WO1995025731A1

WO1995025731A1 - NOVEL 3-(φ-(4-BENZOYLPIPERIDINO)ALKYL)-4H-BENZOPYRAN-4-ONES, PREPARATION AND THERAPEUTICAL USE THEREOF

Info

Publication number: WO1995025731A1
Application number: PCT/FR1995/000327
Authority: WO
Inventors: Jean-Pierre Rieu; Jean-François Patoiseau; Gareth John; Bruno Le Grand; Jean-Pierre Valentin
Original assignee: Pierre Fabre Medicament
Priority date: 1994-03-18
Filing date: 1995-03-17
Publication date: 1995-09-28
Also published as: FR2717479A1; AU2076195A; FR2717479B1

Abstract

Novel 3-(φ-(4-benzoylpiperidino)alkyl)-4H-Benzopyran-4-ones and derivatives thereof having formula (I), wherein the radicals have the following definitions: R1, R2, R3, R5, R6, which are the same or different, are hydrogen, lower alkyl, lower alkyloxy, hydroxyl, acetoxy, halogen, nitro, an amino grouping optionally substituted by lower alkyl, acetamido or methanesulphonamido, and two radicals may be fused to give a methylene dioxy; R4 is hydrogen, lower alkyl, benzene optionally substituted by one or more of hydroxyl or methoxyl; and A is an optionally branched C2-12 alkylene grouping.

Description

News 3- (ω- (4-benzoylpiperidino) alcoyl) -4H-Benzopyran-4-ones, their preparation and their therapeutic application.

Coronary heart disease is the leading cause of death in the western world. Myocardial ischemia has a very complex etiology and is only treated with drugs acting indirectly. The derivatives currently used in angina and myocardial infarction are β-blockers, nitrates and calcium channel blockers which all act indirectly through a hemodynamic phenomenon.

However, it is recognized that metabolites produced very early in ischemia (phospholipid catabolism and glycolysis) interfere with the inactivation of sodium current and therefore cause sodium overload. This generates, via the sodium-calcium exchange in the myocyte, a calcium overload (Kohlhardt M. et al, (1989) FASEB J. 2 p 1963-7 and Undrovinas AI et al, (1992) Circulation Research 21 p 1231-41). This final calcium overload induces myocyte contracture.

Recently, new compounds without significant hemodynamic effect and acting on sodium overload have been claimed (Massingham R., John GW and Van Zwieten, Drugs of Today (1991) 22 (8) p 459-77) by the Janssen laboratories (E. Boddeke et al, TIPS (1987) 1Q p 397-400; Ver Donck L., Borgers M., Verdonk F. Cardiovascular Research (1993) 22, p 349-357; Brevet EP 0184257) and Syntex (Patmore L. et al Br. J. Pharmacol (1991) 104, supplement 175 P; Alps BJ, Br. J. Clin. Pharmacol (1992) 24, 199-206 and US Patent 4,829,065).

However, these compounds do not have an anti-aggregating action and cannot be used in the case of ischemia of the heart induced by a thrombus and in attacks of unstable angina which call upon aspirin and other anti-aggregating agents.

Derivatives of 4H-benzopyran-4-ones substituted in 2 or 3 have been recently claimed (cf. Patent FR 2694005 of 28.01.94). These products have a strong selective affinity for sigma receptors and are useful in disorders of the central nervous system. The object of the present invention is the development of a cardiac cytoprotective molecule acting on the two main causes of myocardial ischemia: at the level of the thrombus by an anti-aggregating action and directly at the level of the cardiomyocyte by opposing the sodium and calcium overload inducing contracture. Such compounds are active in cardiology as a preventive and curative measure in cardiac and cerebral ischemia, angina attacks of all types, in myocardial infarction, and as an anti-atheromatous agent. MOLECIJI.ES REVENDIQUEES.

The molecules of the present invention belong to the class of substituted 3- (4-benzoyl piperidino alcoyl) -4H-Benzopyran-4-ones and have the formula I:

in which the radicals are defined as follows: Ri, R2, R3, R5, R6 equal or different represent

* hydrogen,

* a branched or unbranched alkyl containing from 1 to 4 carbon atoms,

* an alcohol; xy branched or not containing 1 to 4 carbon atoms,

* a hydroxyl * an acetoxy

* a halogen group

* a nitro group

* an amino group substituted or not by a branched alkyl or not containing from 1 to 4 carbon atoms * an acetamido or methanesulfonamido

* and two radicals can merge to give a methylene dioxy. R4 represents

* hydrogen

* a branched or unbranched alkyl containing from 1 to 6 carbon atoms * a benzene substituted or not by one or more hydroxyl or methoxyl

A represents a branched or non-branched alkylene group containing from 2 to 12 carbon atoms.

When the compounds of formula I contain an asymmetric carbon, the present invention relates both to racemic mixtures and to the various enantiomers or diastereoisomers or their mixtures.

The present invention also includes the therapeutically acceptable inorganic or organic salts of the compounds of general formula I and their possible hydrates.

The present invention also relates to the use of the compounds of general formula I as a medicament and to the pharmaceutical compositions containing it. These preparations can use one or more compounds of formula I in combination, possibly ^'with other active principles.

Finally, the synthetic methods allowing access to the compounds of general formula I also form part of the present invention.

SYNTHESIS OF T-STRUCTURE COMPOUNDS:

The compounds of the present invention are prepared by condensation of a substituted 4-benzoyl piperidine II with an ortho [ω- bromo (or chloro) acyl] phenol III, at reflux in an alcohol in the presence of tertiary amine to give a substituted ortho [ω- (4-benzoyl piperidino) acyl] phenol IV (reaction A).

This derivative IV is cyclized:

- in the presence of dimethylacetal: dimethylformamide (R4 = H) or dimethylacetamide (R4 = CH3) by heating between 25 and 80 ° (Reaction B).

(B)

- either with the anhydride or acid chloride pair, sodium salt of the corresponding acid by heating around 140 - 180 ° when R4 ≠ H (reaction C). (VS)

Intermediate III can be prepared using two methods:

1 °) Or by Friedel-Crafts reaction followed by a selective demethylation: the condensation of a chloride of ω-chlorinated acid or bromine V on a substituted methoxy benzene VI in the presence of AlC ^ in a chlorinated solvent gives the Corresponding orthomethoxylated ketone VII which is not isolated and is selectively demethylated with an additional mole of AlC 4, in the presence (or not) of an Ether-acetonitrile mixture according to reaction D to give compound III:

σ>)

< ^V1 > (V) (VII)

2 °) Or by Claisen condensation when ketones III are not accessible by Friedel Crafts reaction (in particular if Ri = R2 = R3 = H). Thus the condensation of a substituted orthoanisate VIII on an appropriate lactone (IX) in the presence of a sodating agent in toluene gives an anisoyl lactone (X) which is then hydrolyzed by concentrated HBr. Decarboxylation is immediate followed by demethylation (hot) to directly give compound III according to reaction (E).

(VII!) (IX) (Xa or enolic form Xb)

Compounds containing an amino group can also be prepared by catalytic reduction of the corresponding nitro compounds. The condensation of the amino derivative with acetyl or mesyl chloride provides the substituents acetamido and methane sulfonamido. The compounds containing a hydroxyl group can also be prepared by demethylation of the corresponding methoxylated derivatives. Example 1:

3- [3- [4- (4- (4-fluorobenzoyl) piperidino] propyl] -6- methoxy-4H-Benzopyran-4-one] hydrogen maleate. I (Rι = R2 = R4 = R6 = H; R3 = 6-MeO; R5 = 4-F; A = (CH2) ₃ ). a) Synthesis of 5-Bromo-2'-hydroxy-5'-methoxy-valerophenone III (Ri = R2 = H, A = (CH2) 3). A solution of 3.45 g (25 mmol) of 1,4-dimethoxybenzene and 5.24 g (26 mmol) of 5-bromovaleryl chloride in 40 ml of dry methylene chloride is cooled to -10 ° and then treated with fraction with 3.50 g (26 mmol) of anhydrous aluminum chloride previously ground. After addition, an additional 1/4 h is stirred at this temperature and then left to return to 25 ° overnight. The dark orange-red reaction mixture is cooled to -10 ° and then treated with 3.5 g of additional aluminum chloride, then 5 ml of acetonitrile and then 10 ml of ether are added dropwise and the mixture is brought to 10 h at reflux. After returning to 25 ° the mixture is poured into 200 ml of crushed ice plus 20 ml of concentrated HCl. The expected compound is extracted with ether, washed with water and then with salt water and dried over sodium sulfate. The residual oil obtained after evaporation of the solution is triturated in isopropyl ether to give 5.63 g (Yield: 78%) of pale yellow crystals of formula la.

(the)

Gross formula: C12H15B1O3

Molecular mass: 287.15

Melting point: 92 ° C

NMR (CDCI3) δ: 1.75 - 2.1 (m, 4H); 3.03 (t, 2H); 3.4 (t,

2H); 3.8 (s, 3H); 6.95 (d, 1H); 7.06 - 7.3 (m, 2H); 11.9 (s, 1H). b) Synthesis of 2- [5- [4- (4-Fluorobenzoyl) piperidino] pentanoyl] -4-methoxy Phenol IV (Rι = R2 = R4 = R6 = H; R3 = 5-MeO, R5 = 4-F) . To a solution of 2.00 g (7 mmol) of derivative present in 30 ml of ethanol RP is added 3.00 g (8 mmol) of paratoluene sulfonate of 4-parafluorobenzoyl piperidine and the mixture is brought to reflux for 10 hours and a overnight at 25 °. The mixture is evaporated to dryness and the oily residue is taken up in methylene chloride, washed with water, then with salt water, dried over sodium sulphate and evaporated to dryness. The residue is purified by Flash chromatography, eluting with a CH2θ2-MeOH 97/3 mixture. 2.31 g (yield 80%) of a brown oil of formula lb are obtained.

This oil is used as is in the next step.

