LU80680A1 - NOVEL CINNAMOYLES PIPERAZINES AND HOMOPIPERAZINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS - Google Patents

Description

1., / *. ·

The main patent application No. T9 ^ 8 relates to trimethoxy-3,5 cinnamoyles piparazines of formula:

Ciï3 \ 5 C% 0 ^ \ - ~ CH = CH-CO-ï / ^ -CH2 - CH - CHg - Xq - ArQ (I)

(CHp) OH

Cr ^ O 2 no their preparation procedure and their application in therapy, in particular as an antianginal agent and as a peripheral vasodilator.

The present application for the first certificate of addition relates to ~ new cinnamoyl piperazines having a basic structure identical to that of the compounds of formula (lo) and having the same therapeutic properties as the latter.

More specifically, the compounds according to the invention correspond to the general formula: · · -ad R '(I) I Ü ^^ Vn

HO

in which: 25 00% represents 1s group 3, 5 trimethoxyphenyl% COy ^> _ OCH, in which case the set of parameters (n, X, m) takes; / + either the value (1? Oïï, Oxygène, 0), the radical Ar then representing: Γ "30 · IL · r M 5 - a mono or polysubstituted phenyl nucleus: —Û% in which: ... 62% rU , R,., 3j ,, 3C and simultaneously represent the following values: έ o -rjo •; Rp then represents the acetamido group, '^. Rg ^ Ri ^ R · R „represents the .acetamido or acetyl group; • δ2 = ^ 3 = "5 = ^ β = ^> \ then represents the group benzoyl, linear or branched alkyl having 3 to 5 carbon atoms, cyclohexyl, alkanoyl of which the alkyl residue contains 2 or 3 carbon atoms, or the chains cyanomethyl or carboxamidomethyl; ^; R2 represents the fluorine atom and represents the group H ^ 2 * ^ ".

v acetvle; . R ^ = Rj- = Rg = H; Rg represents the chlorine atom and R ^ represents either the nitro or acetyl groups, or the chain ïl-msthyl-carbaraoylamino; 5. R ^ R ^ R ^ R; Rg represents the methyl group and R) (represents either the chlorine atom, or the acetyl or acetamido groups; or the IT-methyl carbamoylamino sequence;. Pi2 = Rc; = B. £ = H; Rg represents the methoxy group and R ^ represents the propionyl, formyl, cyano, acetamido or IT-methyl carboxamido group; 10. R2 = P ^ = R ^ = H; represents the methyl group and represents the nitro or acetamido group or the ï-methyl- chain carbamoylamino;.? * 2 = R6 = H »R3 e ~? '5 represent the methyl group and R ^ represents the chlorine atom;. E ^ = Rg = H; Rg and R ^ represent the methoxy group and R ^ the group 15 R-methyl carbamoylamino;. R ^ = Rj- = H; Rg and Rg represent the chlorine atom and R ^ represents the acetyl group or the chain Îî-methyl carbamoylamino;. R ^ R ^ H ; Rg and Rg represent the methoxy group and R ^ represents the acetyl or ethyl carboxylate group or the chain 17-2! Ethyl carbamoylamino;:. R = fl; R,, P.,. And R ,. represents the methoxy group and H represents the f ^ d U- p o c.

acetyl group; V & '- a. heterocycle of formula W "'9 in which: p, R ^., Rg and 25. Ηλ R ^ nrend simultaneously the following meanings:. Q ~ y. ρ = 2; R ^ = Rg = H; represents either the group hydroxy, acetoxy, methoxy, cyano, alkoxy carbonyl in which the alkyl residue is linear or branched and contains 3 to 5 carbon atoms, cyclo hexyloxy '30. ^ carbonyl, carboxamido, ïï-cyclohexyl carboxamido, li-phenylcarboxamido, alkanoyl amino whose linear or branched alkyl residue has 2 to 5 carbon atoms, cyclohexyl carbonylamino, benzoylamino, H-alkylcarbamoylamino whose linear or branched alkyl residue has 2 to 5 carbon atoms, 'O ^ H- (paramethoxyphenyl) -carbamoylamino, li-R-dimethyl carbamoylamino, morpholinocarbonylamino, K-M'-dimsthyl carbamoylamino or ethoxy carbonylamino, either the chains ethyl acetate, carboxamido methyl or N methyl carboxamido methyl;. p = 2; E ^ = Rg = H ; Rg represents the acetyl group; 40, p = 2; Rg = R ^ = H; R ,, represents the acetamido group; * * 3 *. p = 1 or 3; R ^ = Rg = H; represents either the hydrogen atom or the acetyl, acetamido or N-methylcarbamoyl amino group;

-Fr

- a naphthalene nucleus of type 10 in which R ^ q represents an acetyl, acetamido or N-methyl carbamoyl amino group; - a heterocycle of the type / \ ^ in which q takes the values 1 or 2 and R10 has the same meanings as previously, R1Q cannot however represent an acetyl group When q = 1; - 10 - the motif of formula (cxo-1, tetrahydro 1-2-3-b naphthyl-6 of formula - + either the value (2, OH, Oxygen, 0), the radical Ar then representing: 15 ~ or a aromatic motif of the type: - ^ I ^ C0CH ^ ans which represents

hydrogin atom or methoxy group V

-Fr

- or a heterocycle of the type d ~ a in which R ^ has the same signi fication as previously; , 20 + or the value (l, H, Oxygen, 0), the radical Ar then representing a "~ O" R12 heterocycle of the type: in which R represents the acetyl group, acetamido, N-methyl carboxamido or N-methylcarbamoylamino; + either the value (1, OH, S, 0), the radical Ar then representing: 25 - either an aromatic unit of the type ~ ^ 3'C0CH ^. in which represents R11 the hydrogen atom or the methoxy group, „ -Oh * 30 - or a heterocycle of the type / Λ 13 in which R represents v_9 the hydrogen atom or the acetyl group.

+ either the value (1.0H, -N-, 0), the radical Ar then representing the phenyl group, ch3 h ... ................... ..... k .......... ...............................

V ’· '.

»+ Either the value (l, OH, O-tygsus ·» l), the radical Ar then representing the '"N. phenyl group, == represents: 5 + either the U-fluorophenyl group; 3.5 dinethoxyphanyl, or 3, ^ ~ methylene-dioxyphenyl; Cïï3 ° + is an aromatic unit of the type in which represents CH3 ° the hydrogen atom or a linear or branched alkyl residue having 2 10 to 3 carbon atoms ^ which case all parameters (n, Rj s xj a) takes the value (î, OH, "Oxygéna, 0) and the radical Ar represents the motif COCH ^

O O

,. , 0CS3 W

15 - represents the pattern in which case 1 ’set of parameters (η, P ^, X, m) takes the value (1, OH, Oxygen, 0) and the radical

Ar represents the motif - ^ “^ -. COCH ^“

CH

The process according to the invention for the preparation of the compounds of formula I, with the exception of the following 7 compounds of formula I, namely: '[' + the compound of formula I in which the representative HO—— + · is compound of formula I in which X represents the group mettylamino t -H-. · · 25 CH3 + the compound of formula I in which Ar represents the unit and, _ + the four compounds of formula I in which R, {represents the hydrogen atom, consists in condensing a piperazine or a homopiperazine of formula (il): R 'Γ ^ ΐΐ N î! -H (II} 35 · 0 in which n takes the values 1 and 2 and has the same if unifications as Λ — in formula I with the exception of the value U0 CH 0 KO -fV- ..... ....................................... .................. 5 '\% “- <with an epoxide of formula (III):

Ar '(IJI) 5 in which Ar' has the same meanings as Ar in formula I except for the value / = \ ng and X 'represents the oxygen or sulfur atom, or with aMv> l 2,3 epoxy benzyloxy-1 propane to obtain the compound of formula I where \ _ / m = 1.

This condensation is preferably carried out in ethanol at reflux. lO According to the same process as above, but using suitable reagents, the compound corresponding to formula (la): 0H3 ° \ will also be prepared.

15 εΗ3ε0αΟ ^ γΟ '^ Ύν ^ 00 ^ (Ia)

CH3 ° / ^ 0 oh O

The new composites of formula II, in particular those corresponding to formulas 20 (m>) and (lia): \ „.çh p. . -Q. ....

. „(Iib) ch3 ° ^ 25 0 '·“ (lia) "30.

R "in which represents the following aromatic groups r 35 0CH_ ¢ .11 q Λ \? 3 v_? -F \ - 3_Q iQ— CHjCOCL ^^ - ~ CH-0 ^ CH_0 '^ = ^ 3 3 nir r CH-, 0

Cd30 ^ 3 \ tO c2H5 ° —C5— or. ") 0 — Cj / Λ GH_0" Cï30 ^: T · ν 6 * * * are obtained by condensation of the compounds of formula (iV) and (IVa) CV \ '5 CK3 ° - (Iv) CH30 x 10 R ,; 0 ^ YC1 (ITa) 0 15. .

in which H ”has the same meanings as in lia with 1’ homopiperazine and piperazine respectively. This condensation is preferably carried out in solution in acetic acid.

The new comooses of formula (IVa), in particular those for which. * CK_0 CH 0 20 R "_„ represents the units -'v. "J> C2ÎI ^ β4> -? Γ ^ - are obtained by the action of thionyl chloride in toluene solution on the corresponding cinnamoxic acids of formula (v): 2 "0CH3 B, ll4.0 ^^ 3Sv ^ NkCOOH (V)

0CiS

in which R ’^ represents the ethyl and isopropyl groups.

The compounds V are obtained by saponification of the ethyl esters of the corresponding cinnamoic acids of formula (VI): ch3 ° ^ R · (VI) CH, 0 '35 3 1ms which 3 * ,, has the same meanings as in (V) .

The composites of formula VI have been used crude and are prepared by the action of ethyl iodide, or isopropyl iodide on the ethyl ester of sinapic acid, in solution in acetonitrile and in the presence '..... τ w of potassium carbonate.

"

The compounds of formula (ill) ^ X’-Ar ’(ill) σ 5 are partly new and in particular those for which: - X’ represents an oxygen atom and the radical Ar ’represents:

RV

X / 5

A) a mono or polysubstituted phenyl ring:, _ \\ __ R

10 R '^ NS'j in which R ’^, R' ^, E '^ a and R’g simultaneously represent the following values:. R’3 = R’5 = R'6 = H; R’2 = F; R '^ COC: ^. R'3 = S · = R * g = E; r, 2 = och3; R ’^ COCH ^, COSt 15. R’3 = R’5 = R’6 = H; R’2 = C1; R ’^ COC ^, ÏTO ^

. R1 _-R * = RV = H; R ’= CH; R ’, = 110. , KH-COIIH-CS

250 33 42 3. R "-R * g * H; R'2 = R’3 = 0Chr3; R'u * NHCŒIÏÏ-C ^

. R * = RV = H; R '= RV = C1; R ’, = C0GHo, îIHCONHCH

3 0 2 o 4 3 3. R · 3 = R ’5 = ïï; R '2 = R' g = 0CH3; R j ^ COCF ^, COOEt, or HHCOHEGH ^ 20 · R'3 “H; rt '^ RyR R’2 = C0CH3. Λ · Ε, 2 = Β, 3 = Χ, 5 = Κ, 6 = Η. *.

R’7 R’o ^ / 8 · b) .a heterocycle of formula - in which 25 H · P "R’ο ·" R * o and Ri take simultaneously the following values: 7 O y =. p = 2: Η ’^ = Η'β = Η; R '^ represents the metioxy ·, acetoxy, cyano, alkoxyearbonyl groups in which ”5 30 the alkyl residue is linear or branched and contains from 3 to .6 carbon atoms, cyclohexyloxy car’oonyle, carboxamido,. H-cyclohexylcarboxamido, lî-phenyl carboxamido, ^ alkanoyl-amino in which the linear or branched alkyl radical has from 2 to U carbon atoms, cyclohexylcarbonylamino, benzoylantino, -35 îl-alliylcarbanoylamino in which the linear or branched alkyl radical has from 2 to 5 carbon atoms, li- (paramethoxyphenyl) carbanoylamino, Ιΐ, Ν dimethylcarbamoylamino, morp'aolino carbonylanino, lî-K 'dimethyl carbamoylamine or e fchoxyearbonylamino or alternatively HO sequences ethyl acetate, carboxamidomethyl or / 3 * “*“ ϊί- mé t hy 1 ca rbox baby friend t hy 1 e.

. p = 2; R ’^ = H '^ = H; R’g represents the acetyl group.

