compounds, process for their preparation and use as medicaments.

The Applicants mention as inventors:

Guy BOURGERY, Alain LACOUR, Gerard MOINET, Bernard POURRIAS,

Anne-Marie RUCH.

The invention relates to new 3,4,5-trimethoxy-cinnamoylpiperazine compounds, a method of their preparation and their use as medicaments.

The new compounds have the general formula 1 of the formula sheet, wherein Ar represents the 4-acetyl-2-ethoxyphenyl group of formula 17 of the formula sheet or a benzodioxane group of the formula of formula 18 of the formula sheet, wherein R represents the 2-methylthioethoxy- group of the formula: SCH ^, an ester group of the type -COGR ^ wherein R ^ is a methyl, n-propyl, n-butyl, isobutyl, 2-ethyl-10-n-butyl, n-octyl -, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclomethyl-ethyl, 2-cyclopropyl-ethyl, cyclopentyl, phenyl or 3-methyl-n-butyl group and in the latter case the corresponding compound of formula 1 having an asymmetric carbon atom either in the form of a racemic mixture of two enantiomers, or in the form of the counterclockwise enantiomer of the S configuration, or a carbamate group of the -NH-COOR2 type, wherein R2 represents a methyl group, a straight or branched chain alkyl group with 3-5 carbon atoms, a cycloalkyl group with 5-6 carbon represents atoms or a benzyl group.

The invention also relates to the pharmacologically acceptable salts of the compounds of formula 1, i.e. the salts of non-toxic inorganic and organic acids and in particular the salts of hydrochloric, oxalic, maleic, etc.

The method according to the invention for the preparation of 800 4 4 34

1 I

- 2 - the compounds of formula 1 with the exception of the compound of formula 1, in which Ar represents the group of formula 19 and the compound of formula 1 of the particular formula la, is characterized in that in the presence of an alcanol (methanol .5, ethanol, butanol) 3,4,5-trimethoxycinnamoylpiperazine of formula 2 of the formula sheet condenses with epoxides of formulas 3a, 3b, 3c and 3d, wherein R ^ has the same meanings as in formula 1 and R ^ a methyl group, a straight or branched chain alkyl group with 3-5 carbon atoms or a cycloalkyl group with 5-6 carbon-10 atoms.

The compounds of formulas 3a, 3b and 3c are new compounds and are obtained by condensation of epichlorohydrin or epibromohydrin under reflux in acetonitrile (or acetone), in the presence of potassium carbonate with compounds 15 of formulas 4a, 4b and 4c of the formula sheet wherein R 1 and R 2 have the same meanings as in formulas 3b and 3c.

The new compound of formula 3d is obtained by condensation of epichlorohydrin under reflux in benzyl alcohol in the presence of potassium carbonate with the compound of formula 4d of the formula sheet.

The new compound of formula 4a of the formula sheet is obtained by a reaction of FRIES with 1-acetoxy-2-ethoxybenzene of formula 5a of the formula sheet, which is also a new compound and is obtained by the action of acetyl chloride on 2-ethoxyphenol.

The compounds of formulas 4b, 4c and 4d are new compounds and are obtained by hydrogenolysis in the presence of 5% palladium on carbon, in an ethanolic medium of the benzyl group of the compounds of formulas 5b and 5c, d, wherein R ^ 30 has the same meanings as in formula 4b and R '^ a methyl group, a straight or branched chain alkyl group with 3-5 carbon atoms, 800 44 34 * - 3 - a cycloalkyl group with 5-6 carbon atoms or the phenyl group for states.

The new compounds of formula 5b are obtained by a two-stage esterification, whereby the compound of formula 6, which is described in Belgian patent 865,990, is treated with thionyl chloride and the crude compound thus obtained is reacted with alcohols of formula 7 of the formula sheet, where R ^ has the same meanings as in formula 5b,

The new compounds of formula 5c, d, wherein R 1 'represents a methyl, isopropyl, n-butyl, isobutyl, or phenyl group, are obtained by reacting chloroformates of formula 8 of the formula sheet, wherein R 1 represents a methyl, isopropyl, n-butyl, isobutyl, or phenyl group, with the compound of formula 9 of the formula sheet, which is described in Belgian patent 15 865,990, in toluene.

The new compounds of formula 5c, d, wherein R 2 "represents an n-propyl, 3-methylbutyl, cyclopentyl or cyclohexyl group, are obtained by condensation of alcohols of formula 10 of the formula sheet, wherein an n-propyl, 3 -methylbutyl, cyclopentyl-20 or cyclohexyl group, with the isocyanate of formula 11 of the formula sheet.

The new compound of formula 11 of the formula sheet is obtained by the action of phosgene on the compound of formula 9.

The process according to the invention for the preparation of the compound of formula 1, in which Ar represents the group of formula 19 of the formula sheet, is characterized in that in the ethanolic medium 1-chloro-2-methylthioethane is condensed in the presence of potassium carbonate. compound of formula 12 of the formula sheet, which is described in Belgian patent 865,990.

The process according to the invention for the preparation of the compound of formula la is characterized in that in acetone 800 4 4 34 - 4 - or acetonitrile in the presence of potassium carbonate the compound of formula 2 is condensed with the compound of formula 13 of the formula sheet obtained by the action of paratoluene sulfonyl chloride on the compound of formula 14 with S-configuration. This compound of formula 14 is obtained by acid hydrolysis in acetone of the compound of formula 15 of the formula sheet with S-configuration. itself is obtained by condensation of the tosylate of formula 16 of the formula sheet with S-configuration described in J. Org. Chem. 42, 1006, (1977) with the compound 10 of the formula 4b, wherein the (3-methyl) represents n-butyl group.

The invention is further illustrated by the following examples.