This intermediate can be characterized in the form of a salt by hydrochlorination with a solution of HCl 2N in ethanol, the hydrochloride crystals are filtered and recrystallized from a boiling alcohol-water mixture 85-15. Gross formula: C24H29CIF NO4

Molecular mass: 449.95 Melting point: 208 - 209 °

NMR (DMSO d6) δ: 1.7 - 2.3 (m, 8H); 35-4 (m, 9H); 3.76 (s, 3H); 6.95 (d, 1H); 7.17 (d.d., 1H); 7.3 - 7.5 (m, 3H); 8.11 (q, 2H); 10.45 (broad 1H); 11.38 (s, 1H).

IR. v C = O: 1670 and 1639 cπr *. c) Synthesis of the hydrogenomaleate of 3- [3- [4- (4- fluorobenzoyl) piperidino] propy l] -6-methoxy-4H-Benzopyran-4-one. The preceding oily base (1 g, 2.4 moles) is dissolved in 4 ml of DMF then treated at 25 ° with 1 ml, dimethyl formamide dimethylacetal and stirred for a weekend at this temperature (or 2 h at 70 ° VS). The mixture is then evaporated to dryness and the residue is taken up in 50 ml of CH2Cl2 washed with water, with salt water, dried over sodium sulphate and then evaporated to dryness under vacuum. The solid residue is recrystallized from 40 ml of ethanol at 95 ° to give 610 mg (yield 60%) of white crystals (melting point: 157 °). This base is dissolved in 25 ml of hot ethyl acetate and then treated with 166 mg of maleic acid dissolved in 5 ml of the same solvent and stirred for 2 h at 25 °. 520 mg (yield: 40%) of white crystals of formula 1 are recovered.

(D

Gross formula: C29H30FNO8

Molecular mass: 539.53

Melting point: 180 °

NMR (DMSO d6) δ: 1.8 - 2.1 (m, 6H); 2.4 - 2.6 (m, 2H); 2.8 -

3.8 (m, 7H); 3.86 (s, 3H); 6.02 (s, 2H); 7.3 - 7.5 (m, 4H);

7.63 (d, 1H); 8.08 (q, 2H); 8.30 (s, 1); 9.08 (s, wide

2H).

IR (KBr): V C = 0: 1668 and 1646 cm-1.

Example 2:

Preparation of 3- [3- [4- (4-fluorobenzoyl piperidino] propyI] -6-methoxy-4H-Benzopyran-4-one-4/3-hydrate hydrochloride I (Ri

= R ₂ = R4 = 6 = H; R3 = 6-MeO, R ₅ = 4-F; A = (CH ₂ ) 3). By operating in the same manner as in Example 1 but by treating the base obtained dissolved in alcohol with a solution of hydrochloric acid (gas) 2N in ethanol RP, the hydrochloride hydrate is obtained with a yield of 50% of formula 2.

-

Gross formula: C25H27CIFNO4, 4/3 H2O

Molecular mass: 483.96

Melting point: 230 ° Example 3:

Preparation of 3- [3- [4- [benzoylpiperidino] propyl] -6-methoxy-4H-hydrogen hydrogenateate Benzopyran-4-one. I (RI = R2 = R4 = R ₅ = H, R ₃ = 6-MeO, A = (CH ₂ ) ₃ ).

By condensing 2- [5- (4-benzoylpiperidino) pentanoyl] -4-Methoxy-phenol (prepared according to lb with a yield of 56%) on DMF-DMA 1a according to the process described in the example, we obtain with a yield of 49% for the compound of formula 3.

Crude formula: C29H3 NO8 Molecular mass: 521.55

White crystals

Melting point: 147 °

NMR (CDI3) δ: 2-4 (m, 15H); 3.90 (s, 3H); 7.2 - 7.8 (m, 6H);

7.85 - 8.15 (m, 3H), 12 (s, wide, 2H). IR (KBr) v (C = O): 1680 and 1633 cm " ¹ .

Example 4:

Preparation of 3- [3- [4- (4-Methyl benzoyl) piperidino] propyl] -6-methoxy-4-H-Benzopyran-4-one I hydrochloride (R = R2 = R4 = Rβ = H; R3 = 6 - MeO; R ₅ = 4-Me). Cyclization of 2- [5- [4- (4-Methyl benzoyl) piperidino] pentanoyl] -4- Methoxy phenol (prepared with a yield of 51% according to the lb process) carried out according to procedures 1C and 2 leads with a yield of 61% to the compound of formula 4.

Beige needles Gross formula: C26H30CINO4

Molecular mass: 455.96 Slow melting point: 216 °

NMR (CDCI3) δ: 2 - 3.9 (m, 15H); 2.33 (s, 3H); 3.80 (s, 3H); 7.1 - 7.5 (m, 5H); 7.70 (d, 2H); 7.94 (s, 1H); 11.88 (s, large, 1H).

IR (KBr): v C = O: 1667 - 1641 cm "l. Example 5:

Preparation of 3- [3- [4- [4- (4-fluorobenzoyI) piperidino] propyl] -5,7-dimethoxy-4H-Benzopyran-4-one hydrochloride monohydrate. I (Ri = R4 = R6 = H; R2 = 5-MeO; R3 = 7-MeO; R ₅ = 4-F; A = (CH ₂ ) 3). The condensation of 5-bromovaleryl chloride on 1,3,5-trimethoxy benzene according to the process leads it with a yield of 62% to 3,5-dimethoxy-2- (5-bromopentanoyl) phenol (F = 76 °) . This compound condensed with 4- (parafluorobenzoyl) piperidine by adapting the process lb makes it possible to prepare, with a yield of 72%, 3,5-dimethoxy-2- [5- [4- (4- fluorobenzoyl) piperidino] pentanoyl] phenol (F = 115 °). The cyclization of this compound by heating at 60 ° for 2 h 30 min according to the process described in Example 1a and 2 provides with a yield of 72% the compound of formula 5.

(5)

Crude formula: C26H31CIFNO6 Molecular mass: 507.93 Beige powder

Melting point: 214 - 216 °

NMR: (DMSO dg) δ: 1.7 - 2.25 (m, 6H); 2.25 - 2.45 (m, 2H);

2.8 - 3.2 (m, 4H); 3.25 - 3.8 (m, 5H); 3.81 (s, 3H); 3.82 (s. 3H); 6.55 (d.d., 2H) 7.38 (t, 2H); 8 - 8.2 (m, 3H); 10.59 (s, wide 1H).

BR (KBr) v C = O 1678 and 1650 cπrl.

Example 6:

Preparation of 3- [3- [4- (4- (

Fluorobenzoyl) piperidino] propyl] -6,7-dimethoxy-4H-Benzopyran-4-one. I (Ri = R4 = R6 = H; R ₂ = 6-MeO; R3 = 7-MeO; R ₅ = 4-F, A =

(CH ₂ ) 3).

By condensation of 5-bromovaleryl chloride on 1,2,4-Trimethoxy benzene according to the process, it is prepared with a yield of 80%.

4,5-dimethoxy-2- (5-bromopentanoyl) phenol (mp 106 °). By reaction with 4- (4-fluorobenzoyl) piperidine according to process 1b, 4,5-dimethoxy-2- [5- [4- (4-fluorobenzoyl) piperidino] pentanoyl] phenol is obtained with a yield of 78% under form of oil which is cyclized directly according to process le and 2 with a yield of 40% to give the compound of formula 6. (6)

O

Crude formula: C26H29CIFNO5 Molecular mass: 489.95 White powder

Decomposition point: 245 °

NMR (DMSO d6) δ: 1.85 - 2.1 (m, 6H); 2.49 (t, 2H); 2.4 - 4.2 (m, 7H); 3.85 (s, 3H); 3.90 (s, 3H); 7.19 (s, 1H); 7.3 - 7.5 (m, 3H); 8 - 8.2 (m, 2H); 8.26 (s, 1H); 11 (s, large 1H). IR (KBr) V .C = O: 1682 and 1635 cm-1.

Example 7:

3- [3- (4-benzoylpiperidino) propyl] -6,7-dimethoxy-4H-Benzopyran-4-one hydrochloride. I (Rι = 4 = R5 = R6 = H; R2 = 6-MeO; R3 = 7-MeO; A = (CH2) 3). By using 2- [5-bromopentanoyl) -4,5-dimethoxy-phenol prepared as in Example 6 but by condensing it on 4-benzoyI piperidine according to Example 1b, a 4% yield is obtained. , 5-dimethoxy-2- [5- (4-benzoylpipe-ridino) pentanoyl] phenol in the form of an oil. This derivative is directly cyclized according to the process 1 and 2 with a yield of 32% to give the compound of formula 7:

(7)

O

Crude formula: C26H30CINO5 Molecular mass: 471.96 White crystals Decomposition point: 235 °

NMR (CDCI3) δ: 2 - 3.9 (m, 15H) 3.93 (s, 3H); 3.95 (s, 3H);

6.82 (s, 1H); 7.39 - 7.65 (m, 4H) 7.8 - 8 (m, 3H); 12 (s, wide,

1H).

IR (KBr): v C = O: 1678 and 1640 cπr. Example 8:

3- [3- [4- (2,4-difluorobenzoyl) piperidino] propyl] -6,7-dimethoxy-4H-Benzopyran-4-one hydrochloride hydrochloride hydrate

I (Ri = R4 = H; R ₂ = 6-MeO; R3 = 7-MeO; R ₅ = 2-F; Rg = 4-F; A = (CH ₂ ) ₃ ). By adorning as above 2- [5-bromovaléyl] -4,5-dimethoxyphenol and condensing it on the 4- [2,4-difluorobenzoyl) piperidine according to example lb is prepared with a yield of 67% the 4,5-dimethoxy-2- [5- [4- (2,4-difluorobenzoyl) piperidino] pentanoyl] phenol in oily form which is cyclized according to process le and 2 with a yield of 30% of compound of formula 8:

(8)

Crude formula C26H30CIF2O6 Molecular mass: 525.96 White crystals Decomposition point: 200 ° NMR (CDC1 ₃ ) δ: 1.82 (s, 2H); 2 -3.85 (m, 14H); 3.96 (s, 3H); 3.98 (s, 3H); 6.75 - 7.15 (m, 3 H); 7.48 (s, 1H);

7.80 - 7.94 (m, 1H); 7.96 (s, 1H); 12 (m, 1 H). IR (KBr) V C = O 1686 and 1638 cm "l.