. p = 2; R’g = R '^ = H; R '^. represents the acefcartido group. p = 1 or 3 5 R ’^ - R’g = H; R '^ represents the acetyl, acetanido or li-raethylcarbanoylanino groups c) a naphthalene nucleus of type _ ^ j \ _R10 w in which R ^ represents the acetyl, acetanido or Ii-msthylcarbamoylamino groups j _ / Γλ_ρ · 10 d) a tyoe oc heterocycle. in which q and R ', “take 10“ simultaneously the following values: q = 1 in which case R' represents the acetanido groups and If-methyl— c art) amoylami η oq = 2 in which case R '^ represents the acetyl groups, acetanido and 15 E-methylcarbamoylamino Ö e) the motif î and - X 'represents a sulfur atone "and the radical Ar' z-epresente: 2Ô f) an aromatic notifier of the COCH type ^ ^ · | ... ... Pt11 in which R ^ represents the hydrogen atom or the nethoxy group. G) heterocycle lin of the type - ^ - R-jg in which R ^ represents the hydrogen atom or the acetyl group.

The compounds of formula (ill) result from the condensation of the phenols of formula (Vil): H - X * - Ar * (VII)? In which X 'and Ar' have the same meaning as in formula (III), with epichlorohydrin or 11 epibromhydrzne. This condensation is preferably carried out at reflux in acetone or acetonitrile, in the presence of carbonate potassium.

The compounds of formula VII above are partly new and are then prepared by various methods depending on the nature of X * and Ar ’.

More precisely: ί) the compounds of formula VII corresponding to the formulas (VI Ja} 3 (vilt), and (Vile):

ho

...... '..... -4 4 ^. φ .. .. ^ 9 k * R "R" v / HO ——ïIH-CO-îïH-CK ^ (Vlla) 5 in which R ”2, -R '^, R" ^ and R''g simultaneously the following values: R "3 = R''5 = R" 6 = H; R "2 = CH0 10. R "5 = R" 6 = H; Rm2 = R ,, 3 = 0CK3

. R ’’ = R ”= H; R ”= R” = C1 3 j. d O

. Rn3 = R’'5 = H; R ”2 = R’t6 = 0CH3 '! 15 H0 _ ^ - IIH-COîIH-CH3 (Vllb) 2: 3 H0H ^) - NH-C0NH-CH3 (VTIc) \ _ (C ’) r ·. : 2¾ in which q takes the values 1 or 2; 25 are obtained by the action of methyl isocyanate, in chloroform solution, respectively on the amino phenols of formulas R’V R ’’ 5 HO. _ (/% - HH. (Villa) T 30> <r / ^ r ”3 in which R” 2, R "3, R" ^ and R "g have the same meanings as in (ma-), 35 ÏÏH2 (VlIIb), and H0_ (f ^ _M2 (VTITc) to 0ch \ ~ 10 - “Λ in which q takes the values 1 or 2.

2) the compounds (VIi) corresponding to the formula (ΥΙΙά): KO - (Vlld)

J

10 in which q takes the values 1 or 2 / are: obtained by condensation of acetic anhydride on the compounds (Ville) in aqueous solution.

3) the compounds (Vil) corresponding to the formulas (vile) andCviIf): 15 hs_AA_coch (Vile) «* c io HS-0-R, 3 (ïllf) 0 0 · f N_ / \ * a 25 in which represents the hydrogen atom or acetyl group are obtained by treatment with a sodium hydroxide solution in methaiol v of the compounds of formula (iX) and (iXa), T 30 CV ^ _s — c0cH3 (IX) CH3 0 OCH ^ 7 3 * 135 Cïï_ r-, ^ 777 ^ 0- ^ (IXa) CH ο '<S >>

Ho in which represents the hydrogen atom or the steel group.

Compounds (IX) and (XXa) are obtained by thermal transposition of compounds (X) and (Xa) 11 r "CH3 \ 5 ch ^ î! 'Y ^ °' ^>. Coch3 (X) οοκζ ^ (Za>

O O

W

in which has the same meanings as in (iXa).

The compounds (X) and (Xa) are themselves obtained by condensation of i-N-diraithyl thiocarbamoyl chloride with the phenols of formulas HO coch3 s) OCH ^ f 29 3. . - Γ '. (seen h.) o o J_l 25 H0 - ^ - COCH ^ (Vil x)

00 \ _I

T 30 k) The compounds of formula (VII) corresponding to the formula (Vllk): R’J-R’g

.HO R "9 (VII

’0 ^ 0

(CKJ

35. 2'p.

in which p, R "^, R" ^ and R "^ take simultaneously the following values: ^ 0. p = 2; R" ^ =: R ,, g = H; R "^ represents either the acetoxy or cyano groups.

12 aicoxy carbonyl in which the alkyl residue is linear or branched and contains from 3 to 5 carbon atoms, cyclohexyloxy carbonyl, carboxamido, N-cÿclohexyl carboxamido, N-phenyl carboxamido, 5 alkanoylamino in which the alkyl residue is linear or branched and contains 2 to 5 carbon atoms, cyclo— 'hexylcarbonyland.no, benzoylamino, fl-alkylcarbamoylm.

amino, the alkyl residue of which is linear or branched and contains from 2 to 5 carbon atoms, ïï-paramethoxyphenyl carbamoylamino, N-ÏT-dimethyl carbamoylamino, morpholinocarbonylamino, ïï-ïï ’dimethyl carbamoylamino or ethoxycarbonylamino; or the sequences of ethyl acetate, carboxamidomethyl and N-methylcarbo-xamido methyl.

15 * p = 1 or 3; E "= R" g = H; R "^ then represents the acetyl, acitamido or N-methylcarbampylamino groups, ^ '2o are obtained by hydroginolysis in the presence of palladium on carbon of the compounds of formula (Xi) B" rh "8'; <Qo ^ L,.! ( XX) v: (Cf ^ P!! 3 °. ·...

in which p, 3 "^, R" g and R "^ have the same meanings as in (Vllk) Λ 13 *» 4 «

The compounds of formula (XI) above necessary for the preparation, compounds of formula (VII k) are partly new and are obtained by different methods according to the nature of p, RMg and R ”^ -

Similarly, is new the compound of formula (ZCEaJ: 5 Ο-0Λ ° 0Η3 Cxia)

O

* which can be used for the synthesis of a compound of known formula (VII> *) 10 - η ° - ^ ° οη3 \ J> (vil k ') 15 More precisely: 1) The compound corresponding to the formula (Xïa) ret {V- ° <V> ch3 (xïa) 20 is obtained by the action of methyl sulfate. On the compound of formula (XIII) ~ 25 O ^ ° -Q-0H (XIII)

• T O

The compound (XIIl) is obtained by the action of ootassiura carbonate on the compound (XI b; following: * / h „t u tu 6 0-0- ^ 0000¾ (XI b) \ _ / ° 5 which is itself obtained by reaction of Baeyer Williger on the compound of formula: (XIV) 0 0 10

The compound ΧΓ7 is obtained by the action of · benzyl chloride '"in solution in acetonitrile or acetone, in the presence of potassium carbonate on the compound (YII · / ·): 15 / - \ K0 _ / ^ _ £ 0CH3 (Vil.) 20 2) The compounds (XI) corresponding to the formula (Xï c): ^ —'0 - ^^ “C00B.jcj (XI e) 0 0

W

In which 5 ^ represents the isopropyl, tert-butyl, n-pentyl or cyclohexyl groups are obtained by a two-step synthesis which consists in "treating the compound of formula: f 30 0 ^ 0 - £ V C00H (xv)

w H

o o N_t, 35 with thionyl chloride and then reacting on the brown product thus obtained the alcohols of formula b0 R15 ~ 0H (XVI) 1. * 15 * in which has the same meaning as in formula ^ le) 5 The compound of formula XV is obtained t> ar oxidation.

by the iodine-pyridine complex, in the presence of sodium hydroxide, of the compound of formula .: ’0_Q_ COCÏtj (XIV)

10 V

3) The compounds (Xi) corresponding to the formula (XXd) 15 0 / VO - ^^ - C0M-Rl6 (XI d) 0 0 \ _y F 20.

in which represent either the hydrogen atom or the groups. cyclohexyl or phenyl are obtained by a two-step synthesis which consists in treating the compound of formula (XV) with thionyl chloride, then in reacting on the crude product thus obtained the amines of formula * 16 ~ IÎH2 (XVII) In which represents a hydrogen atom or a cyclohexyl or phenyl group.

35 U) The compounds (XI) corresponding to the formula (XI e} 0 — EH-C0-R, T ^ * v_ /

Uo in which represents either a linear or branched alkyl group having

U

* Ιζ "from 2 to 5 carbon atoms, either the cyclohexylef group or the phenyl group, are obtained by the action of the acid chlorides of formula; R ^ COCl (XVIII) - 5 in which R has the same meanings as in Xle, on the compound · of formula: 0 ^ o _ ^ _ m2 (XIX) 0 0 10 \ _1 in a tetrahyrofuranic medium.

5) The compounds of formula (X3) corresponding to the formula (Xlf) o - ^^ - M-C0Z1H-R18 (Xlf) 0 0 ..

20 ^ CH / p f- 1 '' in which p and R g simultaneously take the following values:. p = 2; R.g represents either a linear or branched alsyl group having 2 to 5 carbon atoms. Or paramethoxyphenyl, '. p = 1 or 3; RiQ represents the methyl group, ^ are obtained by the action of isocyanates of formula ’f 30 R18 îico. (XX) on the compounds of formula (XIX) above and (XIXa): “35 0 ^ ° - ^ NH2 (XIXa) 0 0 \ / lo in which p / takes the values 1 or 3i Μ ** '17 6) The compound (Xi)> corresponding to the formula (zi g) ο - / '"A-JIH-COOC ^ 0 0 (XI g) 5 w is obtained by the action of ethyl chloroforsiate on · the compound of formula ( XIX) 'above.

The compounds of formula '(XIXa) used in the syntheses given "' 10 under points H) 5) and 6) above are new and obtained by hydrolysis with ethanolic potassium hydroxide of the compounds of formula (XIîx) 0 ÏÏHCOCI ^ ( XI b) 15 ο o

'H

in which p takes the values 1 or 3 [, The compounds of formula (XIh) are obtained - 20, by a Beckmann rearrangement, in acidic medium, of the compounds of formula '. : / - {. 1Ί — OH 0 0 25 CC ^ p, in which p * takes the values 1 or 3; 30 s t f 35 h 18

The compounds of formula (XXI) above are obtained by the action of hydroxylamine on the compounds of formula (Xli): 0 ^ 0 (xxi) ΓΛ \? (Œ2> p · in which p 'takes the values 1 or 3 *

The compounds of formula (Xli) are themselves obtained by the action of a diode or dibromo derivative of formulas (XXII): s J:, I- (Cii2) p, - I or Br- (CH2) pt - Br (XXII ) in which pT takes the values 1 or 3 on the compound of formula: ("h,

OH OH

* ί · * F '19 5 * in solution in dimethyl sulfoxide, or U-N-dimethyl formamide in the presence of potassium hydroxide.

The compound (2Œ1I) is obtained by the action of benzyl chloride on 10 · gallaeetophenone.

7) The compound (Xi) corresponding to the formula (XI j):

CH

° —h / 3 îvt *> \ = / y-χ XC0ÏÏH-CK_ (XI J) ir 0 0 3 V_y: is obtained by the action of methyl isocyanate on the compound: j 20 - \ y— 0 0 ( XXIV).

i,

The compound (XXIV) is obtained by a two-step synthesis which consists in treating the compound of formula (XIX) with a mixture of 5% formaldehyde and 5.5-dimethyl hydantoin in ethanolic solution, then in making react on the crude reaction compound with sodium borohydrid in solution in dimethylsuLfoxide, at a temperature of 100 ° C.

8) The compound (XI) corresponding to the formula (XI k) 30 O ^ 0 -p-te-CO-lQo (xi k)

O

"S ^ is obtained by the action of morpholine at reflux on the compound of formula (XI g) kb. - 20 ...

! r \ ^ ° ._ ^ 0_HECOOEt (jŒg) Ό0 5 9) The compound (XI) corresponding to the formula (XI l) / -λ! / V \ 0 —V \ —- Î'IH-COîïf '5 »V = /) = ((XI 1) 0 0 w 5 10 is obtained by the action of II-ff-dimethylearbamoyl chloride on the compound of formula ( XIX): 10) The compound (XI) corresponding to the formula (XI m) (TV ^ O —CH - COKH, 15 WH (XI m) U. 'Is obtained by treating the compound (XI n) with potassium hydroxide solution in tertiobutanol 20 \ (XLn) * 0 0 Ï vy · i '> resulting itself from the action of sodium cyanide on the compound of formula i V j 2q The compound (XXV) is obtained by the action of chloride of thionyl on the compound of formula: o - ^ - ch2 oh (xxr) 11) The compound (XI) corresponding to the formula (XI o) jo * -f \ - ch2 cokh_ch3: 35 00 (XI o) \ - / λ ”and λΉ + .οπιι mi · ηητ-Αηη Λρ methvlamine according to the procedure for anhydrides 21: 'CH2 ~ C00H (XXVI) 0 0 i \ J. ! |

The compound (XXYl) is obtained by saponification with an aqueous sodium hydroxide solution of the compound (XI n).