EXAMPLE I

(4-acetyl-2-ethoxy) 1-phenoxy-3 / * 4- (3,4,5-trimethoxycinnamoyl-15 piperazine) / - 3-propcinol-2, oxalate, hydrated (1), Code no. 1

A solution of 3 g of 3,4,5-trimethoxycinnamoyl-piperazine (2) and 2.7 g of 1- (4-acetyl-2-ethoxy-phenoxy) 2,3-epoxypropane (3a) (prepared in step 3 of) is boiled Example III) under reflux in 50 ml of ethanol for three hours. The solvent is then evaporated, the residue is dissolved in acetone and a solution of oxalic acid in acetone is added, and the resulting precipitate is filtered, yielding 5.6 g of product.

Yield: 87 $

25 * Melting point stl60 ° C

Raw formula s ^ 33 ^ 40 ^ 2 ^ 11 + 3/4

Basic analysis:

CRN

Calculated (JÉ) 57.61 6.47 4.34

Found (JÉ) 57.57 6.24 4.33 In the same manner, but starting from the corresponding reagents, the compounds of formula I, which are listed in Table A below and code numbers 3-19.71, are obtained. and 73-77. A . 800,8434

TABLE A

- 5 -! f 'i

Tt CO CO [s. is -Η Ό CS CS ^ 'O jH.

z co CO CS O st CN H * O O Ή CS ^ K, H- O s N -Hst Ov N N O jH '

m τ rj- CN NOCOCNCSOfsCO ^ OOCO

m .. .. .. - · ->,> Ο \ 0ΌΌΌΌΌ> 0> 0ΌνΟΌ r—) --------- ----- ------------- ------ -— »

C -HK 'H'H ^ CO IS.' O IV ^ -COCO

. <O io * <tCO10. φιΟίΧΟ'ίΟΉ-Ή

Tj (N *. .... V. · »K '". 2 is. Rs. St-H-ininO'Oisrsrsrs.

.0 In in mmin ininioinininin k .__ / ______ i ______. ,, S ”~ · * · * · * * v * *> *

= k> tH> 1 - 1> M> M

0 ¾¾. 3 φ φ φ φ Φ o φ φ 2.¾ ¾¾ Ζί; ^ σ> ja oi Ji o> -Q σι ü o) .o o) ω _ --1 ----- J -------- ^ 1 / i Ü) c r? rs o co m On cs

1 Φ oo sO W) Ό IS CO

Okay - '0 JÜ _

-k -—N

. ή + »o o <n co m o Q

O C O ^ N, LD st LD SD

E O '-' pH iH »H rH Ή Ή wo.

-H

-C Ό On O CO CM MO

• O p-ι fH 'Ή Ή * 0 N

i — ί * H ·, «. «S *». * »· 0> no cs. oo tri es ε φ Νφ nq cm m <h rs cn no no NO Ό N si * ^%, T- x X «V.

^ X

co rs + + + + 10 O O + o

Φ On Ή Ή H

H, -h o O O H- O

= ή CS _CS CS rH CS

E O 2 Z Z Cf, Z

k CM fH ï — 1 i — I> CS Ή o z o o υ o. z C>, u o «+ - co η. h cs 2 csco cs

^ sT CO Η "X Η" X Η1 2 3 4 5 X

Φ -T- X X X X X

> pH O On * H p H- in CS CM

O CO CO CM (O> s CO V. CO V.

k (J o o r- (O COO> —I

800 4 4 34 -, --- +> - -4-1 U 4-1 ^ • ο ο ο τι σ k o ό ό o

M k O k O also kO

Ή 3 φ k Φ 'k Φ k o O) k 2 "<» 0) Ό φ "O + * Ό Φ ΦΤ3

Φ +1 + i> 4-> >> O> N + ·> -k> N

Ή σ k O -C O JC O +> O -C

O E kO kkkkKkkKkk

E k "O O" O O Ό O> »0 Ó O ^ 3. O

k O>. f — l>, 0> n O -CO >> Η> °

O> x o x Η X Η Φ p-4 -CO _C <—I

Μ- ΦΧ Q) JZ O ^ 0i-C ΦΧ O -C

0) 0 0) 0 0) 0 O 0) 0 0) 0 + * 3 Φ -: - 1 ----- 4

E

o f— (CM CO H- m

c k CS CS CS cs CS CS

Φ <O) φ Φ Φ Φ Φ Φ

Cl pH i — I> H pk Ή Η • k 3 3 3 0 0 0

* 2 Λ E E E E E E

5 ° k. k k k k k

• H o O O O O O

.O u— u_ 14. <4- <4- * + · k ----- Φ ----> k

1 Φ Φ E

R E rH CS COst ID O

OO

o c I I

TABLE A (continued) cv \ W 'li) ri · H N iH If) co h- —i h-ts.

2 O o CN rH 00 00 00 O 't -V- CN OM On · *%. * »* · <***» ^ ^ ^ »-V- -V -v- -v CO CO CO V" ND ΌΌ Ό Ό Cf) 0 _______________

vL ND ND ^ CO in On Ό Ό m Η- H "Ό '' t CN

, Ηχ 00 On If) ND CN CN ID hs CO O ND rf ND 't M «. ^ ¼¾¼¾¾ ^

C ND N N Ό N N lil lil N ON) ND ND ND

<_______________ .¾ CN CO K Ό Ό N Ό O On IOND C0ND On 3 <j 00 NO K Ή "CN in NO ND Nf in CN m CN CN ^ *. *» <** »« »* ·« · ^ * * »» * »^