Example 9:

6,7-Dimethoxy-3- [3- [4- [4-methoxy-benzoyl) piperidino] propyl] -4H- hydrochloride

Benzopyran-4-one. I (R-ι = R4 = R6 = H; R2 = 6-MeO, R3 ≈ 7-MeO,

R ₅ = 4 MeO; A = (CH ₂ ) ₃ ).

The 2- (5-bromovaleryl) -4,5-dimethoxyphenol prepared in Example 6 is condensed with 4- (4-methoxybenzoyl) piperidine as in the process described in Example 1b to give with a yield of 73% 4,5- dimethoxy-2- [5- [4- (4-Methoxy-benzoyl) piperidino] pentanoyl] ρhenol (F =

205 °) whose cyclization according to and 2 leads with a yield of 74% to compound 9 of formula:

Gross formula: C27H32CINO6

Molecular mass: 501.99 White crystals Decomposition point: 235 239 ° C NMR (DMSO d) 1.8 - 2.25 (m, 2H); 2.3 - 2.65 (m, 3H) 3.3 - 3.75 (m, 6H); 3.85 (s, 6H); 3.90 (s, 4H); 7.07 (d, 2H) 7.37

(s, 1H); 7.97 (d, 2H); 8.27 (s, 1H); 10.3 (m, 1H). IR (KBr) v C ≈ O: 1667 and 1634 cm "!. Example 10:

7-Methoxy-3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -4H-Benzo-pyri.n-4 one hydrochloride. I (Ri = R2 = R4 = R6 = H; R3 = 7-MeO, R ₅ = 4-F; A = (CH ₂ ) ₃ ). By condensation of 5-bromovaleryl chloride on 1,3-dimethoxybenzene according to the 2- (5-bromoρentanoyl) -5-methoxyphenol (M = 62 °) is prepared with a yield of 61%. The N-alkylation of 4- (4-fluobenzoyl) piperidine with the preceding derivative according to lb leads to 2- [5- [4- (4-fluorobenzoyl) piperidino] pentanoyl] -5-methoxy-phenol (F hydrochloride: 218 °) with a yield of 59%. This derivative is cyclized with DMF-DMA according to process 1c and 2 to give, in a yield of 76%, compound 10 of formula:

Gross formula: C25H27CIFNO4

Molecular mass: 459.93

White powder Melting point: 237 ° C

NMR (DMSO dg): 1.8 - 2.3 (m, 6H); 2.35 -2.7 (m, 3H); 2.8

- 3.85 (m, 6H); 3.89 (s, 3H); 7 - 7.25 (m, 2H); 7.3 - 7.6 (m, 2H);

7.96 (dd, 1H); 8.03 - 8.24 (m, 2H); 8.28 (s, 1H); 10.53 (s, large 1H) BR (KBr) v C ≈ O: 1670 and 1638 cm " ¹ .

Example 11:

7-methoxy-3- [3- (4-benzoylpiperidino) propyl] -4H hydrochloride-Benzopyran-4-one. I (Ri = R2 = R4 = R5 = Rό = H; R3 = 7-MeO; A = (CH ₂ ) _3. The N-alkylation of 4-benzoyl piperidine by 2- (5-bromopentanoyl) -5- methoxyphenol according to lb and 10 provides 2- [5- (4- benzoylpiperidino) pentanoyl] -5-methoxyphenol with a yield of 49%. Cyclization of this derivative with Dimethyl formamide dimethyl acetal according to and 2 gives the compound of formula 11 with a yield of 59%.

Crude formula: C25H28CINO4 Molecular mass: 441.93 White crystals F = 262 ° C NMR (DMSO d) δ: 1.8 - 2.25 (m, 6H); 2.3 - 2.7 (m, 2H); 2.8 - 3.7 (m, 7H); 3.89 (s, 3H); 6.95 - 7.1 (m, 2H); 7.45 - 7.8 (m, 3H); 7.9 - 8.15 (m, 3H); 8.26 (s, 1H); 9.75 (s, wide 1H). IR (KBr) v C = O: 1666 and 1633 cπrl.

Example 12:

3- [3- [4- (2,4-difluorobenzoyl) piperidino] propyl] -7-methoxy-4H-Benzopyran-4-one hydrochloride. I (Ri ≈ R2 = R4 = H; R3 = 7-MeO;

R ₅ == 2-F; R6 = 4F; A = (CH ₂ )).

Using the procedures: 1b and 10 but starting from 4- (2,4-difluoro benzoyl piperidine, the 2- [5-

[4- (2,4-difluorobenzoyl) piperidino] pentanoyl] -5-methoxyphenol (F =

108 ° C) which by condensation according to, 2, 10 leads with a yield of

30% to compound 12 of formula:

Gross formula: C25H26CIF2NO4

Molecular mass: 477.92

White powder

Melting point: 201 - 204 °

NMR (CDCI3) δ 1.9 - 3.85 (m, 15H); 3.91 (s, 3H); 6.8 - 7.15 (m,

4H); 7.75 - 8 (m, 2H); 8.07 (d, 1H); 12 - 12.4 (m, 1H).

E (KBr) v C = O: 1670 and 1637 cπr *.

Example 13:

3- [3- [4- (4-fluorobenzoyl) piperidino] propyI) -6-methyl- hydrochloride

4H-Benzo-pyran-4-one. I (Rι = R2 = R4 = R6 = H; R3 = 6-Me; R5

= 4-F; A = (CH ₂ ) ₃ .

By operating as in Example 1a but always using the same solvent and after stirring, 24 h at 25 °, 2- (5-Bromovaleryl) -4-methyl phenol is prepared with a yield of 93%. This compound condensed on 4- (4- fluorobenzoyl) piperidine according to lb gives 2- [5- [4- (4- fluorobenzoyl) piperidino] pentanoyl] -4-methyl phenol (yield: 75%), which is cyclized according to the and 2 into a compound 13 (yield: 72%) of formula: (13)

Gross formula: C25H27CIFNO3

Molecular mass: 443.93

White crystals

Melting point: 228 - 229 °.

NMR (DMSO of) δ: 1.8 - 2.2 (m, 6H); 2.35 - 2.6 (m, 5H); 2.85 - 3.2 (m, 4H); 3.4 - 3.95 (m, 3H); 7.3 - 7.5 (m, 2H); 7.54 (d,

1H); 7.62 (d.d., 1H); 7.85 (s, 1H); 8 - 8.2 (m, 2H); 8.33 (s,

1H); 10.2 - 10.8 (m, 1H).

IR (KBr) v C = O: 1674 and 1634 cm "l.

Example 14: 3- [3- [4- (4-fluorobenzoyI) piperidino] propyl) -6-chloro- hydrochloride

4H-Benzo-pyran-4-one. I (Ri = R2 = R4 = Rβ = H; R3 = 6-C1; R5 =

4-F; A = (CH ₂ ) ₃ .

By operating as in Examples 1a and 13 in the same solvent and stirring for 90 h at 25 °, 2- (5-Bromovaleryl) -4-chlorophenol (F = 58 °) is obtained with a yield of 72. The condensation of this compound on 4 (4-fluorobenzoyl) piperidine gives 2- [5- [4- (4- (fluorobenzoyl) piperidino] pentanoyl] -4-chlorophenol (Yield: 45%). This compound is cyclized by DMF-DMA according to Example 1a and 2 to give the derivative 14 (Yield: 70%) of formula: (14)

O

Crude formula: C24H24CI2FNO3 Molecular mass: 464.35 White crystals Decomposition point 235 ° NMR (DMSO d6) δ: 1.8 - 2.1 (m, 6H); 2.2 - 2.30 (m, 2H);

2.35-4 (m, 7H); 7.25 - 7.5 (m, 2H); (7.74 (d, 1H); 7.88 (dd,

1H); 7.95 - 8.2 (m, 3H); 8.37 (s, 1H); 9.5 - 10 (m, 1H).

IR (KBr) v C = O: 1680 and 1645 cπr *. Example 15:

3- [3- (4-Benzoyl piperidino) propyl] -6-chloro-4H-Benzopyran-4-one hydrochloride. I (Ri = R2 = R4 = R5 = Rβ = H; R3 = 6-Cl; A = (CH ₂ ) ₃ ).

Using the bromine derivative prepared in Example 14, the 2- [5- (4-benzoyl piperidino) pentanoyl] -4-chlorophenol (Yield: 70%) is likewise prepared, the cyclization according to and 2 providing with a yield of 86% the compound 15 of formula: (15)

Gross formula: C24H25CI2NO3

Molecular mass: 446.36

Off-white crystals

240 ° decomposition point

NMR (DMSO d6) δ: 1.8 - 2.15 (m, 6H); 2.25 - 2.35 (m, 2H);

2.35-4 (m, 7H); 7.5 - 8.1 (m, 8H); 8.38 (s, 1H); 9.8 - 10 (m,

1H)

IR: (KBr) V C = O: 1678 and 1649 cπrl.

Example 16:

3- [3- [4- (2,4-difluorobenzoyl) piperidino] propyl] -6-chloro-4H-Benzopyran-4-one hydrochloride. I (Rι = R2 = R4 = H; R3 = 6-Cl; R5

= 2-F; RO = 4-F; A = (CH ₂ ) ₃ ).

Starting from the bromine derivative prepared in Example 14 but condensing it on 4- (2,4-difluorobenzoyl) piperidine, one obtains with a yield of 62

% 2- [5- [4- (2,6-difluorobenzoyl) piperidino] pentanoyl] -4-chlorophenol.

This ext oil which is directly cyclized according to examples 1c and 2 to give, with a yield of 42%, the compound 16 of formula: (16)

Gross formula: C24H23CI2F2NO3

Molecular mass: 482.34

White powder

Melting point: 215-220 °

NMR (DMSO d ₆ ); 1.75 - 2.2 (m, 6H); 2.35 - 2.6 (m, 2H); 2.8 -

3.25 (m, 4H); 3.26 - 3.65 m, 3H) 7.15 - 7.55 (m, 2H); 7.72

(d, 1H); 7.78 - 8.05; (m, 3H); 8.37 (s, 1H); 10.47 (s, large, 1H).