12) The compound (XI) corresponding to the formula (XI p) ^ ”^^ 0 - Cîi 0_J> (XI p) 10 is obtained by the action of phosphorus pentachloride on the compound (Xld) for which represents the atom d 'hydrogen.

13) The compound (XI) corresponding to the formula (XI q) ° -O — ch2_co0 c2e5 15 ~ 0 0 (XI q) \ _y.

is obtained by the action of ethanol in the presence of hydrochloric acid on the compound of formula: i 20 ch2-cooh (XXVI) θ '0 \ _ /

The process according to the invention for the preparation of the compounds of formula I in which:> V i - represents the unit - (^ V "-0E or aans which; 0CE3

- the radical Ar represents the motif_j ^ y_0H

30, Ö consists in hydrolyzing the aeetoxy group of the compounds of formulas (la) and (Ib) 3a

0CH

25 0 - £ V-C0CH3 (la) 0C ^ 0 0H 00

W

CH3 ° \ lo Y I> <3 i h.

22 with an alcoholic solution of baking soda.

The compounds of formulas (la) and (Ib) are obtained by a process identical to that used for the synthesis of the compounds of formula (I) described above.

The process ^ according to the invention for the preparation of the compound of formula (I) in which X represents the methylanino group: "'ΊΊ'" ". K consists in condensing an epoxide of formula (illh) 10 CH30 _ j / xZX ( nih) | CH 0 * ^..-1 0 15 with N-methylaniline in alcoholic medium.

The compound of formula (III.h) is' obtained by condensing epibromomyctrine on latrimethoxy-3, ^, 5 cinnamoyl piperazine of formula (lie): 20 · ch3o 0 * (Ile)

CH3O

25 * in solution in 1 * acetonitrile, in the presence of potassium carbonate.

The process according to the present invention for the preparation of compounds f of formula I, in which represents the hydrogen atom, consists in condensing the ninerazine of formula (II) above with a chlorinated derivative of formula C

Cl / \ / \ 0 ——R., “W 12 (XXVII) · · 35 0 0

W

in which R ^ represents the acetyl, acetamido, ï-methyl carboxantido or II methylearhamoyl amino groups, in solution in acetonitrile, in the presence of potassium carbonate.

23

The new compounds of formula (XXVII) are obtained by condensation of 1-bromo-3-chloro propane with the phenols of formula (VII): H - X * - Ar * (VII) 5 in which X1 represents the oxygen atom and Ar 'represents the pattern in which R ,? has the same meanings as in the formula cQb '(XXVII).

10

The following preparations are given as examples to illustrate the invention.

AT

i- S * 2k

Example 1: ["* (2-methyl acetate / l-k) 3-phenyl hydroxy -2 propylj -1 (trimethoxy -3, h, 5 cinnamoyl) ~ h Operazine hydrochloride (1) code code: 770 993

A mixture of 9.2 g of trimethyloxy-3, ^, 5 cinnamoyl piperazine and 6.2 g of (2-methyl acetyl- pberyl} -! 2,3-epoxy propane in 65 ni of ethanol, then the solvent is evaporated off, and the residue is chromatographed on a column of silica, eluted with a chloroforn-mefchanol mixture: 93% / 2% · 12 g of an oil are obtained which are dissolved in Acetone-. We then s pass a gaseous stream of dry hydrochloric acid to acidic pH, then the precipitate obtained is filtered.

Yield: V? % '-

Melting point: 1 ^ 0 ° C Crude formula: C ^ gK ^ ClH ^ O ^ * Molecular weight: 5 ^ 9.05

Elementary analysis:

C H B

Calculated% 61.25 6.79 5 »! 0 φ = Found $ 6l, 12 6.62 5» Oh \ ^ '* By the same process, but from the corresponding reagents, we obtain the compounds of formula I listed in Table I follows-^ ^ except the compounds of formula I for which F. = ïï which are obtained according to the orocédé of Example 3 "compounds of code number J702Jh, 73 -,„ nr ,, -. _ ί “3120. .Contents in example 2) and 770 ^ -95 (obtained in example h).

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Sxsnple 2: £ (acety-U ethylene dioxy -2.3 phenoxy) -3 hydroxy-2 propylJ-1 (dirr.athoxy -3.5 hydroxy - ** cinnamoyl) -! * Piperazine; oxalate (i)

Code number: 770 2h

A mixture of 9.6 g (0.0155 moles) of 5 Qacetyl -U ethylene dioxy -2.3 phenoxy) -3 hydroxy-2 propyVj-1 (dimethoxy -3.5 acetoxy-1 is brought to reflux for 5 hours. * cinnamoyl) -! * piperazine (1¾) (used raw) and 3.9 g (0.0 ** 65 moles) 3 t of baking soda in 60 cm of ethanol. Then the solvent is evaporated, the residue is taken up in acetone and a solution of 1.1 * g (0.0155 mole) of oxalic acid in acetone is added. Filtered, thus obtaining 6.3 g of product. _ '10. ''

Yield: 65%. Melting point: 170 ° C - -

Crude formula: ¢ 30¾¾0 ^ + 3Λ HgO ’Molecular weight: 61 * 6.12 15 Elemental analysis

C H N

Calculated% 55.76 5.85

-20 Found% 55.81 5.7V MT

j .. By the same process, but starting from the compound of formula (1¾) te.

OCH, 25 0C0CÎI3. (¾)

Jr S ok 'f \ 0Cn3 0n 30 with coda number 780OOI * we get 1' £ (hydroxy-t ethylene dioxy -2,3 phenoxy) -3 .. hydroxy-2 propyll-1 (trimathoxy-3, t, 5 cinnamoyl) -U piperazine; hydrochloride hydrate

Code number: 780 120 ’Efficiency: 22%

. 35 Melting point: I7U0 C

“_Rough formula: C ^ H ^^ ClI'IpO ^

Molecular weight: 535.0 **

Elementary analysis: 1 * 0 Λ ‘'53'.

C H K

Calculate $ 55M - 6.31 ^, 79

Found% 55.25 6.22 5.00 ^ Example 3: £ (acetyl-h ethylene dioxy-2,3 phsnoxy) -3 propylj- '; (trimétfcoxy -3 Λ, 5 cinnamoyl) -! + pipêrazine (i)

JoO code number 939. 1st step ; (acetyl '·', —U ethylene dioxy —2.3 pnenoxy) —3 caXoro — 1 propane (XXVII) 10 'This compound is obtained according to the same procedure as eu 1' (acetamido-k ethylene dioxy -2.3 phenoxy ) -3 ehloro-1 propane with code number-TT1 17-1 For which:

The mixture is refluxed for three hours, a mixture of 25 g of acetamido -y hydroxy-8 benzodioxane, of 50 g of. potassium carbonate and 35.5 ml of 1-bromo-1-chloro propane in 500 ml of acetonitrile. Then filter, evaporate, and recrystallize from ethanol. 30 g of product are obtained.

Efficiency: 83%

Melting point: 163 ° C 20 "RM spectrum; (DMS0) bppm: j- 6, 51, d; T, 22, d; L, 20, s: 6 let’s take benzodioxarmiques 9.31, s and 2.00, s: NE-C0CH3 U, oo, t (j = 6hz) -o-ch2 ^ \ ^ ci

25 3.7 ^, t (J = oHz) -O

2.07, t (J = 6ïz) -0 ^ \ CE9 ^ \ C1 ·

IR spectrum: îîHCOCH ^ bands at 1660-1555 and 3330 cm ^

By the same process, but from the corresponding reagents, the compounds of formula (XXVII) are obtained, listed in table II below * · 30 35 '

L

ho A _

TA3LEAU II

. D-A-R-0 (XXVII)

‘Y = C

5 ° W °

Code number -H ^ p Efficiency point RHM spectrum or fusion ° C% analysis. . elementary ‘10 TT 1162 -COHÏÏ-CH 103 100 RM (DM30) Snpm: T, u (J = 1QÊ2l); 6.5 d (J = 10 Hz) and 3.3 s (6 benzodoxyannan protans) T, 8 (m) and 2.83 d (T = 5 Hz) COHHCH (J = 6 Hz); 3, T5, t, (J = 6Hz) and 2.1 q. .

15 (J = 6Kz) O ^ X / ^ JCl T80039 -NHCOïïHCE 216 το. ’J C H li.

Calculated ^ 51.92 5, TO 9.32 Found% 51.68 5.5T 9.33 20 _. _- __ ί -. 2nd stage: £ (acstyl-U ethylenedioxy-2,3-phenoxy) -3 propylj-1 (trimethoxy “3, ^, 5 cinnamoyl) - ^ piperazine (I) A mixture of 15.3 g is brought to reflux for 12 hours (0.05 moles) of trimethoxy -3, ^, 5 cinnamoyl piperazine, of 13.6 g of (acetyl -U ethylene-dioxy -2,3 phenoxy) -3 chloro-1 propane, crude employee, and of 20 , T g of potassium carbonate in 100 ml of acetonitrxle. Then, the mixture is filtered, the solvent is evaporated, the residue is filtered on a column of silica, eluted with chloroform, and the product obtained is crystallized from ether.

5 g of product are obtained.

Yield: 21%

Melting point: 13¾. ° C Crude formula: C ^ H gî ^ Og 35 Molecular weight: 5 ^ 0.59

Elementary analysis:

CHU

Calculated% 6k, k3 6, T1 5.18 fcO 'Found% 6 ^, 10 6, TT 5.00 ‘55

By the neme proceae but from the corresponding reagents on. obtains the compounds of formula (l) listed in Table I and bearing the coda numbers: 7711o3> 771172 and 7δ00ΐ0.

Sxeraple 1: £ (N-methyl-3-hydroxy-2-hydroxy) -propylJ-1 (trimethoxy -3,1,5 5 cinnamoyl) -! piperazine, hydrated oxalata (i)

Code number: 770 ^ 95 • 1st stage: (epoxy -2,3 propyl) -! (trimethoxy -3Λ> 5 cinnamoyl) -! piperazine. "

Code number: 770319 10 A solution of 6l, 2 g of trimét-hoxy-3,1,5 cinnamoyle pipérazine, 137 g of epihromhydrin and 133 g of potassium carbonate in 300 ni is brought to reflux for 8 hours. 'acetonitrile- Then, the solvent is evaporated off and the residue is chromatographed on a silica column. Elected by chloroform, we get the product that we.

15 'crystallizes from ethyl ether.

Weight obtained: 26.1 g Yield: 3o%

Melting point: 12o ° C Crude formula: 2Ö Molecular weight: 302.11 | Elementary analysis: I *

25 C H N

Calculated% 62.96 7.23 7.73

Found% 62.18 7.33 7.17. 2nd stage: dd (iT-nêthyl anilino -3 hydroxy -2) -propylj-1 '30 (trimethoxy -3,1,5 cinnamoyl) -! piperazine, hydrated oxalate

We. carries 93 hours at reflux, a solution of 3.62 g (0.01 mole) of (epoxy -2.3 propyl) -1, (trimethoxy -3.1.5 cinnamoyl) -! piperazine (IIIh) and 1.07 g (0.01 mole) of N-methyl-aniline in 20 ml of ethanol. Then the solvent is evaporated, the residue is taken up in chloroform, extracted with an aqueous solution of methane sulfonic acid, basifies the aqueous phase using sodium bicarbonate, extracted with chloroform, evaporates the solvent, takes up the residue in lo acetone and adds 0.75 g of oxalic acid in solution in 10 ml acetone. Then, we filter. 1.9 g of product are obtained.

-, 56

Yield:%

Melting point: 15I0 C Gross formula:

Molecular weight: 615,127 5 Elemental analysis: c h ir,. Calculated% 56.5k 6.12 6.83 10 Found% 56.80 6.23 6.82

Sxeixsle 5 * · parafluoro cinnamoyle piperazine lia Code number: 770125 To a tolusniq.ua solution of 20 g of parafluoro cirmamoiaue acid, on.

3 15 add 20 cm of thionyl chloride, and bring the mixture to 70-80 ° C for 1 hour.

The solvents are then evaporated off, and the residue is slowly added (11 g) to a solution of 13.2 g of piperazine in 150 ml of acetic acid. The mixture is left in contact for 3 days at room temperature and then the solvent is evaporated, the residue is taken up again. 20, in a mixture of chloroform and dilute hydrochloric acid, decant and basifle. the aqueous prase with a concentrated sodium hydroxide solution, extracted with chloroform, washed with water, evaporates the solvent and filters the residue on silica. Ort obtains 11.5 g of product.

Yield: If%

25 Melting point: 90 ° C

NMR spectrum: £ ppm = o, 82, d, and 7.68, a, (J = 16 Hz) -CH = CH- = T, 52, m, and 7.08 m, aromatic protons = 3.62, mf 2.91, El} and 1.92, s, piperazine protons.