C K N. On On On On OnCO CO m lOLO UD

φ in mmmmmm mm mm mm m 3 tl> H> M> M> M> M> M> ΓΊ NO mm Φ Φ Φ Φ Φ (U 01 0) 0) 0) 0) 0) ω _q o) J2 O) -QO -Ü O J2 O -OO) -O ü> 4-> w 1 O)

n in N. Ό ^ N} 00 ON

° SnÏ ts m no m no h- no

-Q

iL-TjO O o ND -H m -¾ 0 coU nd nd o co ^ m nd g 2 iH i — 1 <H iH · Η Ή Ή V) Cl _i_______ + - i “c oo n n o O mm» O ND γ-ΗΓνΓν Ή [Ns is t I «, *,. K. % ^ ^

03 hs CO On Η "Ή- CO CO

c φ CO Ό CN CN m S. K

fcO) ND NDISN ND ND ND

+ -> + + + + o o o o o o

0) tH iH Ή Ή Ή fH

ij o oo- ^ ooq ^

0 CN CN CN .H CO CO CO

1 2 z 2 C> z z z U <H rH Ή CN rH r — I '-j oooo o o z o o o o o o

c £ m CN CO rH CN Q CO CN CN CN CN CN

m x - *; m x ^ co x η- χ _jt x

XXX X XXX X X X

~ e CO 00 ND m NO On m H CN - (CN

3 CO \ CO CO St, CO CN - CO «CO * ·

£ o 1 m o υ ^ o ü ^ u-HOrH

! 1 +3 +3 X “ï>

-o O O T3 O Ό O

M O O MO MO

O) Μ M Φ M O M

φ TJ "O <D ~ 0 Φ TS

+ *>> + * >> + S

o x jz o -c + · σ x

= MM M MM O MM = S

E TJ O O "000 Ό0 O> 0 0> 0 iH> .0

5 JC i-I rH -C rH O XH

^ 0) SI _C <D _C X Φ _C

ο> υ o o> υ ο ου

nO tN. CO On O -H CN

CN CN CN CN CO CO CO

r. φ φ φ φ Φ Φ β) 3333330 1 ε ε ε ε ε ε ε 1 Μ Μ Μ Μ Μ Μ Μ Ο Ο Ο Ο Ο Ο Ο Ο w Η-Μ-Η-Μ-Μ-1 + -Μ- Μ I Φ II IN C0C O Η «2 800 4 4 34 - 7 - TABLE A (continued) * 4 7 cm τ * OO M CM in H It) · η K <Ν 0"> ΟΟ -Η Ζ ο if) ο (Ν ο ή ο ο · I «λ Ο CO IS Ο Ο ^ s ^ j ** ·· *». ^ · “'** NO Ό ν0 Ό Ό Ό Ό ΙΟ ΙΟ ΙΟ ΙΟ ΙΟ C0' 'Τ S Ό CO CM 00 C0O «δΐ Is S 'S ί ίΐ) 2

> s X COO ¢ 0 Ό. CO Ό CM CO CM

"ο vo" Ό * Ν Ό Ό Ο Ό Ό η Ν Ν

C

<“Ο -Μ- Ο -τ Ό m CM 00 CM 00 is ~ 3Γ

μ ο CO If) N IS 00 Ό CO OQ M CMCMOCO

a if> 10 m m όό Ό Ό 0 is 00 00 00 00 +1 mm in in m m m m mm m m m m c Φ _____________________.

E .... .... ....

J2 *> 0 μ s μ> μ> μ> μ> μ ^ μ ^

Hj φφφφφφφφ φφ®®®, _CU) ^ O) -DO) J2CJ) J0 O) -QO) -QO) • μ w O)

I φ ^ * + co 0 co - + <0 Q

α. μ w is rs is m -o m ^ ·

0 -Q

h ^ π Ό m Ό 0 £ M r-1 if5 φ c 0 m. rs is co £ φ v__ M M <H Μ Ή Ή ^ WO.

+> CO rs CN CO '.IS -O »

f— Ό CO Ή N.1-r fs CM

(J «,«. W V ^ ^ s. * H rs m co o C rf co

m 5 <> o <> <> <> P

O0 Ό Ό Ό n0 hs rs rs EO) + + + + + +

O O O O + OO

. — I ”—f <—I i — I -f * —Τ’1 Φ O O o CD 5 o o 1 — i co co co CO Ή co -T4 o X X X X o X x

u O ° CM o O O O ΰ O ~ Z? OOOOO

-Γ "ld T" ZC ZC ΠΖ i -U, 0, CM IS CM in co coCM ^^ incM; + co -¾ (o 1 «COS. Co CO CON co <* cos ou« h 'os om om o - + o-Hom μ ________; __ -—.----— 33—— --- * d -μ _ + · -α σ μ -ο σ -o σ h ο φ μ σ μ σ φ l ® φ μ φ μ φ -ο -μ φ * σ φ -σ .μ>, σ +> + * >> +;> c _c μ σ σ -c ρ -cc μ μ -σσμμμ ^ £ -ο ο = = =>, μ ο ο ο ο ο> ο .c ο>. ο ^ ο> .CM Φ X -CM -C Μ 'φχ σ> ο φ -c οι £ Ο ο Ο) ο σ> ο co + m 'O rs 22 Si. co co co co co co co mm φ φ φ Φ Φ μ Μ Μ Ή Ή * · Μ' ^ 'ίί <3 0 3 3 3 5 2 ε ε ε ε ε ε ε ι μ μ μ μ ϊ S «ο ο ο ο ο ο ο ο« + - Μ- «4- <+ Μ- Μ- Μ- μ I Φ Φ Ε - -α ε ττ m ό rs 00 ον μ ο Ο Ή Μ Μ UC Μ Ή ts UC: 8 0 0 4 4 34 -οι Α (continued)