IR (KBr) v C = O: 1686 and 1849 cm "l. Example 17:

7,8-Dimethoxy-3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -4H hydrochloride-Benzopyran-4-one. I (Ri = R4 = R6 = H; R2 = 7-MeO, R3 = 8 -MeO; R5 = 4-F, A = (CHfcte). Using the process described in the above, we prepare with a yield of 79% the 2,3-dimethoxy-6- (5-bromovaleryl) phenol, which gives by N-alkylation of 4- (4-fluorobenzoyl) piperidine according to lb 2,3-dimethoxy-6- [5- [4- (4 - fluorobenzoyl) piperidino] pentanoyl] phenol (yield: 59%; M = 140 °). This compound is cyclized according to and 2 to give compound 17 (yield: 71%) of formula:

(17)

Crude formula: C26H29CIFNO5 Molecular mass: 489.95 Decomposition point ~ 235 ° White powder NMR (CDCI3) δ: 1.7 - 3.3 (m, 12H); 3.35 - 3.9 (m, 3H); 3.96 (s, 3H); 3.99 (s, 3H); 6.95 - 7.35 (m, 3H); 7.8 - 8.2 (m, 4H); 12.15 (s, large, 1H). IR (KBr) v C = O: 1678 and 1640 cπrl.

Example 18:

Sesquihydrate of 3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -5,7,8-trimethoxy-4H-Benzopyran-4- one hydrochloride. I (R4 = R6 = H; Ri = 5-MeO, R2 = 7-MeO; R3 = 8-MeO; R5

= 4-F; A ≈ (CH ₂ )).

By applying the process described in la to 1,2,3,5-tetramethoxybenzene, 2- (5-bromovaleryl) -3,5,6- trimethoxyphenol (F = 82 °) is prepared with a yield of 72%. the process lb to au 2- [5- [4-

(4-fluorobenzoyl) piperidino] pentanoyl] -3.5.6 trimethoxyphenol (Yield: 71%

M = 157 °), the cyclization of which according to the process le and 2 gives compound 18 of formula:

(18)

Gross formula: C27H31CIFNO6, I .5H2O

Molecular mass: 546.98

Off-white crystals Melting point: 150 °

NMR (CDCI3) δ: 1.9 - 2.3 (m, 8H); 2.35 - 2.55 (t, 2H); 2.6 -

3.2 (m, 5H); 3.25-4 (m, 3H); 3.83 (s, 3H); 3.92 (s, 3H); 3.96

(s, 3H); 6.38 (s, 1H); 7 - 7.25 (m, 2H); 7.8 (s, 1H); 7.8 - 8.05

(m, 2H); 12 (s, large, 1H). IR: (KBr) v C = O: 1680 and 1648 cπrl.

Example 19:

3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -6,7-methylenedioxy-4H-Benzopyran-4-one hydrochloride. I (R3 = R4 = Rg = H; Rι R2 = 6.7-OCH20; R ₅ = 4-F; A = (CH ₂ ) 3). 19a) Preparation of 2- (5-bromovaleryl), 4,5-methylenedioxyphenol: To a solution of 5 g (36.2 mmol) of sesamol in 40 ml of dry ether add 7.04 g (43.4 mmol) of 5-bromovaleronitrile and then 2 g of anhydrous zinc chloride under a stream of nitrogen. The reddish mixture is cooled to 0 ° and then treated with a stream of hydrochloric gas for 2 h and is maintained for an additional 3 h at this temperature and then allowed to return to 25 ° overnight. The supernatant ethereal phase is separated from the lower brown oil. This oil is washed with ether and then treated with cold water (50 ml) and the mixture is brought to reflux for 45 minutes. The expected product is extracted with ethyl acetate, washed with water, with salt water; dried over sulfate and evaporated to dryness. The residual oil is purified by flash chromatography, eluting with a hexane-ethyl acetate mixture. m = 4.26 g Yield: 40% F = 88 ° * * The compound contains a little chlorine derivative 19b) Preparation of 2- [5- [4- (fluorobenzoyl) piperidino] pentanoyl] -6,7- methylenedioxy- phenol: This derivative is prepared from the above mixture by condensation on 4- (4-fluorobenzoyl) piperidine according to the process described in example lb (Yield: 72%).

19c) The preceding oil is cyclized by heating for 2 h at 60 ° according to the process described in example le and 2 to give, with a yield of 61%, compound 19 of formula:

(19)

O

Crude formula: C25H25CIFNO5 Molecular mass: 473.91

White powder Decomposition point ~ 240 °

NMR (DMSO d6) δ: 1.75 - 2.25 (m, 6H); 2.3 - 2.55 (m, 2H); 2.85 - 3.15 (m, 4H); 3.4 - 4 (m, 3H); 6.21 (s, 2H); 7.25 (s, 1H); 7.3 - 7.5 (m, 3H); 8 - 8.2 (m, 2H); 8.27 (s, 1H); 10.3 - 10.9 (m,

1H).

IR (KBr) v C = O: 1684 and 1640 cnrl. Example 20:

3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -4H hydrochloride-Benzopyran-4-one. I (Rι = R2 = R3 = R4 = R6 = H; R5 = F; A = (CH ₂ ) ₃ ). 20a) Preparation of 2- [α-hydroxy-2-methoxybenzylidene] -tetrahydro-2H- pyran-2-one. Xβ (Ri = R2 = R3 = H; A = (CH2) 3): In a 250 ml reactor, a suspension of 4.08 g (0.1 mole) of 60% sodium hydride in 80 ml of Dry toluene is treated dropwise at 95 ° with a mixture of 16.6 g (0.1 mole) of methyl orthoanisate and 10.5 g (0.105 mole) of freshly distilled δ-valerolactone. The reaction mixture turns orange then after adding 3/4 of the mixture there is a lively effervescence. Heating is continued for an additional 1 h, then the mixture is allowed to return to 25 ° and the reaction mixture is poured into 300 ml of crushed ice plus 100 ml of N hydrochloric acid, stirring by hand. The expected derivative is extracted with ether (2 x 200 ml), washed with a 5% NaHCO 3 solution, with brine and then dried over sodium sulfate and evaporated to dryness (22.6 g of oil brute). This oil is purified by Flash chromatography on 900 g of silica, eluting with a mixture of hexane-ethyl acetate 70-30. 13 g of expected derivative (Yield 58%) are recovered after evaporation in enolic form and of formula 20a. (20a)

N.) CH O

Gross formula: C13H14O4

Molecular mass: 234.24 White crystals Melting point: 95 - 96 °

NMR (CDCI3) δ: 1.8 - 2 (m, 2H); 2.15 - 2.4 (m, 2H); 3.85 (s, 3H); 4.25 - 4.45 (m, 2H); 6.9 - 7.1 (m, 2H); 7.15 - 7.5 (m, 2H);

13.8 (s, 1H).

BR (KBr) VC = O: 1618 cπrl. 20b) Preparation of 2- (5-bromovaleryl) phenol: 5.70 g (24.3 mmol) of the preceding o-anisoyl-δ-valerolactone are added at 0 ° to 40 ml of an aqueous solution of HBr at 48% and the mixture is stirred for 20 minutes at this temperature then it is. - get back to 25 ° and m; , angel is gradually brought to 90 ° for 1 h, then added every 3 h 10 ml of 48% HBr. After 8 h this total reflux, the mixture is cooled, diluted in 200 ml of cold water, extracted with ether, washed with water and then with salt water, dried and evaporated to dryness and triturated in isopropyl ether to give the compound of formula 20b (Yield: 79%).

Gross formula: CnHi3Brθ2

Molecular mass: 257.12 Off-white crystals Melting point: 64 °

NMR (CDCI3) δ: 1.85 - 2.1 (m, 4H); 3.04 (t, 2H); 3.46 (t, 2H); 6.8 - 7.1 (m, 2H); 7.4 - 7.6 (m, 1H); 7.7 - 7.85 (dd, 1H).

IR (KBr) v C = O: 1641 cm "1. 20c) Preparation of 2- [5- [4- (4-fluorobenzoyl) piperidino] ρentanoyl] phenol. This compound is prepared from 20b, as described in l Example 1b with a yield of 76% and a melting point of 80 ° 20d) The cyclization of the preceding compound according to the methods 1b and 2 leads with a yield of 85% to the compound 20 of formula:

Crude formula: C24H25CIFNO3 Molecular mass: 429.90 Decomposition point: 210 ° NMR (CDCI3) δ: 1.8 - 4 (m, 15H); 7.05 - 7.3 (m, 2H); 7.3 -

7.55 (m, 2H); 7.6 - 7.8 (m, 1H); 7.85 - 8.1 (m, 3H); 8.1 - 8.3 (m, 1H); 12.13 (s, large, 1H). IR (KBr) v C = O: 1674 and 1631 cm-1.

Example 21 Hydrate of 3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -8-Methoxy hydrochloride

-4H-Benzopyran-4-one. I (Ri = R2 = R4 = R6 = H; R3 = 8-MeO; R5 = 4-F; A = (CH ₂ ) 3) - From methyl 2,3-dimethoxybenzoate and using procedure 20a, 2- [α-hydroxy-2,3-dimethoxybenzylidene] tetrahydro-2H-pyran-2-one is prepared (yield: 35%, F = 97 °), the hydrolysis of which according to 20b provides 2- (5-bromovaleryl) -6-methoxy phenol (yield: 81%, M = 66 °). This product condensed on 4- (4- fluorobenzoyl) piperazine according to lb leads to 2- [5- [4- (4- fluorobenzoyl) piperidino] pentanoyl) -6-methoxyphenol (yield: 65%, M = 110 ° C) . Finally, the cyclization of this derivative according to and 2 makes it possible to prepare, with a yield of 63%, the compound 21 of formula:

(21)

Crude formula: C25H27CIFNO4, H2O Molecular mass: 477.95

White crystals

Melting point 166 °

NMR (DMSOd ₆ ) δ: 1.8 - 2.3 (m, 6H); 2.35 - 2.55 (t, 2H); 2.8 -

3.2 (m, 4H); 3.25 - 3.85 (m, 5H); 3.94 (s, 3H); 7.1 - 7.5 (m, 4H); 7.5. - 7.65 (m, 1H); 8.82 (m, 2H); 8.4 (s, 1H); 10.2 -

10.5 (m, 1H).