30 For the process marl but from the corresponding reagents we obtain% -the trimesnoxy “3,1,5 ennanoyl homopiperazine hydrochloride (11 ^) with code number 760360:

Yield: $ 73

Melting point: 151 ° c 35 / Gross formula: C ^ H ClNgO ^ + hgO

Molecular weight: 371,859 Elemental analysis: 10 57.

C Η Ι · Γ

Calculated% 5Mi 7.26 7, ^ 7

Found% 5 ^, 52 7.26 7.3½ - the compounds of formula \ 31 a) appearing in Table III below ^, and '^ —1'acetoxy — U tithe tlioxy — 3,5 cinramoyl piperazine Iüâ yes is used crude for the synthesis of the compound used it in Example 2.

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59 Λ

Example 6: ethoxy-U 3,5-dimethoxy-cirmamoïque (V) code number: 770 ^ 31

A solution of 100 g of ethyl ester of sinapic acid, 203 g of ethyl iodide and 18 k g of potassium carbonate in 1500 ml of acetonitrile is brought to reflux for 6 hours. Then, the mixture is filtered, the filtrate is evaporated and the residue is recrystallized, which is dissolved in a solution of 36 g of sodium hydroxide in 30 ml of water. The mixture is brought to reflux for 2 hours, then washed with chloroform, acidified with using concentrated hydrochloric acid and extracted with chloroform. The solvent is evaporated and the oil obtained is crystallized from isopropyl ether: 18.5 g of product are obtained.

Yield: 20%

Melting point: 120 ° C

FJffiI spectrum: £ ppm: 6.71, d; and 7.62, d, (J = 16 Hz): -CH0CH

7.08, s ‘, aromatic protons.

15 3.82, s,: 2 CH30-

By the same process, but from the corresponding reagents, isoprcpoxy-U dimethoxy-3,5 cinnamoïque (V) is obtained which is used crude in the synthesis of the compound of formula IIa with the number of code 770Ö23 and appearing in table III.

2. Example 7 = (2,3-cyano-2,3-ethylenedioxyphenoxy) -1 2,3-epoxy propane (III)

Code number: 77058U

ί - "A mixture of 31 g of cyano-5 hydroxy-8 bensodxoxanr.e-1, U (Vil) (code number: 770583), 38.35 g of epibromhydrin and 133 is brought to reflux for 12 hours. g of potassium carbonate in 300 ml of aeetonitrile-25 It is filtered, the product then crystallizes in the filtrate, it is filtered and recrystallized from acetonitrile.

31.6 g are obtained.

Efficiency: 79%

Melting point: 1Ô7 ° C 30 Crude formula: C ^ H ^ NO ^

Molecular Weight: 233,116 Elemental Analysis: 35

C K N

Calcula% 6l, 82 ^, 76 6.01

Found% 61.92 U, 76 5.95 kO By the same method, but using the corresponding reagents; we ' - . 6ο obtains the compounds of formula III appearing in table IV below, thus naked the following compounds of formula III: - (2-acetyl trinethoxy-U, 5,6 phsnoxy) -! 2,3-epoxy propana - (cyanomethyi- 1, pI \ i-noxy) -1 2,3-epoxy propane z (5-acetyl-ethylene 2,3-dioxy phenoxy) -! epoxy-2,3 propane - epozy-2,3 propozy-7 acetamido-k indane * yes are used crude in the synthesis of the corresponding compounds of formula I, appearing in table I according to the process, used in the example 1.

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Example 8: nethyl-2 I mi -mi t hy 1 c ar b amoy 1 friend η o - H -p’n e η ο 1 (Vlla)

Code number: 770 702 To a suspension of 2-methyl-hydroxy-U aniline (12.3 g) in 300 cm of chloroform, slowly added 5.9 cm of methyl isocyanate. It is left in contact for 3 hours at room temperature then the solvent is evaporated and the residue crystallizes from ethanol. 5.5 g of product are obtained.

Yield: 30%

Melting point: 198 ° C Raw formula:

Molecular weight: 180.20 Elemental analysis:

C H H

Calculated% 59.98 6.71 15.55

Find% 59.57 · 6.70 15.96 iv '* By the same process, but using the corresponding reagents, the compounds of formula Vlla with code number: 770920, 730290, and 780355, the compound of formula, are prepared. Vllb with code number 771029, as well as the compounds of formula YIIc with code number 771151 and 771155, appearing in table V below.

/ k 72,! · 1 i ‘

Example 9 · 'acetami'do-U hydroxy ~ 7 indane (VII d)

Code number: 77 130-

We. agitates for 30 minutes a mixture of 25 g of aydroxy-T · anîno — l * indane and 3 ml of acetic anhydride in U00 al of ice water. Then filter the bones, wash the precipitate with water and ethyl ether and. recrystallizes from isopropaaol. 25 g of product are obtained.

Yield: $ 78

Melting point 220 ° C Crude formula: C ^ H ^ NQg 10 Molecular weight: 191.22 _. Elementary analysis:

C H ÎT

Calculated% 69.09 6.85 7.33 15 Found i 69.17 7.08 7.08

By the same process, but from the corresponding reagents, the compound of formula (Vlld) is obtained bearing the coda number τ3θθ'-2 and appearing in table (V) below.

Example 10: acetyl-U 2-methoxy thiophenol (VII e) code number: 780U72 ...... 1st stage: acetyl-2-methoxy-phenol O-N-N-dirJthyluhiocarbamoyl (x)

Code number: YftOhJO

A solution of 3.3 g of acetovanil-2o'ne, 2.9 g of dimethyl thiocarbamoyl chloride and 8.2 g of potassium carbonate in 80 cm 3 of solution is brought to 70 ° C. for 30 minutes. acetonitrile. Then, the mixture is filtered, the solvent is evaporated off and the residue is recrystallized from ethanol. 3.3 g * of product are obtained.

Yield: 66%

30 Melting point: 130 ° C

Spectrum ï & EÎ: £ ppm = 7.5 ^, m and 7.11, d, (1 = 9¾) ^ aromatic rotons = 3.82, s,: -0CH3 ch - 3.21, s, and 3.15, s,: -N ^ ^ '35 XcH3 = 2.56, s,: COCH ^

By the same procedure, starting from corresponding reagents "orI obtains the compounds of formula (Xa) as follows: - u — fi, fl — üiméthy 1tniocardamoyloxy — 5 benzodioxane -1, -Î.Q Code number 780385 ί“

Yield; 93 1>

Melting point: 98 ° C. Crude formula: C ^ H ^ NQ S Molecular weight: 239.39 5 Elemental analysis:

C H H

Calculated% 55.21 5Λ3 5.85

Found% 55.10 5, b0 5, o2; - acetyl-5, N, Ν-dimethylthiocarbamoyl oxy-3 "benzodioxane-1 Λ

Code number: 780380 Efficiency: 75%

15 Melting point: 1U9 ° C

Gross formula: C ^ H ^ NO ^ S Molecular weight: 281.32 Elemental analysis: 20

C H K

!

Calculate% 55.50 5.37 ^, 93

Found% 55.3b 5.21 ^, 68 25. 2nd etane: 2-acetyl-2-methoxy thiophenol S-1-I-dimethylcarbastoyl (IX) -

Code number: 780V7I

, "13 g of acetyl-2-methoxy-phenol O-IT-N-dimethyl thiocarbamoyl obtained in the preceding step are heated, under an argon stream, for 35 minutes at 250 ° C. residue on a column of silica, eluted with chloroform, 6 g of product are obtained.

Yield: k6%

Melting point: 116 ° C

RI'EÎ spectrum: £ ppm = 7.57, s, aronatic protons = 3.91, s,: -OMe CR 35 = 3.03, s,: - 3 Cü3 = 2.52, s,: C0CE3

By the same process but from the corresponding reagents, the following compounds of formula IXa are obtained: 1 ”0 75 · · '- S-N-N-dimethyl carbamoyl -thio-5 benzodioxane — 1 Coda number: 78039ο Yield: 59%

Melting point: 78 ° C. 5 NMR spectrum:

Sppn = 6.98, a; and U, 22, s: benzodioxin protons "» 3.02, s, -â <5

3, / CH

IR spectrum: band at 161-0 cm -S-CQ-N. .

CH3 10 '· acetyl-5 S-N, N.-dimethylearbamoyl thio-8 benzodioxane-1 code number: 780381 Yield: 39%

Melting point: 155 ° C Gross formula: C ^ H ^ NO ^ S

15 Molecular Weight: 281.32

Elementary analysis:

C H -K

Calculated% 55.50 5.37 M8 20 Found% 55.73 5.5¾ 5.05. 3rd etane: acetyl-R 2-methoxy thiophenol (¥ 11 e)

Code number: 730 ^ 72

A solution of 5.6 g of Ιί, ΙΤ dimethyl thiocarbamoyl-3-methoxy-acetophenone obtained in the previous step ^, 2 g of sodium hydroxide in 210 ml of methanol and 60 ml of water is brought to reflux for 2 hours. Then, the solvents are evaporated off, the residue is taken up in water, washed with ethyl acetate, the aqueous phase is acidified with concentrated hydrochloric acid, extracted with chloroform, dried and the solvent is evaporated. 3.5 g of product are obtained.

Yield: Qj%. Melting point 50 ° C NMR spectrum: <£ ppn = 7.20, m: aromatic protons

“35 = * H, 16” S: -SH

= 3.96, s,: -0CH3 * 2.57, s,: -C0CH3 by the same process, but from corresponding reagents, the compounds of formula VII f are obtained, bearing the code numbers: 780387 and ItO 780382 and appearing in table (V) below.

Example 11: îf-cyclohexyl carboxamido-'S 5-hydroxy-benzodioxane-1, h VII k Code number: JJO 829

A solution of 3.5 g of benzyloxy-5 N-cyclohexylcarboxamiäo-8-benzodicxaane-5 1, Η (XI d) code number 770828 is hydrogenated in an autoclave at pressure and at room temperature in an autoclave. , 8 g of palladium on charcoal at 5? · The absorption of hydrogen finished, one filters, and the filtrate is evaporated-Yield: 92%

Melting point: 182 ° C NMR spectrum: 10 Sporn = T, 2h, d; · 6, ^ 8, d, · (J = 103z) and k, T8 s, dioxin protons = 7.62, d, (J = 7H.): -C0HH- = 10.1, m,: -OH = 3.78, net 1.5 m,: 15. By the same process, but from the corresponding reagents, the compounds of formula -VII corresponding to formula VII K are obtained, indicated in table V below.

AT

/ -

Y

77 ".

\ E; r; ale yp '; benzyloxy-5 nethoxy-S benzodioxane-1 Xla Coda number: 780 006. 1st stage: 5-acetyl-3-benzyloxy-benzodioxane-1 yk (XIV)

Code number: 700.

A suspension of 97 g (0.5 mole) of 5-acecyl-3-hydroxy-benzodioxane-1 (Vlli), of 127 g O mole) of benzyl chloride and of 155 g (1, 2 hours) are refluxed for 2 hours. 12 mol) of potassium carbonate in 150 ml of absolute alcohol. Then filtered, the solvent is evaporated, the residue is taken up in chloroform, washed with a 1N sodium hydroxide solution, the solvent is evaporated and crystallized from alcohol. 135 S of expected product are obtained.

- Efficiency ': 95%

- Melting point: 133 ° C

|. - Raw formula: 0 ^ 1 - Molecular weight: 28 ^, 29 - Elemental analysis:

C H

Calculated% 71.82 5.67

Found% 71.76 5.76 • 2ene and 5ne: 5-acetoxy-8-benzyloxy-benzodioxane — 1.4 (XXb)

Code number: 7Ö0 001 To a solution of 58 g of 5-acetyl-8-benzyloxy-benzodioxane-1, ¾. (XIV) v obtained in the previous step in 300 ml of formic acid, is added at -5 ° C, 2? g of a 36% solution of hydrogen peroxide in 10Ö ml of acid, fornic. The mixture is left at 0 ° C. for 72 hours, then it is poured onto a mixture of water and ice, the precipitate formed is filtered, washed with water and recrystallized from a mixture of ethyl acetate and isopropyl ether.

- Efficiency: 89%

- Melting point: 10h ° C

- Gross formula: C ”H 0 ..

17 16 5 - Molecular weight: 300.39 - Elemental analysis:

/ .CH

- Calculated% 67.97 5.37

Found t 68.15 5.55 s.

Τ8. 3rd stage: benzyloxy-5 hydroxy ~ 8 benzodioxane-1, 1 (XIIl).

Code number: 780 005 To a solution of 58.3 g of 5-acetoxy-bensyloxy ^ 8 benzodioxane-1, 1 obtained in the previous step, in 100 ml of methanol, 75 g of potassium carbonate are added, to room temperature, then after 30 min, filter, evaporate the solvent, take up the residue in water and acidify with concentrated hydrochloric acid. We. filters the precipitate obtained and recrystallizes from alcohol. Vf, 3 g of product are obtained.