N Csl O i — I O .— (o ^ <P CO Os O

z O CN i — l O O —i o O o o OO

* «* *» »» ^ ** * »« * *. «. h, τί · 00 'ïJ · tJ · "« t τί-Tj ·' φ'φ 'Φ ^ · Φ ϊ - no m - <t m oom' ίο co tv

Jy χ ^ a m .p on coco 00¾ ό co - »^ K *» «. S S k, V S IN «, * NO VO no Ό 'O'O Ό' Ο ΌΌ Ό Ό <* _________—

μ CO iH OSCOCO'O 'OO' ^ O COOO

.μ ON O CM Os P COO 'ΦΌ OO On n # »N ^ W S W N ^ ^ ^ ^ H ^

+! ^ N N NN NOO CO CO 0000 NN

^ mm mmmmmmmm m m Φ ________; -; -; -; -; -; -]; M m> M ^ M> M> M> M>

Yy NvO £ flj Φ ΦΦΦΦΦΦΦΦΦ

Hi ^ .OiiCn -001-001-00-001-001 μ 50

CD

c

1 2 Q N CM P CN P CM

0-0 νΟ ^ «ο - + CM N CM

i 4-> P P ^ '1§0 ° CM CO 00 00 - + 0 m cl' _- - ° m n ό ό ό 1 — i ι — ί iH i “H f-H r — ί

V- 00 - + N On Os N

.o'0 1-1 Ή Ό N N

0 5 N CO - + Os 00 - + p s 00 N 00 On On 00 fcg, N0 SO Ό nQ Ό so + + + + +

O O O O O O

m <—I I-1 Ή I— (I-f I-I

x o o o o o o

CM CM CM CM CM CM

f z z z z z z

Fj «Η P r — I P I — I I — I

0 OO OO OO OO OO OO

i £ m cm p cm co cm mcM mcM cocn

_- + X M! - + X P X - + X

n \ -L 3 · j_ 33 33 X

S CO - + CM CO C0NO - + - + -m- cm CO CM

5 CO N CO - CON. CON CON CO - μ om ο i— (on om op op

P 'P

o o o tj σ

CO O CO "-" MO

Φ Μ ^ X Φ M

ΦΌΝΟ Φ Ό

P N CO P N O -C li X 0 -C

M MO O MM = z s z Ό OCMQ * Ό 0

p> 0 ^ CM NO

£ £ H \ II -C P

2 Φ -C i Ο Ο Φ JC

S 'Ο) ϋ N w 01 U _____ O A <h cm co - * + m - + ^ - + "* + * + - + - + .φ ° φφφφφ

_ << iH, -j Ή ιΗ P P I — I

<3 ^ t £ 3 3 3 3 3 1 ε ^ ΐ® ε ε ε ε ε Μ ο .μ Μ Μ Μ Μ Μ Ο Ο (Λ μ ρ Ο Ο Ο Ο Ο ι ~> ν; u + - q_ < 4_ <+. 14- <4- _ I Φ φ ε • 1 S ”R" SF: ί 0 4 4 34 --9-.

# · '♦

EXAMPLE II

1-4 (2-methyl, |: hio-ethoxy-ethylene-2,3-dioxyphenoxy / -3 - / (3,4,5-tximethoxycinnamoyl-4-pipexazine. 7 pxopanol-2-chlooxhydxate, hydrated) (1)

Code index 2.

5 A mixture of 13.3 g (4-hydxoxy-ethylene-2,3-dioxy) 1-phenoxy 3 - / (3,4,5-tximethoxycinnamoyl-4-pipexazine) 7 propanol-2 (l2) is boiled , 3.5ml of 1-chloox-2-methylthioethane and 10.3g of potassium carbonate in 150ml of ethanol 18 ux index reflux. Then, the filtrate is evaporated, the filtrate is evaporated, the xesidu is taken up in chloxofoxm and washing with water. The organic phase is dried over sodium sulphate, the solvent is evaporated and the residue is subjected to chromatography on a silica column. The mixture is eluted with pure chloxoform and a mixture of 99% chloxofoxm and 1% methanol and 13 g are added.

dairy product, which is dissolved in acetone. 4.5ml of 6.5N is added

15 add salt in ethanol, filter the vexkx gene off, and dissolve it in a minimal amount of alcohol and vex it with acetone. 9.35g of product is added.

Melting point: 175 ° C

Raw fox mule: C3QH ^ ClN20gS + 7/6 f ^ O

Elemental analysis:

20 C Η N

calculated% 54.41 6.60 4.23 found% 54.31 6.37 4.07 EXAMPLE III Γ

To a solution of 30.4 g of 2-ethoxyphenol in 10 ml of tetxahydxo-fuxan and 29 g of txiethylamine, 17.3 g of acetyl chloro-25xide are added on cooling, left to stand for 24 hours, the extract is filtered off, the filtrate is evaporated and the residue is distilled. 27.2 g of product are added.

/ * 4 * - (2,3-epoxy-pxopoxy) 3'-ethoxy-acetone-phenone (3a) 1 txap: 1-acetoxy-2-ethoxybenzene (5a) 800 4 4 34 - 10-

On brst: 69 $

Boiling point at 9mm Hg ï 115 - »- 123 ° C

Raw formula:%.

NMR Spectrum (CDCl3 - - (A,. \ 3: rpm = 7.00, m, (4 benzene protons) 5 = 4.00, q, (- CH2 of 0-CH2-CH3) = 2.25, s, (- CH3 of OCOCH2) - 1.32, t, (- CH3 of O-CH2-CH3) 2nd stage: 3-ethoxy-4-hydroxy-acetophenone (4a).

To a solution of 17.6 g of the compound of formula 5a obtained in the previous step 10 in 100 ml of nitrobenzene, 24g of aluminum chloride is added, and it is left to stand at room temperature for 20 hours. The reaction mixture is then poured into ice and concentrated hydrochloric acid and extracted with ether. The ether solution is extracted with a 2N sodium hydroxide solution, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with chloroform.