IR (KBr) v C = O: 1672 and 1641 cπr *. Example 22:

3- [2- [4- (4-fluorobenzoyl) piperidino] ethyl] -6-methoxy-4H-Benzopyran-4-one hydrogen maleate. I (R2 = R3 = R4 = Rβ = H; Ri = 6- MeO, R5 = 4-F; A = (CH2) ₂ ).

The reaction of 4-chlorobutyryl chloride on 1,4-dimethoxybenzene according to the conduit with a yield of 83% with 2- (4-chlorobutanoyl) -4- methoxyphenol (M = 80 °). This derivative condensed on 4- (4-fluorobenzoyl) piperidine according to lb gives 2- [4- [4- (4- (4-fluorobenzoyl) piperidino butanoyl] -4-methoxyphenol (yield: 30%). The adaptation of the procedure le to this derivative makes it possible to prepare, with a yield of 51%, the compound 22 of formula:

Gross formula: C28H28FNOg

Molecular mass: 525.51

Beige sequins

Melting point: 171 ° C

NMR (DMSOdό): 1.8 - 2.15 (m, 4H); 2.3 - 3.9 (m, 10H); 3.86

(s, 3H); 6.01 (s, 2H); 7.15 - 7.5 (m, 4H); 7.5 - 7.75 (d, 1H); 8 -

8.2 (m, 2H); 8.4 (s, 1H); 8.4 - 10 (m, 1H); 19.3 - 20.2 (m, 1H)

IR (KBr) V C = O: 1684 and 1640 cπrl. Example 23:

3- [2- [4- (4-fluorobenzoyl) piperidino] ethyl] -6-fluoro- 4H-Benzopyran-4-one hydrochloride. I (Ri = R2 = R4 = R5 = H; R ₃ = 6-F; R ₆ = 4-F; A = (CH ₂ ) ₂ ).

By applying the procedure la to 4-chlorobutanoyl chloride and 4-Fluoro anisole, 2- (4-chlorobutanoyl) -4-Fluorophenol is prepared with a yield of 72% (mp = 66 °). The N-alkylation of 4- (4-fluorobenzoyl) piperidine by the preceding compound gives 2- [4- [4- (4- (4-fluorobenzoyl) piperidino] butanoyl] -4-Fluorophenol (yield: 45%), which is cyclized according to and 2 to give, with a yield of 30%, compound 23 of formula:

Crude formula: C23H22CIF2NO3 Molecular mass: 432.93 Beige crystals Decomposition point: 220 ° NMR (DMSOd ₆ ) δ: 1.7 - 2.2 (m, 4H); 2.88 (t, 2H); 2.7 - 4 (m,

7H); 7.3 - 7.55 (m, 2H); 2.65 - 8.45 (m, 3H); 8.05 - 8.2 (m,

2H); 8.46 (s, 1H); 9.9 (broad s, 1H).

IR (KBr) v C = O: 1678 and 1635 cπr *. Example 24:

3- [4- [4- (4-fluorobenzoyl) piperidino] butyl] -6-methoxy- hydrochloride

4H- Benzo- pyran-4-one. I (Ri = R2 = R4 = R5 = H; R3 = 6-MeO - Rg = 4-F; A

= (CH ₂ ) ₄ ). The application of the process la to 6-Bromohexanoyl chloride makes it possible to prepare 2- (6-Bromohexanoyl) -4- methoxyphenol (F <50 °) with a yield of 75%. This condensed compound according to lb provides 2- [6- [4- (4- (4-fluorobenzoyl) piperidino] hexanoyl] -4-methoxy phenol (yield: 60%; M = 96 °). The cyclization of this derivative according to the methods le and 2 gives, with a yield of 82%, the derivative 24 of formula:

Crude formula: C26H29CIFNO4 Molecular mass: 473.95

White crystals

Decomposition point: 264 °

NMR (CDCI3) δ: 1.6 - 1.8 (m, 2H); 1.85 - 2.2 (m, 4H); 2.3 - 2.7

(m, 4H); 2.8 - 3.2 (m, 4H); 3.3 - 3.7 (m, 3H); 3.88 (s, 3H); 7 - 7.3 (m, 2H); 7.36 (d, 1H); 7.5 (d, 1H); 7.75 - 8.05 (m, 3H);

11.95 (large, 1H)

E (KBr) v C = O: 1677 and 1634 cπr.

Example 25:

3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl) -7- methoxy-4H-Benzopyran-4-one hydrogen maleate. I ÇR \ = R2 = R4 = R5 = H; R3 = 7-

MeO; R6 = 4-F; A = (CH) 4).

Using the process it is prepared easily 2- (6-bromohexanoyl) -5-Methoxyphenol (yield: 79%, F = 40-2 °) which is condensed on the 4- (4-fluorobenzoyl) piperidin to give 2- [6- [4- (4- fluorobenzoyl) piperidino] hexanoyl] -5-Methoxyphenol (Yield: 75%; F = 97 - 98%). This product cyclized according to the conduit to compound 25 (Yield: 46%) of formula: (25)

Gross formula: C30H32FNO8

Molecular mass: 553.57 White powder Melting point: 140 °

NMR (CDCI3) δ: 1.6 - 1.95 (m, 4H); 2 - 2.6 (m, 6H); 2.7 - 3.3 (m, 4H); 3.3 - 3.8 (m, 3H); 3.9 (s, 3H); 6.27 (s, 2H); 6.82

(d, 1H); 6.96 (dd, 1H); 7.05 - 7.3 (m, 2H); 7.75 (s, 1H); 7.8 - 8.2 (m, 2H); 12 (broad s, 1H). IR (KBr) v C ≈ O: 1684 and 1645 cm " ^1. Example 26: 6-Fluoro-3- [4- [4- (4- fluorobenzoyl) piperidino] butyl] -4H- Benzopyran-4- hydrogen-maleate one. IR = R2 = R4 = R ₅ = H; R ₃ = 6-F; R6 = 4-F; A = (CH ₂ ) ₄ ). 26a): Preparation of 2- [6-bromohexanoyl] -4- fluorophenol: A mixture of 2.10 g (19 mmol) of parafluorophenol and 2.92 g (15 mmol) of 6-bromohexanoic acid is heated to 30 ° then treated with a gas stream of BF3 and gradually heated to 80 ° The gas circulation is maintained for 2 hours at this temperature, then allowed to return to 25 ° and hydrolysis is carried out with 20 ml of water and extracted with CH2Cl2. The organic phase is washed with water, with salt water, dried over sulfate, evaporated and then purified by flash chromatography, eluting with a hexane - ethyl acetate mixture (90-10) (Yield: 40%).

NMR (CDCI3): 1.4 - 1.7 (m, 2H); 1.7 - 2.1 (m, 4H); 2.97 (t,

2H); 3.45 (t, 2H); 6.9 - 7.1 (m, 1H); 7.1 - 7.3 (m, 1H); 7.35 - 7.5

(m, 1H); 12.06 (s, 1H). 26b): The adaptation of the process lb to the preceding derivative 26a makes it possible to prepare (Yield: 61%) 4-fluoro-2- [6- [4- (4- fluorobenzoyl) piperidino] hexanoyl] phenol.

26c): The cyclization of derivative 26b according to gives compound 26 (Yield: 51%) of formula:

coo

Gross formula: C29H29F2NO7

Molecular mass: 541.53

White crystals

Melting point: 118 °

NMR (CDCI3) δ: 1.6 - 1.95 (m, 2H), 2 - 2.6 (m, 6H); 2.7 - 3.3

(m, 4H); 3.3 - 3.9 (m, 2H); 6.27 (s, 2H); 7 - 7.6 (m, 4H); 7.7 -

8.1 (m, 4H); 11.5 - 12.7 (m, 1H).

IR (KBr) v C = O: 1684 and 1645 cm-1. Example 27:

6-chloro-3- [4- [4- (4- (4-fluorobenzoyI) piperidino] butyI) - 4H-Benzopyran-4-one hydrochloride. I (Ri = R ₂ = R4 = R ₅ = H; R3 = 6-Cl; R6 = 4-F; A = (CH ₂ ) 4).

By adapting the procedure la to 6-bromohexanoyl chloride and 4-chloroanisole, 2- (6-bromohexanoyl) -4-chlorophenol (F = 58 °) is prepared with a yield of 31%. the usual way according to lb to give (yield: 68%) 2- [6- [4- (4- (4-fluorobenzoyl) piperidino] hexanoyl] -4-chlorophenoI (M = 130 °). The cyclization of this derivative according to and 2 makes it possible to prepare compound 27 (Yield: 72%) of formula:

Gross formula: C25H26CI2FNO3

Molecular mass: 478.38

White glitter

Decomposition point: 255 °

(Base melting point: 167 °)

NMR (CDCI3) δ: 1.6 - 2.25 (m, 8H); 2.4 - 2.55 (t, 2H) 2.65

- 3.25 (m, 4H); 3.25 - 3.9 (m, 3H); 7.1 - 7.25 (m, 2H) 7.42 (dd, 1H); 7.6 (td, 1H); 7.87 - 8.05 (m, 3H); 8.16 (d, 1H); 12 -

12.3 (m, 1H).

IR (KBr) v C = O: 1676 and 1633 cm-1.

Example 28:

Hydrogenomaleate of 3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl] -6- methyl-4H-Benzopyran-4-one. I (Ri = R2 = R4 = R5 = H; R3 = 6-

Me; R ₆ = 4-F; A = (CH ₂ )).