- Yield: 9 ^%

- Melting point: 131 ° G

- Crude formula: C ^ _ 0 ^ - Molecular weight: 258.25 - Elemental analysis:

CH

Calculated% 69.75 5M

Found% 69.83 5.39 • stable bene: 5-benzyloxy-8-nethoxy-8 benzodioxane-1, 1 (Xla) code number: 780 OOo Has a solution of 15 g of 5-benzyloxy-8-hydroxy-benzodioxane-1, 1 obtained in the previous step, and 52 g of potassium carbonate ['in 500 ml of acetone, 33.5 g of dimethyl sulphate are then added slowly and then 20 ml of a 10% solution of methanolic potassium hydroxide. The solution is then brought to reflux for 2 hrs and 30 min, filtered, the solvents are evaporated, the residue is taken up in ethyl ether, washed with water, dried and the solvent is evaporated. Hj g of product is obtained.

- Yield: 98% - Feint of fusion. : 70 ° C Spectrum da_RMN: fppm = 7.36, d, and, 6.17 "d, (J = 2lz) and 1.23, s, benzodioxane protons = 7.35, m and 5.03, s: -CH -0 = 3.78, s,: -0CH3

Example 1 -¾: isopropoxyxycarbonyl-8 benzyloxy-5 benzodioxane-1.1 (XIc)

Code number: 780 370 • 1st stage: (5-benzyloxy-benzodioxane-1,1 acid) yl-8 earboxylic (XV)

Code number: 760 695 To a solution of 29 g (0.1 mole) of 5-acetylbenzyloxy ~ 8-benzodloxauue-1.1 (XIV obtained in the 1st step of Example 12 in 150 ml of pyridine , 25.8 g (0.1 mol) of iodine are added, then the mixture is brought 79 \ 1 hour to 100 ° C., removes the excess of pyridine, takes up the residue in water, filters and puts. the precipitate obtained in solution in U50 ml of a 50/50 alcohol-water mixture. A solution of OJ g of sodium hydroxide in 200 μl of water is slowly added, then washed with chloroform, the precipitate formed is filtered and dissolved in a aqueous sodium hydroxide solution. Aidified to pH using hydrochloric acid, concentrated and filtered. 2 g of product are obtained. - Yield: 95%.

- Melting point: ÙL 200 ° C

- Gross formula: 0 ^ - Molecular weight: 286.27 - Elemental analysis:

'C H

Calculated% 67.12 k, 93 ·.

Found ii '66.91 5.00. 2 donkey and year a: isopropoxycarbonyl-8 benzyloxy-5 benzodioxane-1 To a toluene solution of 31 g of acid (5-benzyloxy-benzodioxane-1, l) yl- 8 carboxylic obtained in the previous step, 50 ml of thionyl chloride and the mixture is brought to TO-8O0 C for 2 hours. Then, the solvents are evaporated, the residue is dissolved in 200 ml. of tetrahydrofuran, and adds 15 cm3 of isopropyl alcohol and 70 cm3 of triethylamine. The mixture is brought to 60 ° C. for 3 hours, then the precipitate is filtered, the filtrate is evaporated and the residue is chromatographed on a column of silica, eluted with chloroform? 20 g of product are obtained which is recrystallized from isopropyl ether.

- Yield: 71% - Melting point: 96 ° C Spectrum: £ ppm = 7.38 (d), and 6.57, d, (J = 10 Hz) and U, 23, s, benzodioxin protons = 7, 23, s, and 5.08 s: CH2 - 0 - 5.09, quintet, and 1.1 b, d (<J = 6 Hz) - C00- ^

IR spectrum: 1710 and 1200 cm "1 band: C00- <

By the same process, but using the corresponding reagents, the compounds of formula (XIc) appearing in table VT and bearing the code numbers: j80 366, j8o 298 and j80 330- jir <80

Example Ui. : benzyloxy-p-cyclohexyl carboxanido-8 benzodioxane-1 »U (Xld)

Code number: 770 823 To a toluene solution of 30 g of (5-benzyloxy-bensodioxane-1,4) yl-8 carboxylic acid obtained in the 1st step of Example 13 "30 ca3 of thionyl chloride are added and door at 70-80 ° C for 2 hours. Then, the solvents are evaporated off, the residue is dissolved in 200 e · 1 of tetrahydrofuran and 2 μl of trlethylarnine and 19 μl are added. of eyclohsxyiamine. The mixture is then brought to 60 ° C. for 3 hours, filtered, the filtrate is evaporated and the residue is recrystallized from a mixture of ethyl acetate and hexane.

- Yield: 82.5%

- Melting point: 117 ° C

- Raw formula r C Hot- N0.

- Molecular weight: 367, ^ 9 - Elemental analysis:

C H H

Calculated% 71.91 6.86 3.81

Found% 71.99 6.78 3.69

By the same process, but from the corresponding reagents; on | _ obtains the compounds of formula (Xld) appearing in table VI and 'bearing the following code numbers: 770 202 and 770 8 ^ 9.

Example_15: propionanido-8 benzyloxy-5 benzodioxane-1, ¾ (Xle)

Code number: 770 5 ^ 2 ------------- ~ À-une-Solution de 30g d! Amino-5-benzyloxy-8 benzodioxanne-1, k fXIX); code number j6o 727, in 250 ml of chloroform and 21.3 ml of triethylamine, cooled to 0 ° C., slowly adding 12.1 cm3 of propionyl chloride - Then stirred for 1 hour, wash with a solution of dilute hydrochloric acid, with water ”with an aqueous solution of sodium bicarbonate, then with water, evaporate the organic phase and recrystallize the residue in ethyl acetate.

- Yield: 73% - Melting point: 139 ° 0 NMR spectrum:

Sppm = 7, ^ 2, d; 6.51, d, (J = 10 Hz) and 4.20, s: benzodioxin protons = 7.78, d, (J = 9 Hz): -NH-CO- = 7.35, s and 5.03 , s: CHg-0 = 2.17, q, and 1.11, t (J = 7 Hz): CO-CHg-CH ^ SOeçÎre_XR: bands at 3 ^ 00, 16? 0 and 1510 cm 1: -NH -C0-

By the same process, but using the corresponding reagents, we θι

Example Ιο-: benzyloxy-t methylene 2,3-dioxy aniline (XIXa)

Code number: 7δ0 Λθ5

A solution of 3½ g of benzyloxy-1 methylene dioxy-2,3 acé-tanilide (Xlh) (code number 780 3¾) in 120 ml of nethanol is treated with 3½ g of potassium hydroxide for 1 h 30 at reflux. Then, the precipitate formed is filtered and recrystallized from 1 * isopropyl alcohol. We obtain 13, U g of product - - Yield: 50%

~ Melting point: 59 ° C

RlSf spectrum:

Sppm = 6.22, q, (J = 9 Hz) aromatic protons of the benzo- cycle = = 5.au, J, -o ^ c% V dio: tole = 7j3o, s and 5> 03, s,: - CH ^ -0 = 3.17, s, -ITH2

By the same procedure, but starting from the corresponding reagents, the compounds of formula XXEa are prepared bearing the code number 7O0 ½6½: 1-amino-6 benzyloxy-9 benzodioxepine-1,5.

- Efficiency: 82%

- Melting point: $ 2 ° C

"- Gross formula: C ^ H.„ ΓΙ0 1o i f 3 - Molecular weight: 217.29 f _ ".

• - - - .. - Elementary analysis:.

C H II ·

Calculated% 70.89 6.32 5.16

Found% 70.72 6.39 5.13 as well as the compound of formula XIX with the code number 760 727 -17 amino-ô-benzyloxy-8 benzodioxane: - Yield: 73%

- Melting point: 130 ° C

- Gross formula: C1c; H1C HO

- Molecular weight: 257.28 - Elemental analysis: C H Έ

Calculated% 70.02 5.88 5, ½½

Found% 69.73 5.9½ 5.2½

Example 17: Benzyloxy-Λ-methylene-2,3-dioxy acetanilide (Xlh)

Code number: 780 3½3 To a suspension of 100 g of oenzyloxy- ^ metnylene-2,3-dioxy acetophenone (XXl), code number 7O0 3½2, in 500 ml of acetic acid, slowly add 500 al of acetic anhydride, then pass it over ** On

• w / U

1 hour a stream of gaseous hydrochloric acid, at 10 ° C. Then, the solution is brought to U0-50 ° C for 5 hours, the solvents are evaporated, the residue is taken up in chloroform, washed with water, the solvent and recrystallize the residue from ethyl acetate.

- Yield: 3k ° C

- Melting point: 1 ^ 8 ° C

RMq spectrum - "Spps = T, 18 m and 5.18 s: -CHo0 _ Çapm = T, 18, ία (aromatic protons of the benzodioxola nucleus and of CEL0) XCE2 \ = 5.95, s,: -0 ^ 0- = 2.09, s, CH ^ -CO-H- = 6.51 d, (J = 9 Hz): NH-C0-_1

IR spectrum: 32o0, 1650 cm: hande -NH-CO-

By the same process, but from the corresponding reagents, the compounds of formula (Xlh) are obtained bearing the code number j80 b63 and appearing in Table VI. - ·

Example 18: Benzyloxy-U methylene 2,3-dioxy-acetophenone (SS) oxime code number: 780 3 ^ 2

A solution of 192 g of benzyloxy-k, f ....... methylene dioxÿ-2,3'acetophenone (Xli) is brought to reflux for 2 hours; code number 78Ο 305 and (¾ g of hydroxylamine hydrochloride in 500 ml of pyridine and 500 ml of ethanol. Then the solvents are evaporated off, the residue is taken up in water and the precipitate formed is filtered.

- Efficiency: 93%

- Fusxon point: 168 ° C

- Crate formula: ÎJO ^ - Molecular weight: 285.29 - Elemental analysis: • C H lî

Calculated% 67.36 5.30 4.91

Found% 67.31 5.30 U, 91

By the same process, but from the corresponding reagents, the oxime of 6-acetyl benzyloxy ~ 9 benzodioxepin-1.5 (XXI) s code number 780 390 is obtained.

- Yield: 90% - Melting point: 13 ^ ° 0 t

Speçtrejle: "Sporn = 13.00 ·, m ^ = Ν-0Η 83

NMR spectrum (Continued) c> ppa - 6.51 ”d; 6.88, d, (J = 10 Hz); ^, ios m j and 2.08, m: benzodioxepinnic protons 35 5.17 s and 7.19, s. = CHg-0 = 2.20, s; -CK3

Example 1Q: N-ethyi earbamoyl 8-amino-5-benzyloxy-cenzodiox ^ - ^ - j ^ (χτ-τ) code number: 770 30H

! Is maintained at reflux for 20 hours, a mixture of 05 c · 5-amino-5-benzyloxy-benzodioxane-1> h, code number 760 727, and £ ^ i‘iSOCyanate in 300 ml of chloroform. Then the solvents are evaporated in vacuo and the residue is recrystallized from ethanol. "- Yield: 80%

”Melting point: 188 ° C

NMR spectrum:

Sppm = 7, ^ 1, d; 6.56 ", d" (J = 10 Kz) and îr, T9s a, benzodioxin protons = 7.38, s, and If, 97, s,: -CH2-0

= 6.60, m and 7, ^ 0, m: HH-CO-IIH

= 3.02, q and 1.00, t, (J = 7 Hz): -C ^ -CF ^ -

By the same process, but from the corresponding reagents, the compounds of formula (Xlf) appearing in table 71 and bearing 'the following code numbers: 770 07 ^ - 770 U30 - 770 o27 - ~~ 3 o3' 773 708 - 7ô0 220 - 78Ο U06 - 78Ο U65.

Example gn 1: benzyloxy-5 ethoxy carbonylamino-8 benzodioxane-1 (Xlg)

Code number: 770 522

What

To a solution of 30 g of 5-amyl-3-benzyloxybenzodiovov.j ^ .- j J, (xiy) code number 7o0 727, in 250 μl of chloroform, 2] 3 of amine was added, then slowly, to 0 ° C, 15.2 g of chlorofornate ethv'a ^ _ - »- v» ruio, Or X6LLci3ô stir for 7 hours, filter, wash the filtrate with a dilute solution of hydrochloric acid, water, with a solution of baking soda, ^> x * water Qn evaporates the solvent and recrystallizes the residue from acetate ** · - u »- Yield rJ h%

- Melting point: 108 ° C

Spectrum of Ρ2ΈΙ: • ...— 1 .. .1 -.- 1., ......

• · = 6.52, d; Τ, Μ, d, (J = 10 Ez) and! S> 22. 'bensodioxin - - = 7.38, s and 5.08, s: CHg-0 = 4.10, q., and 1, .14, t, (J = 7 Hz): CH -CH = 6.80 , s, -EH- 3

IR spectrum: 3315 and 1692 cm "1 = EHCOOSt

Example 21: 4-benzyloxy-2,3-dioxy-methylene acetophenone (Xxi)

Code number: 780 305

A mixture of ihr g of 4-bensyloxy-2,3-dihydroxy-2,3 acetophenone (XXIII code number 780 3C4, of οος - * e dilo ^ o-, -. Methane and 300 g of potassium carbonate in 1201 ml at- „, __-.„ ["ΛΟΧα.; ΛΠΙΧΟ. ^ ·

Then, it is filtered, the filtrate is evaporated, the residue is taken up in a mixture of ethyl acetate and ether 50/50, washed with water, the organic phase is evaporated, and the residue is crystallized from ethanol. .