The solvent is evaporated and the residue is chromatographed on a silica column eluting with 100% benzene. 50% of the desired compound of formula 4a are obtained.

Melting point: 66 ° C

Raw formula: (^ 0 ^ 12¾ NMR Spectrum (CDCl3): S ppm = 7.50, m, and 6.95, d, (3 benzene protons) = 6.72.5, (-0H) = 4, 10, q, (-CH2 of -0-CH2-CH3) = 2.55, &, (-C0CH3) 25 = 1.20, t, (-CH3 of -0-CH2-CH3), .. Then 50 $ of the isomer of 4'-ethoxy-3'-hydroxyacetophene,

Melting point = 100 ° C

NMR Spectrum (CDCl1): £> ppm. = 7.9, m, and 6.90, d, (3 benzene-2q protons) 800 4 4 34 ί 'ιί - 11 - (continued NMR Spectrum (CDC1 « )): ^ ppm = 6.55, s, (OH). = 4.10, q, (-CH 2 of O-CH 2 -CH 3) = 2.50, s, (CHgCO) = 1.40, t, (-CH 3 of O-CH 2 CHg).

5 * The structure of the two isomers has been confirmed by an NMR study of the influence of the complex formation with Europium salts on the chemical displacement of the aromatic protons (solvent CD ^ OD).

3rd stage: 4 '- (2,3-epoxypropoxy) 3'-ethoxyacetophenone (3a), 10 A mixture of 6.2g of the compound of formula 4a obtained in the previous stage, 5g of epibromohydrin and 14g of sodium carbonate in 70ml is boiled reflux acetonitrile for 5 hours. Then it is filtered, the filtrate is evaporated, the residue is taken up in a mixture of water and chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated. 6.5 g of product are obtained.

Yield: 76%

Melting point: 90 ° C

Crude Formula: C, .H., 0.

14 16 4 20 NMR Spectrum (CDCl 3): & ppm = 7.5, m, and 6.95, d, (3 aromatic protons) = 4.20, m; 3.4, m, and 2.8 , m, (5 protons οΛΔ) = 4.10, q, and 1.40, t, (O-CH ^ CH ^) 25 = 2.50, s, C0CH3

EXAMPLE IV

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

Code number 36

To a solution of 28g (5-benzyloxy-1,4-benzodioxan) yl-30-8-carphonic acid (6) in toluene, 50ml of thionyl chloride is added and the mixture is heated at 70-80 ° C for 2 hours, then the solvents are evaporated , dissolves the residue in 200ml of tetrahydrofuran and adds 1% step: 5-benzyloxy-8-methoxy: axbonyl 1,4-benzodioxane (5b) - 12-8ml of methanol and 38ml of triethylamine. The mixture is heated at 60 ° C for 3 hours, the precipitate formed is filtered off, the filtrate is evaporated and the residue is chromatographed on a silica column eluting with 100% methylene chloride. 20 g of product are obtained.

Yield: 74 $

Melting point: 100 ° C

Raw formula:

The crude product is used in the preparation of the compound of formula 4b corresponding to the compound of code number 28 in the following Table B.

In the same manner, but starting from the corresponding reagents, there are obtained the compounds of formula 5b which are listed in the following Table B and which have code numbers 21-27 and 78-83.

2nd stage: 5-hydroxy-8-methoxycarbonyl-1,4-benzodioxane (4b) code number: 28

A solution of 20 g of the compound of formula 5b with code number 20 obtained in the previous step in 200 ml of ethanol is subjected to hydrogenolysis at normal temperature and pressure in the presence of 2 g of 5% palladium on carbon. It is filtered, the solvent is evaporated and 13 g of crude product are obtained.

Melting point: 153 ° C, crude formula: C ^ qH ^ qO ,.

The crude product is used for the preparation of the compound of formula 3b corresponding to the compound of code number 36 in Table B below.

In the same manner, but starting from the corresponding reagents, the compounds of formula 4b with the code numbers 29-35 and 84-89 listed in Table B are obtained.

800 44 34 - 13 - g 3 step: 5- (2,3-epaxypropoxy) 8-methoxycarbonyl-1,4-benzo-dioxane (3b)

Code number: 36

A mixture of 13g of the compound of formula 4b obtained in the previous step 5, 25.5ml of epibromohydrin and 25.5g of potassium carbonate in 250ml of acetonitrile was refluxed for 4 hours. It is filtered, the filtrate is evaporated, the residue is taken up in methylene chloride, washed with water, then with 1N sodium hydroxide solution, dried over sodium sulfate and the solvent evaporated. The residue is recrystallized from ethyl acetate and 11.4 g of product are obtained.

Yield: 69%

Melting point: 122 ° C

Crude Formula: In the same manner, but starting from the corresponding reagents, the compounds of Formula 3b, code numbers 37-43 and 90-95, listed in Table B are obtained. 1 800 44 54 - 14 -

TABLE B

c r— t ^ 0) C r-s C C C „C q.

c «'-s o o. s * o ü) r— _ / ω r— * o O CL C <U X C Q. ^ C Q. C>. C a. O +> o O O CO O Φ C O Φ ^ -S β> # -N / o φ m

o O + * MO 4-> O O 4-> O C O- \ +> O CD

MM 0 0) 0 O MX O M O Φ O O M iH

Q. O) M> s O M O ^ M O) v 4-> UNCLE O)>

> * α xo o.> O CL> V O MO o.> -H

NOX O XO X {MO) X C

w o Ό rH C Ό O O O O \ α> »C Ό O CU

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800 4 4 34 - 15 - TABLE B (continued) ^ .- *.