In a similar way to the process described in the 2- (6-bromohexanoyl) -4-methylphenol (Yield: 93%, oil) is prepared, then by adapting the process 1b we obtain with a yield of 51% the 2- [6- [4- (4-

Fluorobenzoyl) piperidino] hexanoyl] -4-methylphenol (mp 86-88 °). This last product is cyclized according to the to give compound 28 (Yd: 46

%) of formula:

Gross formula: C30H32FNO7

Molecular mass: 537.56

White powder

Melting point: 154 °

NMR (CDCI3) δ 1.6 - 2 (m, 4H); 2 - 2.6 (m, 6H); 2.45 (s,

3H); 2.7 - 3.9 (m, 7H); 6.26 (s, 2H); 7.05 - 7.25 (m, 2H); 7.25 -

7.4 (m, 1H); 7.47 (dd, 1H); 7.8 (s, 1H); 7.85 - 8.05 (m, 3H);

11, 7 - 12.6 (m, 1H).

IR (KBr) v C = O: 1674 and 1639 cm-1.

Example 29:

6,7-Dimethoxy-3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl) -4H-Benzopyranone hydrogenomaleate. I (Ri = R4 = R5

= H; R ₂ = 6-MeO; R3 = 7-MeO; R ^ = 4-F; A = (CH2> 4).

Using the process, the 4,5-dimethoxy-2- [6-bromohexanoyl] phenol is likewise prepared (yield: 64%, mp = 83 °) which is condensed according to lb to give 4,5-dimethoxy-2 - [6- [4- fluorobenzoyl) piperidino] hexanoyl] phenol (Yield: 79%, M = 84 °). Cyclization according to the conduit (yield: 40%) to product 29 of formula:

coo

Crude formula: C31H34FNO9 Molecular mass: 592.59

White powder Melting point: 99 - 100 °

NMR (CDCI3) δ: 1.5 - 1.95 (m, 4H); 2 - 2.6 (m, 6H); 2.7 - 3.3 (m, 4H); 3.3 - 3.9 (m, 3H); 3.97 (s, 3H); 3.98 (s, 3H); 6.28 (s, 2H); 7.17 (t, 2H); 7.5 (s, 1H); 7.77 (s, 1H); 7.85 - 8.05 (m,

2H); 11.6 - 12.3 (m, 1H). IR (KBr) v C = O: 1678 and 1630 cm-1.

Example 30:

5,7-Dimethoxy-3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl) -4H-Benzopyran-4-one hydrogenomaleate. I (R \ = R4 =

R ₅ = H; R2 = 5-MeO; R ₃ = 7-MeO; R6 = 4-F; A = (CH ₂ ) 4).

The adaptation of procedure 1a to 1,3,5-trimethoxybenzene provides the 2-

[6-bromo-hexanoyl) -3,5-dimethoxyphenol (Yield: 39%) which makes it possible to prepare according to lb the: 3,5-dimethoxy-2- [6- [4- (4- fluorobenzoyl) piperidino] hexanoyl] phenol (yield: 39%, F = 101 °). Cyclization according to gives compound 30 (Yield: 59%) of formula:

(30)

Gross formula: C31H34FNO9

Molecular mass: 592.59

Beige powder

Melting point: 139 - 140 ° C

NMR (CDCI3) δ: 1.5 - 1.95 (m, 4H); 2 - 2.7 (m, 6H); 2.8 - 3.3

(m, 4H); 3.3-4.1 (m, 3H); 3.86 (s, 3H); 3.91 (s, 3H); 6.25 (s, 2H); 6.33 (d, 1H); 6.40 (d, 1H); 7.05 - 7.3 (m, 2H); 7.6 (s, 1H); 7.8 - 8.15 (m, 2H); 11.5 - 12.5 (m, 2H). IR (KBr) v C = 0: 1684 and 1649 cm-1.

Example 31:

Hydrogenomaleate of 6,7-dimethoxy-3- [4- (4-benzoylpiperidino) butyl] -

4H-Benzo-pyran-4-one. I (Rι = R4 = R5 = R6 = H; R2 = 6-MeO; R3

= 7-MeO; A = (CH2) 4).

Starting from the raw material already prepared in Example 29, the same is obtained according to lb 4,5-dimethoxy-2- [6- (4-benzoylpiperidino) hexanoyl] phenol (Yield: 61%, M = 200 ° C. ) the cyclization of which gives compound 31 (Yield: 38%) of formula:

(31)

Gross formula: C31H35NO9

Molecular mass: 565.60

Beige powder

Melting point: 137 °

NMR (CDCI3) δ 1.5 - 1.95 (m, 4H) 2 - 2.4 (m, 4H); 2.48 (t,

2H); 2.8 - 3.8 (m, 7H); 3.95 (s, 3H) 3.97 (s, 3H); 6.25 (s, 2H);

6.84 (s, 1H); 7.3 - 7.65 (m, 4H); 7.75 (s, 1H); 7.8 8.1 (m, 2H);

10.8 - 12 (m, 2H).

IR (KBr) V C = O: 1672 and 1639 cm-1. Example 32:

3- [5- [4- (4-fluorobenzoyl) piperidino] pentyl] -6-mehoxy-4H hydrochloride Benzopyran-4-one. I (Ri = R2 = R4 = R5 = H; R3 = 6- MeO; R6 = 4-F; A = (CH ₂ ) ₅ ).

By condensation of 7-Bromoheptanoyl chloride on 1,4-dimethoxybenzene according to the 2- [7- Bromoheptanoyl] -4-Methoxy-phenol is prepared with a yield of 72% which, by reaction on 4- [4- fluorobenzoyl ] piperidine gives, according to lb, 2- [7- [4- (4-fluoro benzoyl) piperidino] heptanoyl] -4-Methoxyphenol (Yield: 94%). This compound cyclized according to and 2 makes it possible to prepare derivative 32 (Yield: 53%) of formula:

Gross formula: C27H31CIFNO4

Molecular mass: 487.99

Beige crystals

Melting point: 176 - 177 °

NMR (CDCI3) δ: 1.25 - 1.5 (m, 2H); 1.5 - 1.75 (m, 2H); 1.8 -

2.2 (m, 4H); 2.25 - 2.55 (t, 2H); 2.55 - 2.82 (m, 2H); 2.83 - 3.2

(m, 4H); 3.3 - 4 (m, 3H); 3.82 (s, 3H); 7 - 7.18 (m, 2H); 7.2 (d,

1H); 7.29 (s, 1H); 7.48 (t, 1H); 7.78 (d, 1H); 7.84 - 8.05 (m,

2H); 12 (s, large, 1H).

IR (KBr) v C = O: 1678 and 1645 cm "l.

Example 33:

3- [6- [4- [4-fluorobenzoyl] piperidino] hexyl] -6- hydrochloride

Methoxy-4H-Benzo- pyran-4-one. I (Ri = R ₂ = R4 = R5 = H; R3 = 6-

MeO; R6 = 4-F; A = (CH ₂ ) 6).

By operating as in Example 1, successively: 2- (8- Bromooctanoyl) -4-methoxyphenol (Yield 72%) and 2- [8- [4- (4-

Fluorobenzoyl) piperidino] octanoyl] -4-methoxyphenol (yield: 76%) which, by cyclization according to and 2, gives compound 33 of formula 72 with a yield:

Crude formula: C ₂ gH33ClFNθ4 Molecular mass: 502.01 Off-white crystals Melting point: 178 - 180. ^e 0 NMR (CDCI3) δ: 1.2 - 1.7 (m, 6H); 1.75 - 2.25 (m, 4H); 2.43 (t, 2H); 2.52 - 3.25 (m, 6H); 3.3 - 4 (m, 3H); 3.87 (s, 3H); 7.05 - 7.3 (m, 3H); 7.35 (d, 1H); 7.55 (d, 1H); 7.76 (s, 1H); 7.7 - 8.1 (m, 2H); 11.9 - 12.4 (m, 1H). IR (KBr) v C = O: 1674 and 1645 cπrl. Example 34:

3- [7- [4- (4-fluorobenzoyl) piperidino] heptyl] -6-methoxy-4H-Benzo-pyran -4-one hydrochloride. I (R = R ₂ = R4 = R5 = H; R3 = 6-MeO; R6 = 4-F; A = (CH ₂ ) ₇ ).

By operating in the same way as in Example 1, successively: 2- (9-Bromononanoyl) -4-methoxyphenol (yield: 43%, F = 66 °) and 2- [9- [4- [4- fluorobenzoyl] piperidino] nonanoyl] -4-Methoxyρhenol (Yield: 100%) which is cyclized according to and 2 to give compound 34 (Yield: 55%) of formula:

Crude formula: C ₂ 9H35C1FN04 Molecular mass: 516.03

White powder Melting point: 181 ° C

NMR (CDCI3) δ 1.15 - 1.45 (m, 6H); 1.5 - 1.7 (m, 2H); 1.75 - 1.95 (m, 2H); 1.95 - 2.2 (m, 2H); 2.44 (t, 2H); 2.6 - 3.25 (m, 6H); 3.3 - 4 (m, 3H); 3.87 (s, 2H); 7 - 7.28 (m, 3H); 7.35 (d,

1H); 7.55 (d, 1H); 7.74 (s, 1H). ER (KBr) v C = O: 1680 and 1645 cm-1. Example 35:

3- [9- [4- [4- fluorobenzoyl] piperidino] nonyl] -6-methoxy-4H-Benzopyran-4-one hydrochloride hydrate. I (Ri = R = R4 = R5 = H; R ₃ = 6-MeO; Rβ = 4-F; A = (CH ₂ ) ₉ ). By operating in the same way as in Example 1, successively prepare 2- (l 1-Bromoundécanoyl) -4-methoxyphenol (Yield: 48%) and 2- [l l- [4- [4-fluorobenzoyl] piperidino] undécanoyl] -4-methoxyphenol (Yield: 100%). This condensed product according to and 2 makes it possible to prepare compound 35 (yield: 59%) of formula:

Crude formula: C31H39CIFNO4, H ₂ 0 Molecular mass: 562.10

White crystals

Melting point: 136 °

NMR (CDCI3) δ: 1.3 - 1.45 (m, 10H); 1.45 - 1.7 (m, 2H); 1.75 -

2 (m, 4H); 2.05 - 2.25 (m, 2H); 2.3 - 3.3 (m, 8H); 3.3 - 3.9 (m, 3H); 3.88 (s, 3H); 7.07 - 7.3 (m, 3H); 7.36 (d, 1H); 7.57 (d,

1H); 7.76 (d, 1H); 7.85 - 8.04 (m, 2H); 11.7 - 12.4 (m, 1H).