- Efficiency: 93%

- Melting point: 101 ° C

ï. PME spectrum: & ppm - 6.55, d} 7.35, d, (J - 10 uz): aromatic protons of the benzodioxole nucleus = 6.00, s, o / Cu2 ^ o = 7.38, s and 5 , 18, s,: CHg-0 = 2.44 s,: -CH3 —1

Specter_IR: 1670 cm: -CO-CH ^

By the same process, but using the corresponding reagents, the compound (XIi) bearing the code number 73g 238 and appearing in Table VI is ootaent.

Example ... 22 - û & nzyloxy ~ 4 2,3-dihydroxy acetophenone (XXIli)

Code number: 780 304

A mixture of 349 S is stirred for 2 hours at room temperature

fe ......- fis. .

'ie gallacetophenone, 1750 g of baking soda and 20o g of benzyl chloride in ^ 000 ial of acetone. Then the mixture is brought to reflux for 30 hours, filtered, the solvent is evaporated, the residue is taken up in ethyl acetate and diluted in isopropyl ether. 58 ^ of crystallized product are obtained.

- Melting point: 123 ° C '- Crude formula: E ^, 0 ^ - Molecular weight t 253.26 - Elemental analysis:

C E

"

Calculated% 69.75 5, ½

Found% 69, bQ 5.60 jrcemrle 23: benzyloxy-5 N-N'-dimethyl carbaaoyl anino — 8 benzodioxane — 1, ¼ (Xlj) Code number: 771 235 '* 1st and are: benzyloxy-5 N-methylamino -8 benzodioxane-1, ¼ (XXIV)

Code number: 771 23¼

A mixture of tO g of araino-5 benzyloxy — 8 benzodioxane — 1, ¼ (XIX), code number 760 727, of 120 μl of fornic aldehyde (38% in aqueous solution) is refluxed for 12 hours. ) and 29 g of 5.5 dimethyl hydantoin in 300 μl of ethanol. Then, the solvent is evaporated, the residue is taken up in chloroform and washed with the aid of a dilute solution of hydrochloric acid.

The organic phase is evaporated and the residue is dissolved in 500 ml of methylsulfo-xyde. 23 g of sodium hydroxide are added slowly, and the mixture is brought to 100 ° C. for 30 min. Then, dilute in 1500 ml of water, extract with chloroform, wash with 1 ’water and evaporate the solvent. The residue is chromatographed on a silica column. Eluted with chloroform, 3¼% of product is obtained.

- Melting point: 62 ° C

- Crude formula: NO ^ - Molecular weight: 271.30 J - Elemental analysis:

C H N

Calculated% 70.83 6.32 5.16

Found% 70.70 6.29 h, 90. 2nd stage: benzyloxy-5 N-ïï1 -diméthyl earbasoyl amino-8 bcnzodioxanne-1, ¼

A mixture of 22.5 g of N-methyl-8-arnino-5-benzyloxy-1½ ½ obtained in the preceding step and of 10 ml of methyl isocyanate in 100 ml of chloroform is brought to reflux for 2 hours. then the solvent is evaporated and the residue is recrystallized from alcohol.

- Yield: 7¼%

/ 1 - Melting point: 1½ ° C

86 "- Raw formula: KOQ RgO ^ - Molecular weight: 323.3ο - Elemental analysis: C Η ΪΓ

Calculated% 65.84 6.1 U 8.53

Found% 65.71 6.07 8.62

Fxesule 2 U; morpholinoc arbonylara.ino-8 benzyloxy-5 benzoâioxanne-1 (Xlk) code number: 771 lU6 -. The mixture is refluxed for 16 hours, in the presence of a pinch of ammonium chloride, a mixture of 38 g of 8-ethoxycarbonylaaino-8-benzyloxy-benzo-dioxane-1 (Xlg), code number 770 522, and 300 ml of morpholine. Then, the excess morpholine is evaporated and the residue is recrystallized from ethanol at 96 °.

- Yield: 72%

- Melting point: 18h ° C

- Crude formula: C20 H22 H2 0 ^ - Molecular weight: 370.39 - Elemental analysis: *

• C 'H K

Calculated% 6k, 85 5.67 7.56 t Found% 6k, 35-5.95 T, 7k

Example 25: ri-h-dimethylcarbamoyl 8-amino-5-benzyloxy-benzodioxane-1 (XIl) Humerc of code: 771 230 To a solution of 100 g of 5-amino-8-benzyloxy-benzodioxane-1, 4 (XIX), number of code 7βθ 727, and of 100 if of triethylamine, in 1000 ml of chloroform, 47 ml of pure dimethylcarbamoyl chloride are slowly added at room temperature, the mixture is brought to reflux for ^ 8 hours. It is filtered, the filtrate is evaporated and the residue is recrystallized from 1 T, ethanol. 60 g of product are obtained.

- Efficiency: hj%

~ Melting point: lh2 ° C

- Gross formula: Cl8 Ng 0 ^ - Molecular weight: 328.36 - Elemental analysis: c h ir

Calculated% 65.8k 6.1¼ 8.53

Found% 65.67 6.35 8.25 A- 87

Example £ 6-: benzyloxy-5 earboxsmidomethyl-8 benzodioxane-1,4, XI (i)

Code number: 770 383 To a solution of 50 g of benzyloxy-5 ey.anonéthyl-8 benzodioxahne-1, l *, in 250 ml of tertiobutanol, 39 g of pulverized potash is slowly added, then the mixture is brought to reflux for 20 minutes . The mixture is then poured into 500 ml of an aqueous sodium chloride solution, extracted with chloroform, washed with water, the solvent is evaporated and the residue is recrystallized from ethanol.

„N3tiurîi3ci.iu · s'J O

- Melting point: 1oo ° C

.. H-Ci spectrum:.

ippa = 6.51, d; 6.72, d; (J = 10 Hz) and 4.30, s,: benzodioxin protons = 7.37, s, and 5.16, s, = CH2 ~ 0

NMR spectrum (continued)

Sppm = 5.7o. m: -C0?! H2 "3.43, s,; -CHg-CO-

Example 27: benzyloxy-5 N-methylcarboxamidomethyl-8 benzodioxane-1,4 (XIo) • Code number: 770 379

{-. 1st etane: acetic acid-2jjbenzyloxy-8 benzodioxane) l, 4) yl-5j (XXI

Code number: 770 308 200 g of 5-benzyloxy-8-cyanomethyl-1,4-benzodioxane is added to a solution of 57 g of sodium hydroxide in 1 l of 50% aqueous ethanol therein, cooled to 0 ° C. distill the ethanol, add a hydrochloric acid solution to an acidic pH, wash with chloroform, acidify until ph = 3 and filter.

- Efficiency: 78%

- Melting point: 150 ° C

NMR sample: -ppm. = 6.1 * 3, d; 6.65, d, and U, 23, s,: benzo-dioxin protons = 7.38, s, and 5.08, s,: -CH2-0 '= 3.58, s,: -CH2-C00 -

... = S, 20, m, -C00K

• 2nd stage: oenzyloxy-5 K-methylearboxauiiidomethyl-8 benzodioxane-1, 4 To a solution of 80 g of acetic acid ~ 2 d ^ (benzyloxy-8 benzodioxane-1, ^) yl-5d, obtained in step above, in 500 ml of dimethyl formamide,

L

33 cooled to 0 ° C., 50 al of triethylamine and then 31 al of chlorof ormiate-ethyl are added. Then, a gaseous stream of methylaaine is passed through, and the reaction is monitored by chromatography on a thin layer of silica. Then pour into ice water, filter the precipitate and take it up in chloroform. The organic phase is washed with a dilute hydrochloric acid solution, the organic phase is evaporated and the residue is recrystallized from ethyl acetate. 70 g of product are obtained.

* - Efficiency: 85%

- Melting point: 160 ° C

NMR spectrum:, üppm = 6.02, d, 6.23, d (J = 9 R * z) and 3.82, s,: cenzodioxin protons = 6.9 ^, s and ^, 63, s, : -CHp-0 = 3.02, s,: Cü2-C0- = 2.30, d, (J = 5 Hz): -Ciï3 = 5.12, m, -ïïH-

Example 281: benzylcxy-5 cyano-7 benzodioxane -1, ¾ (ΧΙρ) \. .Code number: 770 5-82 d. To a solution of oh-, 5 g of benzyloxy-5 carboxamido-8 benso & ioxanne-l, ¾ '(xid), code number 77C 202, prepared according to the procedure of Example 14, in 1000 ml of benzene, 80 is added. g of phosphorus pentachloride- The temperature rises to k0Q C, after h5 min, the solvent is evaporated, and the residue is taken up in toluene, the solvent is evaporated and the residue is taken up in chloroform, washed with water, and evaporated the solvent. The residue is recrystallized from ethyl acetate.

- Yield: $ 6-2

- Melting point: 1 ^ 5 ° C

Spectrum de_RMN: ippm = o, 50, d, 7.01, d, (J = 10 Hz) and t, 25, s,: benzodioxin protons

= 7.38 s, and 5j05 s,: ΟΗρ-0 IR spectrum: 2210 cm ^: band -CN

Example oq: 5-benzyloxyethoxyearbonylmethyl-3-benzodioxane-1, k (Xlq)

Code number: 770 309 A. a solution of 72 g of acetic acid-2 | T (ben zyloxy-8 benzodioxane-1, ^) yl-5j, obtained according to the procedure of the 1st step of Example 27 In 89 200 ml of ethanol, 100 μl of 7.5 N hydrochloric ethanol are added, then the mixture is brought to reflux, for 30 eu, the solvent is evaporated, the residue is taken up in chloroform, washed with a saturated solution of "baking soda, with water, and the solvent is evaporated. 98% of crystallized product is obtained.

- Melting point: 86 ° C

Pi-EI spectrum;

Sppra = 6, kO, d; 6.61, d (J = 10 Hz) and k, l8, s,: protons, benzodioxins = 7.3o, m, and 5.03, s: -CE2 ~ 0 = 3.37, s: -CH2- C00 '= U, 18, q and 1.10, t, (J = 8 Hz): -CQQ-CK ^ CK ^

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The compounds of formula I have been studied in laboratory animals and have shown antianginal activity, as well as activities on the peripheral and cerebral circulation.

Antianginal activity 5 Antianginal activity is sought in anesthetized dogs (sodium pentobarbital 30 mg / kg / i.v.).

- Oxygen consumption in the left ventricle is estimated by the product of the coronary venous flow by the coronary arteriovenous difference. in oxygen (volume%).

10 The coronary venous flow is measured in the venous-coronary sinus using a modified Moravitz cannula, introduced under fluoroscopic control.

Coronary arterial and venous oxygenation is measured using a blood gas analyzer (IL Meter 213) · 15 - Cardiac effort is estimated according to the KATZ index, by the product of average arterial pressure by the cardiac frequency.

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

Systemic blood pressure is measured at the femoral artery with a pressure sensor (SAIT30RÏJ 2Ô7 ~ 3C).

The results obtained by injecting the compounds of formula I and the [-. - following reference compounds: LIDOFLAZIïiS and AMI0DAR0NE, are reported in Table VII below. It should be noted that the compounds tested are injected by intravenous route as a slow infusion.

25 h 10¾.