s ^ c q c c -H

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8004434 - 16 - o TABLE B (continued) ^ co

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o c N - 17 - TABLE B (continued) ✓> -> '

Ή * “H

X O CL- C ^ "P >>> C: O C CL Ο Φ> 3 X X >>

C Cl ojoMCX-Ω o C O X

φ O C P CL O O -Η Ο- Φ p .'- "Yyyy O

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EXAMPLE V

5- (2,3-epoxypropoxy) -8-metboxycarbonylamino-1,4-benzodioxane (3c) code number 62

1: “OXV

1 stage: 5-benzyi £ 8 - fflethoxycarbor »ylamino-1,4, benzodioxane (5c, d) 5 code number 44

To a solution of 25 g of 5-amino-8-benzyl-oxy 1,4-benzodioxane (9) cooled to 0 ° C in 250 ml of tetrahydrofuran and 17.6 ml of triethyl amine, Iml methyl chloroformate is slowly added and allowed to react for 7 hours . It is filtered, the filtrate is immediately washed with a dilute hydrochloric acid solution, with water, with a sodium bicarbonate solution and with water. The solvent is evaporated and the residue crystallized in ethyl acetate. 17.8 g of product are obtained.

Yield: 58%

Melting point: 100 ° C

Crude Formula: C. JH, N10 NMR Spectrum (CDCl3), r 7. ,, κ. λ * t / 3: o ppm = 7.4, d; o, 5, d, and 4.3, s, (6 pro tones benzodioxane) = 6.82.3, (NH-C00-) 20 = 7.4, m, and 5.18, s (benzyl) = 3.76, s, (COOChL) IR-Spectrum (KBr): carbamate bands at 3420 and 1715 cm.

In the same way, but starting from the corresponding reagents, the compounds of formula 5c, d with the code numbers 46, 47, 48 and 52, listed in table C, are obtained.

2nd stage: 5-hydroxy 8-methoxycarbonylamino 1,4-benzodioxane (4c) code number 53

A solution of 17.8 g of the compound of formula 5c obtained in the previous step, with code number 44 in 400 ml of ethanol, is subjected to hydrogenolysis, filtered at normal pressure and temperature in the presence of 2 g of 5 / l palladium on carbon, evaporates the filtrate to obtain 11.5 g of crude product, which is used as such in the next step.

800 44 34

Yield: 90%

Melting point: 150 ° C

NMR Spectrum (CDCl 3): ppm = 7.95, s, (OH) = 7.3, d; 6.50, d, and 4.3, s, 5 (6 protons benzodioxane) = 7, fc, (NH-) = 3.78, s, (COOH-CHj d -1 IR-Spectrum (KBr) ί carbamate bands at 3410 and 1710 cm.

In the same manner, but starting from the corresponding reagents, the compounds of formula 4c, code numbers 54-60 and the compound of formula 4d, code number 61, listed in Table C, are obtained.

3rd stage: 5- (2,3-epoxypropoxy) 8-methaxycarbonylamino-1,4-benzodioxane (3C7 15 Code number: 62

A suspension of lig of the compound of formula 4c with code number 53, 23ml of epibromohydrin and 17g of potassium carbonate in 200ml of acetonitrile was refluxed for 3 hours, filtered, the filtrate was evaporated and the residue was taken up in chloroform. , washes with water and evaporates the solvent. 13 g of crude product are obtained, which are used as such for the preparation of the corresponding compound of the formula I, code 11, listed in Table I.

Melting point: 134 ° C

NMR Spectrum (CDCl 3): S ppm = 7.5, d; 6.6, d, and 4.35, s, (6 protons benzodioxane) = 6.90, s, (-NH-) = 4.20, m; 3v4, m, em 2.80, m (5 protons epoxypropoxy) 30 s 3.82, s, (C00CI-L) IR-Spectrum (KBr): carbamate bands at 3380 and 1730 cm 8004434 - 23 -

In the same manner, but starting from the corresponding reagents, the compounds of formula 3c, code numbers 63-69, listed in Table C are obtained.

EXAMPLE VI

5 5-benzyloxy 8-cyclopentyloxycarbonylamino 1,4-benzodiaxan (5c, d) code number: 50 le trap ï (5-benzyloxy 1,4-benzodioxane) yl-8-isocyanate (11)

100 g of phosgene are absorbed in a solution of 77 g of 8-benzyloxy-5-amino-1,4-benzodioxane (9) cooled to 0 ° C in 500 ml of toluene.

The temperature is then allowed to rise to room temperature, the solvent is evaporated and the residue crystallizes in warm hexane. 62 g of crude product are obtained, which are used as such in the next step.

2 step: 5-benzyloxy-8-cyclopentyloxycarbonylamino-1,4-benzo-15 dioxane (5c, d) code number; 50

To a solution of 9 g of the compound of the formula 9 obtained in the previous step in 200 ml of tetrahydrofuran and 10 ml of triethyl amine, 5.3 g of cyclopentanol are added and refluxed for 48 hours. The solvent is evaporated, the residue is taken up in chloroform, washed with water, dried over sodium sulfate, the solvent is evaporated and the residue is crystallized in warm hexane. 9 g of crude product are obtained, which are used as such for the preparation of the corresponding compound of formula 25c with the code number 59 listed in Table C.

Yield: 78 NMR Spectrum (CDCl 3): S ppm = 7.4, d; 6.5, d, and 4.3, s, (prot protons benzodioxane) = 7.4, m, and 5.05, s, (5 protons benzyl) = 5, 10, m and 1.75 m, ( 9 protons cyclopentyl) IR-5 spectrum (KBr): carbamate bands at 3415 and 1710 cm.