BR (KBr) v C = 0: 1682 and 1640 cm "!.

Example 36:

6,7-Dimethoxy-3- [5- [4- [4- [fluorobenzoyl] piperidino] pentyl] -4H-Benzopyran-4-one hydrochloride hemihydrate. I (R = R4 =

R5 = H; R = 6-MeO; R ₃ = 7-MeO; R6 = 4-F; A = (CH ₂ ) 5).

By operating in the same way as in Example 1, successively:

(7-Bromoheptanoyl) -4,5-dimethoxyphenol (Yield: 53%, F = 90 °) and 2- [7-

[4- [4-Fluorobenzoyl] piperidino] heptanoyl] -4,5-dimethoxyphenol (Yield: 89%; M = 93 °) which is cyclized according to and 2 to give compound 36 (Yield:

65%) of formula:

Gross formula: C ₂ sH33ClFN05, 1 / 2H ₂ 0

Molecular mass: 527.02

White powder

Melting point: 104 °

NMR (CDCI3) δ: 1.3 - 1.53 (m, 2H); 1.53 - 1.8 (m, 2H); 1.8

- 2.25 (m, 5H); 2.46 (t, 2H); 2.52 - 3.25 (m, 6H); 3.3 - 4 (m,

3H); 3.96 (s, 3H); 3.97 (s, 3H); 6.83 (s, 1H); 7.02 - 7.27 (m, 2H); 7.51 (s, 1H); 7.77 (s, 1H); 7.75 - 8.3 (m, 2H); 11.7 - 12.3

(m, 1H).

IR (KBr) v: 1680 and 1638 cm "l. Example 37:

Sesquihydrate of 6,7-dimethoxy-3- [6- [4- [4- fluorobenzoyl] piperidino] hexyl] -4H-Benzopyran-4-one hydrochloride. I ÇR = R4 = R5 = H; R ₂ = 6-MeO; R3 = 7-MeO; R6 = 4-F; A = (CH) 6). The adaptation of the process described in Example 1 makes it possible to successively prepare the: 2— (8-Bromooctanoyl) -4,5-dimethoxyphenol (Yield: 70%, F = 94 °) then 2- [8- [4 - [4-fluoro benzoyl] piperidino] octanoyl] -4,5- dimethoxyphenol (Yield: 73%, F = 105 °) which is cyclized according to and 2 to give, with a yield of 66%, compound 37 of formula:

Gross formula: C ₂ 9H35C1FN05, 3 / 2H ₂ 0

Molecular mass: 559.03

White powder

Melting point: 189 °

NMR (CDCI3) δ: 1.2 - 1.7 (m, 6H); 1.7 - 2.2 (m, 7H); 2.42 (t,

2H); 2.46 - 3.2 (m, 6H); 3.3 - 4.05 (m, 3H); 3.95 (s, 3H); 3.96

(s, 3H); 6.82 (s, 1H); 7 - 7.3 (m, 2H); 7.51 (s, 1H); 7.71 (s,

1H); 7.3 - 8.05 (m, 2H); 11.8 - 12.3 (m, 1H).

IR (KBr) v C = O: 1672 and 1644 cπrl.

Example 38:

6,7-Dimethoxy-3- [9- [4- [4-fluorobenzoyl] piperidino] nonyl] -4H hydrochloride Benzopyran-4-one. I (R = R4 = R5 = H; R ₂ = 6-MeO; R3 = 7-MeO; R = 4-F; A = (CH ₂ ) 9). The application of the process described in Example 1 successively gives 2- (11-bromo-undecanoyl) -4,5-dimethoxyphenol (Yield: 81%, F = 89 °) and 2- [l l- [4 - [4-fluorobenzoyl] pipéridino] undécanoyl] -4,5-dimethoxyphenol

(Yield: 88%), the cyclization of which according to the processes 1 and 2 gives a compound 38 of formula: (38)

Gross formula: C3 H4iClFN05

Molecular mass: 574, 11 White powder Melting point: 182 - 184 °

NMR (CDCI3) δ: 1.1 - 1.65 (m, 14H); 2.3 - 2.2 (m, 4H); 2.39 (t, 2H); 2.6 - 3.25 (m, 4H); 3.25 - 4.1 (m, 3H); 3.92 (s, 3H); 3.93

(s, 3H); 6.79 (s, 1H); 7 - 7.3 (m, 2H); 7.49 (s, 1H); 7.67 (s, 1H); 7.8 - 8.1 (m, 2H); 12.1 (wide, 1H). IR (KBr) v C = O: 1678 and 1643 cm-1. Example 39: Hydrogenomaleate of 5,7-dimethoxy-3- [5- [4- [4- [4-fluorobenzoyl] piperidino] pentyl] -4H-Benzopyran-4-one. I (Ri = R4 = R5 = H; R ₂ = 5-MeO; R = 7-MeO; R = 4-F; A = (CH ₂ ) s). By operating in the same way as in Example 1, successively prepare 2- [7-bromoheptanoyl] -3,5-dimethoxyphenol (Yield: 40%) then 2- [7- [4- [4-fluorobenzoyl] piperidino] heptanoyl] -3,5-dimethoxyphenol (Yield: 73%) which is cyclized according to and 2 to compound 39 (Yield: 58%) of formula:

Gross formula: C3 ₂ H36FN05

Molecular mass: 597.62

White crystals

Melting point: 118 °

NMR (CDCI3) δ: 1.2 - 1.95 (m, 6H); 1.95 - 2.6 (m, 4H); 2.35 (t,

2H); 2.75 - 3.25 (m, 4H); 3.3 - 4.05 (m, 3H); 3.86 (s, 3H); 3.91 (s, 3H); 6.25 (s, 2H); 6.30 (d, 1H); 6.37 (d, 1H); 7 - 7.25 (m, 2H); 7.54 (s, 1H); 7.85 - 8.05 (m, 2H); 11.8 - 12.7 (m, 2H). IR (KBr) VC = O: 1678 and 1655 cm "l. Example 40:

3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-methoxy-2-methyl-4H-Benzopyran-4-one hydrochloride. I (Ri = R = R5 = H; R3 = 6-MeO; R4 = Me; R6 = 4-F; A = (CH ₂ )).

A mixture formed of 1 g (2.42 mmol) of 2- [5- [4- [4- fluorobenzoyl] piperidino] pentanoyl] -4-methoxyphenol (prepared according to Example 1); 1.25 g (12.1 mmol) of acetic anhydride and 370 mg (4.5 mmol) of anhydrous sodium acetate is stirred at 170 ° under a stream of nitrogen for 10 h. After returning to ordinary temperature, the reaction mixture is poured into 50 ml of 5% NaHCO 3 and extracted with methylene chlorue, washed with water, with salt water, dried over sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography, eluting with a CH ₂ C1 ₂ - MeOH 95/5 mixture. The residual oil obtained is hydrochloride in the usual way (see Example 2) to give 350 mg (Yield: 30%) of compound 40 of formula:

Crude formula: C ₂ 6H ₂ 9C1FN04 Molecular mass: 473.95 White powder

Melting point: 204 °

NMR (CDCI3) δ: 2 - 2.35 (m, 4H); 2.49 (s, 3H); 2.55 - 3.25 (m, 8H); 3.25 - 3.95 (m, 3H); 3.88 (s, 3H); 7.05 - 7.1 (m, 3H); 7.36 (d, 1H); 7.48 (d, 1H); 7.48 - 8.04 (m, 2H); 11.7 - 12.4 (m, 1H). IR (KBr) v C = O: 1678 and 1633 cm ".

Example 41:

Hydrogenomaleate of 3- [4- [4- [4- [4-fluorobenzoyl] piperidino] butyl] -6- methoxy-2-methyl-4H-Benzopyran-4-one. I (Ri = R ₂ = R5 = H; R3 = 6-MeO; R4 = Me; R6 = 4-F; A = (CH ₂ ) ₄ ). Starting from 2- [6- [4- [4-fluorobenzoyl] piperidino] hexanoyl] -4- methoxyphenol (prepared in Example 24) and operating according to the method described in Example 40, a compound 41 of formula is prepared with a yield of 38%:

Crude formula: C31H34FNO Molecular mass: 567.59 White powder Melting point: 192 - 194 ° NMR (CDCI3) δ: 1.5 - 1.95 (m, 4H) 2 - 2.7 (m, 4H) 2.43 (s,

3H); 2.59 (t, 2H); 2.75 - 3.3 (m, 4H) 3.35 - 4 (m, 3H) 3.89 (s, 3H); 6.25 (s, 2H); 7.1 - 7.3 (m, 3H); 7.36 (d, 1H) 7.51 (d, 1H); 7.85 - 8.1 (m, 2H); 11.7 - 12.2 (m, 2H). ER (KBr) v C = O: 1682 and 1631 cm-1. Example 42:

6,7-Dimethoxy-3- [3- [4- [4- [4-fluorobenzoyl] piperidino] propyl] -2-Methyl-4H-Benzopyran-4-one hydrogen maleate. I

(Ri = R ₃ = R5 = H; R ₂ = 6-MeO; R4 = Me; R ₆ = 4-F). Starting from 2- [5- [4- [4-fluorobenzoyl] piperidino] pentanoyl] -4,5- dimethoxyphenol (prepared in Example 6) and operating according to Example 40, preparation is carried out with a yield of 45% the compound 42 of formula: (42)

O

Crude formula: C31H34FNO5 Molecular mass: 583.59

White crystals

Melting point: 157 - 158 °

NMR (CDCI3) δ: 1.8 - 2.7 (m, 8H); 2.41 (s, 3H); 2.7 - 3.85 (m,

7H); 3.97 (s, 3H); 3.98 (s, 3H); 6.27 (s, 2H); 6.85 (s, 1H); 7.1 - 7.3 (m, 2H); 7.45 (s, 1H); 7.85 - 8.08 (m, 2H); 11.8 - 12.3 (m,

2H).