_TA5L2AU VII_

Compounds tested: Toxicity K Dose Decrease in Decrease: î'3 (Mortality) .ng / kg / icons consumption of 0o 'of effort (mg / kg / iv-) _i_2 cardiac (m) in% in time in% in time (in mn.) (in mm) ”7 ^ 939 'j i-00 £ 0¾) j Ü25 Tiï 30 ÏÎ 23 770199 328 1.02 29 15 5 15 77027¾ 336 (30/0 2.5 kl 30' 10 15 770276 2½ 2.5 59 '23 770307 3b7 (10, ¾) 0.15 Î4.3 30 11 30 770312 259 0.1¾ 30 30 9 770382 koo (30.¾) 0.625 36 15 16 15 -. '770356 .... loo (20¾). 0.625 j 30 20 30 770¾53 25c 2.5 72 23 25 15 770¾83 Po.: 2000 (0¾) 0.15 7¾ I15 16 30 7 ^ 37 too (30¾) 2.5 Vf 60 1¾ T70¾S8 225 2.5 78 30 17 15 770 ^ 95 175 2.5 7¾ ^ 5 U3 30 77050¾ 195 2.5 52 15 ... 10 - 770525 325 0.625 66 60 ¾3 60? '770529 In.: 20G0 ( 22%) 0.625 56 30 29 30 7ΟΟ533 in: 2000 (10¾) 0.625 30 25 2S 25 770538 193 2.5 5¾ 15 28 25 7705¾¾ ^ 00 (h0%) 0.625 6l '30 16 15 770585 in: 2000 (0¾) 2 , 5 75 30 lu 30 770 590 290 2,5 60 ¾5 33 U5 770 601 in: 2000 (22¾] 0.625 69 30 25- 30 T70oi0 in: 2000 (0¾) 0.625 56 oO 3¾ h5 ij 77081¾ ''. : 2000 (11¾) 0, b25 ¾9 30 lj-5 30 ί l 760622 uoo (you) 1.25 20 30 17 15! 7: 0630 hoo (ko%) 0.15 58 60 32 | 60

AT

l 105

Compounds tested I Tonicity ïl Dose Decrease in Decrease [Code number (Mortality) (mg / kg / i.v.) Consumption of 0 from &ffo'd; ' (mg / ks / i .v.) _ 2 cardiac ^ f ΤΚΛ in% in time in% in. time _ · __________ (in 32Λ.) (in nude *) T (0ο3 ^ k00 (30.¾) 0.15 69 30 27 30 TTOÖ92 200 (60%) 0.625 oO 15 ij.5 30 7ί0, · 27 130 2 , 5 57 i5 27 30 'TÎ ° T38 too (U03 £)' 2,5 63 k5 U8 h5

Tf0331 ρ.o. : 2000 (0¾) 1.25 k5 30 27 Ij.5 7iCô ^ 4 koo (0¾) 2.5 58 23 35 30 7708U3 U00 (10¾) 0.15 kl 30 5. = 77035k 300 (20¾) 2.5 Vl ko 13 ho 770355 260 2.5 60 60 h5 60 770358 2β0 0.15 16 30 15 30 770 859 150 2.5 30 30 52 60 770 393 koo (0¾) 2.5 U5 k '5 36 38 770963 190 2.5 58 30 66 30 770966 - 2.5 7 - h6 30 770 992 400 (0¾) 2.5 77 kb 36 30, JJ0? 9.?,. ......... .. 2.5 53 23 15 13 'i · * 77101k' iko 2.5 66 30 n 15 771031 - 0.15 20 30 25 30 771036 - 2.5 15 - 25 15 771076 k00 (0¾) 2.5 16 15 22 30 771077 k00 (10¾) 2.5 61 k5 39 30 77 112k 270 '2.5 3k 15 13 23 771lk9 - 0.15 12 30 1k 30

Τ7Π53 - 2.5 31 23 63 kB

771157 210 2.5 53 30 h6 30 771163 - 0.625 61 30 '20 kb 771172 - 2.5 25 15 29 23 771233 310 0.15 29 15 9 15 771233 k00 (03) 1.25 kO 30 33 30 771231 - 2 , 5 23 30 kk 30 ΠΙ306 - 1, 25 58 15 38 30 d "71309 - 2.5 63 k5 31 15 771315 - 1.25 11 - 29 15 771310 - 2.5 63 60 31! 15 77l3k8 - 2.5 59 30 k2 I 30 L · '! Ιοί "y' · ~ r, m 1 '' '1 ι —__ · ___

Compounds leftover Toxicity ~ Dose Decrease in Decrease.

îî ° of code (Mortality) (ng / kg / i „v.) consumption of 0 of the effort (^ .g / ^ g / iv. —._ cardiac ÇliC) in $ in time in% in time ( in nn.) (in nn.) 78000¼ ItOO (10.¾) 1.25 22 30 1k 15 780009 - 1.25 U8 35 20 30 7800 ^ 0 too (30¾) 2.5 59 15 9 - T300ïfîf l} 00 (W%) 2.5 kg 30 36 15 780 120 3 ^ 0 2.5 65 30 29 15 780 128 - 2.5 57 23 17 23 730 138 150 2.5 b6 b5 19 30 780 150 1b2 2.5 5b 1 ^ 5 19 15 730189 - 2.5 63 30 30 h5 780223 - 2.5 62 90 35 90 730269 - 2.5 3¼ 30 kb '- 60 780272 - 2.5 liO 90 51 90 780292 - 2.5 59 90 3¼ lî-5 780301 - 0.15 BO 30 28 60 780 333 - 0.15 51 30 21 23

750339 - 2.5 jb b5 b2 ItO

i, 780369 · - 0.625 37. Î5 U 15 730373 - 2.5 66 30 25 30 78037¼ - '2.5 39 30 31 15 78038U - 0.15 30 25 kb 780389 - 2.5 32 15 15 30 7705 ^ 5 kOO \ b0%) 0.625 61 30 16 15 770 711 in: 2000 (O?) In 12.5 32 780 225 - 2.5 36 30 22 30 - 7802U1 - 0.15 30 23 13 '23.

780267 - 2.5 27 30 8 780302 - 2.5 b6 30 1U 30 780308 U00 ($ 10) 2.5 b9 b5 37 U5 780329 - 2.5 21 30 13 30 7303½ - 0.15 30 2 .. - j 730353 - 2.5 ho 15 16 15! ; "30357 -. 2.5 b3 15 21 15 I 730359 - 0.625 60 b5 32 30 I 730361 - 2.5 58 30 38.. * 5! 780393 bOO ($ 10) 0.625 2b 30 - I5 30

AT

107 /

Compounds tested; Toxicity K Dose Decrease, Decrease iP dg c0de (Mortality) (ng / kg / iv) consumption of effort 0 (m /.- vs / iv) __ cardiac (lie) in% in time in% [in time _____.______ (in one.) ___ (in tone ") T80U01 - 2,5 6k 30 6 T3oU09 kOQ (20¾) 2,5 5k 90 ïtf 90 780415 305 2,5 29 30 70 30 '730456 - 0,625 -13 75 32 30 73040U '- 2,5 69 75 30 LIBQFLAZÎI'IK 25 (50? *) 1,5 U8 30 io 15 ff-IODAROvîS 7 60 (50¾) 10 11 15 22 75 ά DiipO or percentaga ne mortality yes is then indicated in parenthesis h ^ _ 108

Activity on the cerebral circulation Activity on the cerebral circulation is sought in the anesthetized dog (sodium pentobarbital 30 rag / kg / i-v.). The flow of the vertebral artery is ensured by means of an electromagnetic or ultrasonic perivascular probe 5 with Doppler effect.

The intracerebral vascular resistance is estimated by the retrograde pressure of the internal carotid artery,

Systemic arterial pressure is measured at the femoral artery with - a pressure sensor (SAçîBGHII 267-30).

10 The increase in cerebral oxygen extraction is estimated by the following equation: A-V in which:

AT

. A represents the volume of oxygen in the arterial blood (in volume% \ measured by hemoreflectoaetry (apparatus of KIPP and ZODISüi) and assay of hemoglobin (DRABKIîî method).

15 - V represents the volume of oxygen in the cerebral venous blood (internal maxillary vein).

The results obtained by injecting the compounds of formula (i) and the following reference compounds: papaverine, naphthxdrofuryl and cinnarizine are reported in the following TEC table.

It should be noted that the test compounds are injected intra-. - venous (stiff injection).

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p ra î ί h; 110

Activity on the peripheral circulation The activity on the peripheral circulation is studied in the anesthetized dog (sodium pentobarbitai 30 iag / kg / i.v.). The flow of the femoral artery is measured using an electromagnetic or ultrasonic perivascular probe 5 with Doppler effect.

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

The results obtained by injecting the compounds of formula I and the following reference compounds: papaverine, naphthidrofuryl and cinnarizine are reported in the following table IX, (intravenous injection by slow infusion).

TABLE IX

Compound tested Lose Femoral artery flow · Arterial pressure K ° code mg / hg / i.v. average ^ in% of time in% of time (min.) (min.) 770 276 0.136 + 10> 30 -7 770 312 0.139 + 8 15 “2 20 770 525 0.312 + 28 15 -21 ^ 5 i '' 780 301 0.156 + 35 15 -12 780 333 "+11 5 -8> 30 PAPAVERINE 2 +100 1 25 NAPHÎID30FÏÏRYL 2.5 +100 5 -50 2 CIIÛ7A3IZIITE 5 +100 30 -50 15

It appears from the preceding results that the difference between the therapeutic doses and the toxic doses is large enough to allow the use of the compounds of formula I in the treatment of disorders of the cardiovascular systems, in particular as antianginal agents and as active agents on cerebral and peripheral circulation.

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

/ Îa

Claims (26)