800 44 34 - 24 -

In the same manner, but starting from the corresponding reagents, the compounds of formula 5c, d with code numbers 45, 49 and 51 listed in Table C are obtained.

EXAMPLE VII

5 5-benzyloxycarbonylamino-5-fe, 3-epoxypropoxy) -1,4-benzodioxane (3d)

Code number: 70

A suspension of 10g of the compound of formula 4d with code number 61 obtained as described in the second stage of Example V, 20ml of epibromohydrin, 10g of benzyl alcohol and 15g of potassium carbonate in 200ml of acetonitrile, is refluxed for 6 hours. It is filtered, the filtrate is evaporated and the residue is taken up in chloroform, washed with water, dried over sodium sulfate and the solvent is evaporated. The residue is crystallized in ethyl acetate.

Yield: 75 $

Melting point: 110 ° C

Rough formula: C ^ H ^ NO ^,

Basic analysis:

C Η N

20 Calc. $ 63.86 5.36 3.92 Found $ 63.27 5.26 3.80 800 44 34 TABLE 'C .. r -25- 1 1 \ Έ § η ^ -σ I - § 1 -SO 5 «

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- o O C υ Φ 1 CC I X Φ> sJ = __.__ o a__υ__ 2 3 4 5 6 800 4 4 34 2

Φ. I

3 MM> -s * -s 4

O D to "O

5

<+ - E co r = CO

S ^ s_r 6 1 1 —......

"I

Φ ·

-OM hs CO Os O

O C SO ND ND I's υ -31-

EXAMPLE VIII

^ 3-methyl 8-n-butyloxycarbonyl 1,4-benzodioxan5-yl7 3-oxy-1- / 4- ^ f4., 5-trimethoxycinnamoyl-) piperazine-l'r yl7 propanol - (-) J chlorohydrate (hydrated) (la) 5 Code number: 72 le stage: / 3-methyl 8-n-butyloxycarbonyl 1,4-benzodioxane 5-y1 / 4-oxymethyl 1,3-dioxolane- [SJ (15)

A suspension of 14.5 g of the compound of formula 4b with code number 32, 17.5 g of the compound of formula 10 16 and 38 g of potassium carbonate in 300 ml of dimethylformamide is refluxed for 12 hours. It is filtered, the filtrate is evaporated and the residue is chromatographed on a silica column, eluting with mixtures of ethyl acetate (5-20%) / hexane (95-8%). 8g of the desired product are obtained.

15 Yield: 30 $

Melting point: 85 ° C Raw formula: ^ 2 ^ 2 $! fa? 20 = -13.2 ° (C = 1, ethanol)

D

NMR spectrum (CDCl 3): <$ ppm = 7.4, d; 6.5, d, and 4.35, s (6 protons benzodioxane) = 4.25, t (C00CH2 +) = 4.12, m (0-CH2-CH-CH2) = 1.65, m ( -CH2-CH <) 0 0 25 = 1.4, d (CH3 / 0 "= 1.95, d (CH3 2nd phase: ~ 3-methyl 8-n-butyloxycarbonyl 1,4-benzodioxane 5-yl7 3-oxy propanediol-1,2 [§ / (14) 8004434 -32-

A solution of 7g of the compound of formula 15 in 100ml of acetone and 36ml of 1N hydrochloric acid is refluxed for 3 hours. The acetone is evaporated, the residue is taken up in methylene chloride, neutralized with sodium bicarbonate, decanted the organic phase, washed with water, dried over magnesium sulfate, filtered, the solvent is evaporated and the residue is recrystallized in ethyl acetate.

Yield: 92 $

Melting point: 100 ° C

10 'Raw formula: ^ 26 ^ 24 ^ 7 / a / ^ = + 4.8 ° (C = 4, methanol)

D

NMR spectrum (DMSO): & ppm = 7.35, d; 6.6, d and 4.22, s (6 protons benzodioxane) 15 = 4.10, t (-C00-CH2 -) _ = 4.9, d and 4.6, t (OH OH) = 3, 95, m and 3.45, m (OCH ^ -CH-CH) z I jz 0 0 = 1.52, m (-CH2-CH <) 20 = 0.95, d (\ h3 36 stage: / ^ 3-methyl) 8-n-butylcarbonyl 1,4-benzodioxane 5-yl73-oxy ”1” / 4- (3 ^ 4,5-trimethoxy-cinnamoyl) piperazin-1-yl / propanol-2 £ S (~) J chlorohydrate hydrated (1a) 25 Code number: 72

To a solution of 5.7 g of the diol of formula 14 in 10 ml of pyridine and 100 ml of benzene cooled to 0 ° C, 2.4 g of tosyl chloride are slowly added. It is left to stand at room temperature for 45 hours, diluted with benzene and ether, washed with a 1N hydrochloric acid solution, then with water, dried over magnesium sulfate, filtered and dipped solvents. 7.3g (95%) of the and tosylate of the formula 13 are thus obtained, which is dissolved in 50ml of acetonitrile. 50ml acetonitrile. The mixture is refluxed for 15 hours under a stream of nitrogen, filtered, the filtrate is evaporated, the residue is taken up in methylene chloride, wait with water, dried over magnesium sulfate, filtered and the solvent evaporated. 8g (93%) of the desired compound are obtained, which is dissolved in 100 ml of methyl ethyl ketone. Then, a stream of gaseous hydrochloric acid passes through and the precipitate formed is filtered off (3g).

10 Yield: 37%

Melting point: 162 ° C

Raw formula: C00H.cClNo0iri + 4/5 Ho0 oo 40 l iU l [aj = -7.8 ° (C = 2, methanol)

Basic analysis: C Η N

% 57.63 6.96 4.07% 57.71 6.95 3.92

The compounds of formula 1 have been tested in laboratory animals and were found to have an anti-anaerous effect. This anti-angorous action has been demonstrated in anesthetized dogs (sodium pentobarbital 30 mg / kg / l. V.).

The consumption of oxygen in the left ventricle of the heart is determined by the product of the flow in the coronary artery and the difference in oxygen in the coronary artery (volume%).

The debit in the coronary artery is measured at the sinus level using a modified Morawitz cannula, which is inserted under radioscopic control.

The oxygen content in the coronary artery and vein is measured using an artalyzer for the determination of gas in the blood (IL Meter 213).

The effort of the heart is determined according to the index of Katz by the product of the mean arterial pressure and 800 44 34 -34- the heart rate.

Heart rate is determined using an EKG included in lead D £.

The systematic arterial pressure is measured in the femoral vein using a pressure gauge (Sanborn 267-BS).

The results obtained upon injection of the compounds of formula 1 and the comparative compounds Lidoflazine and Amiodarone are shown in Table D below. It should be noted that the tested compounds were injected intravenously with slow perfusion.

80044 34 "-35-

TABLE D

research [toxicity f 1 ANGIOROUS EFFICACY ~~ sought LD 50! Verbirv mg / kg / i. v. Dose reduction, decrease things mg / kg / iv the oxygen - cardiac performance code no, use____% time% 'time • (min.) (min.) - ^ -: - »-“ T -—---- -1 -'-- * -—! - '1 400 (1 ($) 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 2 ^ 00o ^ 0.15 41 15-60 21 25 9 2000 ^ 0.31 '62 45 26 30 lp.o.: / o) 10 - 0.31 69> 30 18 23 11 400 (0%) 0.15 30 30 16 30 12 200 (. <#) 0.15 47 25 18 15 13 2? P? O. x%) 0.15 49 60 18 30 14 200 «#) 0.31 38> 30 25> 45 15 100 (0%) 0.15 42 3Ö 18> 30 16 2 $? o. : Ji) ° '31 62> 45 40> 60 17 132 0.15 43> 30 17 45 18 - 0.15 40 35 24> 45 19 2 (j) 00o ^ 0.31 24 15 '25 30 71> 2000 (pó) 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 76 2000 (po) 0.15 30 30 11 45 77 "0.15 28 60 27 60 800 4 4 34 -36-.

TABLE D (continued)

constituency [ANGOROUS EFFICACY

was looking for LD 50, -. --- compound mg / kg / IV. Dose reduction from reduction of things mg / kg / IV. the oxygenated cardiac performance code no. usage% time% time (min.) - (min.) LIDO'- FLAZINE 25 1,5 48 30 40 15 AMIO- DARONE 180 10 11 15 22 15 1 1 11_1 1_% 00 4 4 34 i -37-

From the foregoing results, it appears that the difference between the therapeutically effective doses and the toxic doses is sufficient to allow the use of the compounds of formula 1 in the treatment of cardiovascular system disorders, particularly as antianglorous medicines.

The compounds are administered intravenously in the form of injection ampoules containing 60-120mg active ingredient or orally in the form of tablets, coated tablets or capsules containing 20-200mg active ingredient (1-3 per day).

800 4 4 34

Claims (5)

Novel 3,4,5-trimethoxycinnamoylpiperazine compounds, characterized in that they have the general formula 1 of the formula sheet, wherein Ar is the 4-acetyl-2-ethoxyphenyl group of formula 17 of the formula sheet or a benzodioxane group of the type of formula 18 of the formula sheet, wherein R represents the 2-methylthioethoxy chain of the formula SCH ^, an ester group of the -COOR ^ type, wherein R ^ represents a methyl, n-propyl, n-butyl, isobutyl, 2-ethyl-n-butyl, n-octyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclomethylethyl, 2-cyclopropylethyl, cyclopentyl, phenyl, or 3-methyl-n-butyl group and in the latter case the corresponding compound of formula 1, which contains an asymmetric carbon atom, is in the form of a racemic mixture of enantiomers or of the left-turning enantiomer with S-configuration, or a carbamate group of the -NH-COOR2 for-15 type. wherein R2 represents a methyl group, a straight or branched chain alkyl group containing 3 ~ 5,000 represents material atoms, a cycloalkyl group with 5-6 carbon atoms, or a benzyl group, and their pharmacologically acceptable salts. 2. Medicament, in particular for the treatment of disorders of the cardiovascular system, characterized in that it contains at least one of the compounds according to claim 1, optionally in combination with a pharmacologically acceptable excipient. 3. Process for the preparation of compounds of formula 1, with the exception of the compound in which Ar represents the group of formula 19 and the compound of formula la of the formula sheet, characterized in that 3,4,5-trimethoxycinnamoylpiperazine with formula 2 of the formula sheet condenses with epoxides in formulas 3a, 3b, 3c and 3d of the formula sheet, wherein the same 8004434 -39- 'Λ ». has meanings when in formula 1 and III represents a methyl group, a straight or branched chain alkyl group with 3-5 carbon atoms or a cycloalkyl group with 5-6 carbon atoms. 4. Process for the preparation of the compound of formula 1, wherein Ar represents the group of formula 19, characterized in that 1-chloro-2-methylthioethane is condensed with the compound of formula 12 in ethanolic medium in the presence of potassium carbonate. of the formula sheet. 5. Process for the preparation of the compound of formula la 10 of the formula sheet, characterized in that the compound of formula 2, as defined in claim 3, is condensed with the compound of formula 13, preferably in the presence of potassium carbonate. of the formula sheet. O. As intermediates for the preparation of the compounds of formula 1, the compounds of formulas 3a, 3b, 3c, 3d, 13, and the compounds of formulas 4a, 4b, 4c, 4d, 5b, 5c, d, 11, 14 with S configuration and 15 with S configuration. 800 44 34