111 1. As industrial products, the new einnanoyles piperazines and homo piperazines corresponding to the general formula (I): 5. H 'crl HO h 10 in which:, OCR ί 3! R \ · == represents the group 3, b, 5 trinethoxyphenyl 15 OCR ^ "in which case the set of parameters (n, R" X, m) takes: + either the value (l, OH, Oxygen, 0), the radical Ar then representing: R / - Rcr '6V /: - a mono or polysubstituted phenyl nucleus: in which R2-H3; ·; Rg, Hg ’R- and Rg simultaneously represent the following values:. R2 = Rj, = R ^ = Rg = H; Rg then represents the acetamido group, - Rg-R ^ = R (_ = Rg = H; R represents the acetamido or acetyl group. '^ 2 = ^ 3 = ^ 5 =% = ^ ”then represents the benzoyl, alkyl group linear or branched having 3 to 5 carbon atoms, cyclohexyli alkanoyl in which the alkyl residue contains from 2 to 3 carbon atoms, the cyanomethyl or carboxaaido-methyl sequences. R2 = R- = Rg = H; Rg represents l fluorine atom and R ^ represents the acetyl group;. Pi2 = Rej = Rg = H; R ^ represents the chlorine atom and represents either the nitro or acetyl groups, or the K-methyl-carbamoylamino chain;. R ^ -Rj-R ^ H; r2 represents the methyl group and R ^ represents either the chlorine ato: yj, or the acetyl or acetamido groups; or the N-methyl carbamoylamino sequence;. R2 = R_ = Rg = H ; R ^ represents the methoxy group and R ^ represents the propionyl, formyl, cyano, acetamido or N-methyl carboxamido group; lo · Rg = R ^ = Rg =; H 'rePr®senÎe the or or methyl and R ^ represents the group »nitro or acetamido or the chain ïï-methyl-carbanoyi- / U 112 friend no; . . R = R ^ = K; S, and R_ represent the methyl group and R, represents the o 3 p '“4 chlorine atom; . R ^ = Rg = K; 3g and represent the methoxy group and the group 5 M-methyl carhamoylamino; . R3 = R, - = H; P> 9 and Rg represent the chlorine atom and R ^ represents the acetyl group or the chain Îl-methyl carbamoyl- • amino; . Rg = R ^ = K; Rg and Rg represent the methoxy group and R ^ represents the acetyl or ethyl carboxylate group or the N-methyl carhamoylamino chain; . R3 = H; R ^, R ^ and Rg represent the methoxy group and represent the acetyl group; 15 RTv_ / 8! - a heterocycle of formula —Rg; in which: p, R ^., Rg and H> p · i R ^ take the following meanings simultaneously: 20. p = 2; R ^ = Rg = H; R ^ represents either the hydroxy, acetoxy, methoxy, cyano, f · alkoxy carbonyl group in which the alfcyl residue is linear or branched and has 3 to 5 carbon atoms, cyclo hexyloxy | carbonyl, carboxamido, H-cyclohexyl carboxamido, .alpha.-phenyl-carboxamido, alkanoyl amino of which the alkyl residue is linear or; Branched with 2 to 5 carbon atoms, cyclohexyl carbonylamino, benzoylamino, K-alkylcarbamoylamino of which the linear or branched alkyl radical has 2 to 5 carbon atoms; II- (paramethoxyphenyl) -carhamoylamino, ΙΓ-Ιί-dimethyl carbamoyla-, * mino, morpholinocarbonylamino, ϊί-ïf'-dimethyl carbamoylamino or 3 ° · ethoxy carbonylamino, either the sequences ethyl acetate, carboxamido methyl or N methyl carboxamido methyl ; . p = 2; R ^ = R ^ = H; Rg represents the acetyl group; ! . p = 2; Rg = R ^ = K; represents the acetamido group; : yj. p = 1 or 3; R ^ = Rg = H; R ^ represents either the hydrogen atom or the group; acetyl, acetamido or H-methylearbamoyl amino; : -0-r - a naphthalene ring of the type> 0 in which represents a group; acetyl, acetamido or N-methyl carbamoyl amino; 40 * '113; ~ a heterocycle of the type) “\ in which q takes the values 1 or 2 * \ _, (CHg) and K.jQ has the same meanings as previously, R not being able to represent an acetyl group when q = 1; 3 '0 - the motif of formula (oxo-1, têtrahydro 1-2-3-½ naphthyl-6 of formula - + either the value (2, OH, Oxygen, 0), the radical Ar then representing: - either a aromatic unit of the type: w ^ C00iwj.aas which R represents; 10 Rl1 J 1 'the hydrogen atom or the methoxy group -O-R10 - either a heterocycle of type 0-¾ in which R1Q has the same meaning as above; + is the value (1, H, Oxygen, 0), the radical Ar then reorienting a 15 _ "Ό ~ Ε12 heterocycle of the type: in which represents the group acetyl, acetamido, îi-methyl carboxamido or K-nethylcartamoylamino ; + either the value (l, OH, S, 0), the radical Ar then representing: 20 d. - or an aromatic motif of the type ~ ^ 3 ^ 0GH ^. in which R ^ represents R11 the hydrogen atom or the methoxy group, -Oa - or a heterocycle of type ni 13 in leauel R, “represents 25 U 13 ‘the hydrogen atom or the acetyl group. -r either the value (1, OH, -H-, 0), the radical Ar then representing the phenyl group, CH_ 30 3 -r either the value (1, OH, oxygen, l), the radical Ar then representing the 'phenyle group, == represents: 35. or the U-fluorophenyl group; 3,5 dimethoxyphenyl, or 3> k-methylene-dioxyphenyl; + or an aromatic unit of the type R-jj.0 — v \ in which represents CK30 ^ the hydrogen atom or a linear or branched alkyl residue having 2 to 11U has 3 carbon atoms, in which case the set of parameters (n, Rj # X ', m) takes the value (T, OH * Oxygen, 0) and the radical Ar represents the pattern COCH ^ OO w R_ ^ OCH3 - represents the pattern in which case 1 * set of parameters (n , R ^, X, m) takes the value (l, OH, Oxygen * O) and the radical 'Ar represents the motif _ ^ _ 000Ηο «y 2. As medicaments, the compounds of formula (1) according to claim 1. 3. Process for the preparation of the compounds of formula (l) according to claim 1 with the exception .cases compounds of formula (l) in which s either - represents the unit ^ * 3 \; either X represents the methylaaino group; let CS ^ O- ^ j H- | represents the hydrogen atom; either Ar represents the motif -Çl ^ characterized .. o o - in that it 1 '—f consists in condensing a piperazine or a honopiperazine of formula (il):, E’-ii iS — h (xil 1 BVgv in which n takes ie3 values 1 and 2 and y./— has the same meanings ch3 ° as in formula (I) with the exception of the value H0_V \ V_ with an epoxide of formula (îll); \ / X'— Ar · (XXI) in which Ar 'has the same meaning as Ar in formula (i) with the exception of the value _5 and X1 represents the atone of oxygen or sulfur or with W l epoxy -2.3 benzyloxy-1 propane. lr. Process according to claim 3, characterized in that the condensation takes place in ethanol at reflux. 5 · Process for preparing the compounds according to claim 1 corresponding to formula (I) in which: R ^ cH3 °; 7 £ aV_ represents the KO motif —or in which the radical CS ° \ 115 Ar represented the motif, characterized in that it consists in hydrolyzing OI the acetoxy group of the compounds of formulas (la) and (ib) OCH_ 0 _A_coCh3 Cto aj) s I 0C "3 / ^ - °, ™! O / 'CH30 o OH o ^ j) by an alcoholic solution of sodium bicarbonate. 6. Process for the preparation of the compounds according to claim 1 corresponding to formula (l) in which X represents the methylamino group: characterized in that it consists in condensing an epoxide of formula (Illii): "Λ o CH3 ° Ν ^ Λτ / \ (III h) CHO ^ 3 ... f with N-methylaniline in alcoholic medium. t T · Process for the preparation of the compounds according to claim 1 corresponding to formula (l) in which R ^ represents the hydrogen atom, characterized in that it consists in condensing the piperazine of formula (lie): CH3 ° . 0 CH3 ° “Ö ^ V ^ Qi-h (II c) ch3o with a chlorinated derivative of formula (XXVII): Cl / \ y \ 0 - ^ - H12 (XXVII) 0 0 w in which R represents acetyl groups, acetamido, ÏT-methyl carboxamido or ïï-methylcarbamoyl amino, in solution in acetonitrile, in the presence of potassium carbonate. '+ Λ S ι Ίο 8. As intermediary, the compound of formula (I): CH3 ° \ '<*) CK3 ° \ 0 OH 9. As intermediates, the compounds of formula (H ^) and (ΙΙ &) CH 0 ^ 3 N ^ = \ LL (lit) - H ... · CH 0 ^ '0 “' - · - <IIa> in which R represents the following aromatic groups: - OCH ^ CH 0. · W C ^ CT; CH ^ / - 7 CH 0 ^ CH3 ° \ W-O “ou> -c ° H · ^ \ Ciï ^ O CH3 ° Ί0. As intermediates, the compounds of formula (III) T ^ X'-Ar '(III) o7 in which: - X' represents an oxygen atom and the radical Ar 'represents: a) a mono phenyl ring or polysubstituted: -V \\ _ R '^ K'a ^' 3 in which R '^, R' ^, R '^, R' ^ and R'g simultaneously represent the following values: • R'3 = R'5 = R'6 = H; R * 2 =? ; R ’^ COC ^. R '3 =? I' = R1 g = H; R’2 = OCH3; R ’^ = COCH ^, COEt -. R’3 = R’5 = R’6 = H; R’2 = C1; R '^ COCH ^ ÏÏ02 * R'2 = R’5 = R’6 = K; R'3 = CH3; R ’^ ÏÏC ^, NH-C0NH-CH3 11T. R · * R'g = H; “OCHg; R '^ = liHCOÏP-CIH ^. R‘3 = R’5 = H; R'2 = R1 g = Cl; R ’^ - COCï ^, KHCOMCH3 - R’ = R * _ = H; R10-R *,. = 0CHo; R = C0CHo »COOSfc, or ÎIHC02IHCER i j 2 o 3 3 3. R '= H; rf \ = R '_ = RV = OCE, R’1 = C0CH_. 3 P 5 o 3 2 _ 3 - -. · .., R, .2 = R'3 = r'5 = R’6 = H; R ’lf ^ T® 'RV Rft <. / 8 '"b) .a heterocycle of formula - ^ ~ ^ -R' ^ in which H, · - p, R '^., R'g and Rg take simultaneously the following values:. P = 2; R * = B * g = H; R '^ represents the groups raethoxy ·, acetoxy, cyano, alkoxyearbony ç. In which · - -. The alkyl residue is linear or branched and contains from 3 to .6 carbon atoms, cyclohexyloxy- earbonyle, carboxamido,. \ - H-cyclohe: <ÿ ± carboxsmido, -ïï-phenyl carboxamido, elcanayi-ardno in which the linear or branched alkyl residue has from 2 to k carbon, cyclohexylcarbonylamino, benzoylamino, îi-allcÿicarbanoylanino of which. the linear or branched alkyl residue has from 2 to 5 carbon atoms, - - [· îî- (paranethoxyphenyl) carbamoylamino, H, Iî diaetiiylcarbamoylamino, morpholïno carbonylamino, II-M 'dimethyl carbamoylamino. or ethoxyearbonylamino or "well acetate linkages ethyl, carboxamidomethyle or iî-Eiéthylcarboxamido-raethyl. . p = 2; R ’^ = R'g = H; R’g represents the acetyl group. - · P = 2; R'g = R ’^ = H; R 'represents the acetamido group. p = 1 or 3; R '^ = R’q = H; R '^ represents the acetyl, ac and ami do or IT-nethyicarbsmoylemxno groups. c) a naphthalene nucleus of type \ j <* / in which R ^ q represents the acetyl, acetamido or isl-methylcarbamoylamino · / ra groups. -r ,, 10 d) a heterocycle of the Çfâty type in leiu®- 1 and? -'- 0 Simultaneously take the following values: q = 1 in which case R'-jq represents the acetamido and lî-ûéthyl— carbamoylamino groups q = 2 in which case R'-jq represents the acetyl, acetamido and N-netbylcarbamoylamino groups H 113 - X 'represents a sulfur atone'and the radical Ar' represents: f) an arcmatial motif of the type ~ (Q- COCK3, .. ... "..... HC .. in which represents the hydrogen atom or the nethoxy group .g) a heterocycle of the type in which represents the atom w. hydrogena "or the acetyl group. 11. As an intermediary, the epoxide of formula (illh): 0 'ch30d / - \ ^ / \ (iiï h) ch3o ^ · 12. As intermediaries, Ie3 compounds of formula (IV ^): R '- ^ rx ci (r, ra ^ 0.> R R ".. OCH_ OCH- in which: represents the motifs \ = / and \ _0.— "0C3 ^ X CïïjOX7 13. As intermediates, the compounds of formula (V): och3 r, iU ° ^^ ooh (v) 0CH3 r in which R * ^ represents the ethyl and isopropyl groups. he·. As intermediates, the compounds of formula (VII); - - H - X '- Ar' (VU) in which: - X 'represents the oxygen atom in which case Ar' represents:. a polysubstituted phenyl ring: t ’y -h / JV-iih-cc-nr-c: ^. n "X ^ p" l · 119 in which: R ”3, R" and R "g take simultaneously the following values. R ”3 = * yR" é = H; R ”2 = CH3 - Rn5 = R” 6 = H; R "2 = R” 3 = OCH3 5. R "3 = R" 5 = H; R "2 = K" 6 = C1. R "3 = R" 5 = H; R'2 = R "6 = 0CH3. A naphthalene nucleus of formula: 10 ——KH-C0irK-CH3 ·. A heterocycle of formula: j 15 .__ ^ -_ KH-C0NH-CH3S OR 11H-C0CH3 \ !. Λ “®2 '* j in which q takes the values 1 or 2. 20”. A heterocycle of formula: R "7 r" 8' -H- S ”g (VHk! 0 ^ 0 25 'WP in which p , R '\ p R'q and R,? 9 take simultaneously the following „„ values: • 0 = 2 J R'r = RUg = H; Rf, 9 represents either the acetoxy, cyano, alkoxy carbonyl groups in which the alkyl residue is Λ linear or branched and contains from 3 to 5 carbon atoms, cyclohexyloxy carbonyl, earboxamido, 35 N-cyclohexyl earboxamido, I-phenyl earboxamido, alkanoylamino, the alkyl residue of which is linear or branched and has from 2 to 5 carbon atoms', cyclohexylcarbonylamino, benzoylamino, K-alkyl-carbamoylamino, the alkyl residue of which is linear or branched and has 2 to 5 carbon atoms. 120 N-paramethoxyphenyl carhanoylemino, IT-IT-dimethyl earbamoylamino, norpholino-carbonylamino, hi-dimethyl earbamoylamino or ethoxycarbonylamino; either the ethyl acetate, carboxamidomethyl and N-methylcarhoxamido methyl chains. p = 1 or 3; R "= R" g = H; R '^ then shows the acetyl groups ac and ami do or II-methylcarhamoylamino, - X' represents the sulfur atom and the radical Ar * represents: 10.a heterocycle of formula: C0CH3 ° ®3 15 .a heterocycle of formula : 0 0 v_y 20 [in which represents the hydrogen atom or the acetyl group. 15. As synthesis intermediates, the compounds of formula: 25 - c \ T 30 in which B represents: - the group —COCH ^ och3 35. representing an atony of oxygen or sulfur, or - the group _π V_a> T 13 in which R represents the hydrogen atom or the acetyl group. ^ 0 A then representing an oxygen or sulfur atom. * 121 16. As synthetic intermediates, the compounds of formula: - <x H · in which: - p = 2 in which case R '"^ represents the methoxy, hydroxy / acetoxy, alkoxycarbonyl group in which the alkyl residue is linear or branched and contains from 3 to 5 carbon atoms, cyclohexyloxy carbonyl, carboxamido, îi-cyclobexyl carboxamido, îl-phenylcarboxamido, alkanoylamino, the alkyl residue of which is linear or branched and contains from 2 to 5 carbon atoms, cyclohexylcarbonyl— auino, benzoylamino , 11-alkylcarbamoylamino, the alkyl residue of which is linear or branched and contains from 2 to 5 carbon atoms, N-pararnethoxyphenyl1 carbamoyl— amino, ethoxycarbcnylamino, NN 'dimethyl carbamoylamino, methylamino, morpho-linocarbonylanino, II-H, dimethylcarbamomethylino, ïï-methyl-carboxamidométnyle, nydroxycarbonylméthyl, cyano, ethyl acetate, - ~ 1 or - * cas ® 9 represents an acetyl group, acetamido, P 'N-methylcarhamoylaminOy anino / acetyloxime. 17. As a synthesis intermediate, the compound of formula ICIII: i (xxiii) OH ^ OK. | '1; '. I. · 13. As a synthesis intermediary, the compounds of formula XXVII: b '· α / ν \ ο-ρ-Βι2 (Hra? V 0. 0 w in which represents the acetyl, acetamido, lî-nethyl carboxamido or · Η methylcarbamoyl amino,