IR (KBr) v C = O: 1684 - 1640 cm "l. Example 43:

3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-methoxy-4H-Benzopyran-4-one. I (Ri = R ₂ = R4 = R ^ = H; R3 = 6-

MeO; R5 = 4-F).

By operating as in Example 2 and by replacing maleic acid with tartaric acid, the compound of formula is prepared with a yield of 91%:

Gross formula: C ₂ 9H3 ₂ FNOιo

Molecular mass: 573.56

Melting point: 169 °

NMR (DMSOdô) δ: 1.5 - 2 (m, 6H); 2.3 - 2.9 (m, 6H); 3.1 - 3.3

(m, 2H); 3.35 - 3.7 (m, 1H); 3.86 (s, 3H); 4.15 (s, 2H); 7.25 -

7.5 (m, 4H); 7.62 (d, 1H); 8 - 8.2 (m, 2H); 8.28 (s, 1H); 6.5 -

10 (m wide, 4H).

IR (KBr) v C = O: 1670 and 1637 cm-1. Example 44:

3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-hydroxy-4H-Benzo-pyran-4-one hydrochloride. I (Rι = R ₂ = R4 = Rg = H; R3 = 6- OH; R ₅ = 4-F).

A mixture of 1 g (2.4 mmol) of 3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -6-methoxy-4H-Benzopyran-4-one in 2.5 ml of a solution aqueous hydrobromic acid at 48% and 2.5 ml of acetic acid is brought to reflux for 7 h by adding 0.5 ml of 48% HBr after 4 h. After returning to 25 ° the reaction mixture is diluted with ice, basified with sodium carbonate until the end of gas evolution and extracted several times with ethyl acetate, washed with salt water and then dried over sulfate. and evaporated to dryness. The residual oil is recrystallized from a 90-10 alcohol-water mixture. The crystals formed are recovered, taken up in ethanol and hydrochlorides with a ~ 2N solution of hydrochloric acid in ethanol. 900 mg (yield: 84%) of compound 44 of formula:

Crude formula: C 4H ₂ 5C1FN04 Molecular mass: 445.90 White crystals

Melting point: 235 °

NMR (DMSO of) 1.6 - 2.25 (m, 6H); 2.25 - 2.6 (m, 2H); 2.7 - 3.2 (m, 4H); 3.2 - 3.8 (m, 3H); 7.2 (dd, 1H); 7.25 - 7.55 (m, 4H); 7.95 - 8.15 (m, 2H); 8.25 (s, 1H); 10.02 (s, 1H); 10.25 (broad s, 1H).

IR (KBr) v C = O: 1674 and 1641 cm-1. Example 45:

3- [3-f4- (4-fluorobenzoyl) piperidino] propyl] -5-hydroxy-7-methoxy-4H-Benzopyran-4-one hydrochloride. I (Rι = R4 = R ^ = H; R ₂ = 5-OH; R ₃ = 7-MeO; R ₅ = 4-F; A = (CH ₂ ) ₃ ).

Starting from 3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -5,7-dimethoxy- 4H-Benzo-pyran-4-one prepared in Example 5 and operating as in Example 44, but only bringing to reflux for 1 hour, with a yield of 45%, compound 45 of formula is prepared: (45)

Gross formula: C ₂ 5H ₂ 6FN05, HC1

Molecular mass: 475.93

White glitter

Melting point: 243 - 244 °

NMR (DMSOd6) δ: 1.75 - 2.2 (m, 6H); 2.45 (t, 2H); 2.8 - 3.25

(m, 4H); 3.4 - 4 (m, 3H); 3.86 (s, 3H); 6.41 (d, 1H); 6.65 (d,

1H); 7.25 - 7.55 (m, 2H); 7.90 - 8.25 (m, 2H); 8.33 (s, 1H);

10.29 (br s, 1H); 12.8 (s, 1H).

IR (KBr) VC = O: 1674 and 1624 cm-1. Example 46:

3- [3- [4- (4-methanesulfonamidobenzoyl) piperidino] propyl] -6-methoxy-4H-Benzopyran-4-one hydrochloride. I (Ri = R ₂ = R4 = R5 = H; R3 = 6-MeO; Rβ = 4-MeS0 NH; A = (CH) ₃ ).

The condensation of 5-bromo-2'-hydroxy-5'-methoxy valerophenone prepared in Example la on 4- (4-methanesulfonamido benzoyl) piperidine according to the method lb gives a yield of 48% 2- [ 5- [4- (4-methanesulfonamidobenzoyl) piperidino] pentanoyl] -4- methoxyphenol (pale yellow powder F = 72 ° slow). The cyclization of this compound by DMF-DMA according to and 2 gives, with a yield of 85%, compound 46 of formula:

(46)

Gross formula: C ₂ 6H3iClN ₂ θ6S

Molecular mass: 534.98

Off-white crystals:

Melting point: 212 - 214 °

NMR (DMSOd6) δ: 1.75 - 2.2 (m, 6H); 2.48 (t, 2H); 2.6 - 4 (m,

7H); 3.13 (s, 3H); 3.87 (s, 3H); 7.32 (d, 2H); 7.36 - 7.5 (m,

2H); 7.99 (d, 2H); 8.35 (s, 1H); 10.39 (broad s, 2H).

IR (KBr) v C = O: 1670 and 1630; S0 ₂ N: 1333 and 1153 cm "!.

BTOT-OGIOIIES EXPERIMENTATIONS:

The compounds of the present invention of formula I and their therapeutically acceptable acid salts have interesting pharmacodynamic properties.

These compounds are strongly antiaggregating, in particular with respect to platelet aggregation induced by the association ADP + 5HT on rat plasma rich in platelets. The compounds of the present invention are also active in the cardiomyocyte by inhibiting the diastolic contracture induced by veratrine in the isolated left atrium of the rat. These compounds are also active in vivo during ischemia-reperfusion in anesthetized rabbits: they inhibit electrical disturbances of the ECG caused by ischemia and reperfusion without significant hemodynamic effect. Finally, they inhibit the pressure responses induced by 5HT in the amyelated rat.

Such compounds are useful as a preventive or curative in the treatment of coronary artery disease, cardiac and cerebral ischemia in all their forms and in the treatment of atherosclerosis. 1 °) Pharmacological study

The experiments to which the chemical molecules object of the present invention have been subjected have made it possible to demonstrate an interesting activity on the cardiovascular system both on "in vitro" and "in vivo" tests. a) "In vitro" action:

* The binding to 5HT2 receptors on the rat cortex was carried out according to the method of Leysen et al. (Mol. Pharmacol. (1982) 21 p 301-14). The results are reported in the following table, by way of non-limiting example:

Compound 1 5 6 10 19 20 22 24 25 26 Example n ° pKi / 5HT ₂ 7.7 7.6 7.7 7.5 7.6 7.8 8.1 7.4 7.7 7.4

Compound 29 30 32 33 36 37 39 Ketanserin Example n ° pKi / 5HT2 7.8 7.7 7.8 8.3 8.1 8.6 7.6 8.4

The inhibition of potentiation by 5HT of platelet aggregation induced by ADP on rat plasma rich in platelets was carried out according to the Born method (Nature (1962) 1-24, 927-9). The results are given in the following table where the IC50s are expressed in micromoles for certain compounds by way of nonlimiting examples:

Compound 1 5 6 10 19 20 22 24 29 Example no.

IC50 μmole 0.21 0.13 0.45 0.2 0.4 0.2 0.2 0.3 0.05 Compound 32 33 36 37 39 R 56865 Ketanserin Example no.

IC50 μmole 0.5 0.1 0.01 0.07 0.05> 10 0.14

* The inhibition of contracture to veratrine at the level of the rat isolated left atrium was carried out according to the technique of Le Grand et al. (Naunyn - Schmiedeberg's Arch. Pharmacol. (1993) 24S, 184-90). The results are given in the following table where the IC50s are expressed in micromoles for certain compounds by way of nonlimiting example:

Compound 1 5 6 24 26 28 29 30 31 32 Example no.

IC50 μmole 1.25 0.13 0.3 0.3 0.3 0.7 0.5 0.2 0.15 0.14

Compound 33 36 37 39 40 R 56865 Ketanserin Example no.

IC50 μmole 0.6 0.3 0.3 0.3 0.4 0.3 9.6

The compounds are not inotropic negative at the concentration of 10 μM. b) "In Vivo" Activity: The compounds of the present invention are also active by the venous and oral route in the following tests by way of nonlimiting example: * Ischemia reperfusion in anesthetized rabbits has been studied according to the method of Verscheure et al. (Fundam. Clin. Pharmacol. (1993) 2, 385). The results and the dose administered are given in the following table for certain compounds by way of nonlimiting example:

Product Dose% Inhibition Number arrhythmias% variation%

Example mg / kg i.v. ST segment under frequency variation n ° reperfusion heart blood pressure

1 0.16 92 0/5 2 - 6

5 0.16 51 i '5 - 10 - 10

6 0.16 100 0/5 - 15 - 7

19 0.16 47 1/5 0 - 4

32 0.16 71 2/5 0 - 10

36 0.16 50 2/5 0 - 6

40 0.16 78 2/5 0 1

Atenolol 0.16 84 3/3 - 10 - 10

D-ltiazeπ- 0.16 61 0/6 - 5 - 27

* The compounds also inhibit the pressive response to 5HT at 100 μg / kg iv in the amyelated rat according to the technique of Korstanje et al. (J. Pharm. Pharmacol. (1986) 2 £, 374-9) and are active orally or intravenously. The results and the dose administered are given in the following table by way of nonlimiting example:

Product

1 1 22 22 24 25 28 29 29 Example no.

Dose i.v. mg / kg

2.5 2.5 2.5 2.5 2.5 2.5

Dose p.o. mg / kg

40 40 40

% inhibition of pressure increase 85 - 40 120> 50 75 120 95 125> 50 arterial by 5HT 2 °) Therapeutic applications:

The compounds of the present invention and their therapeutically acceptable salts are useful as medicaments.

These compounds are more particularly suitable in cardiology for the prophylactic treatment of cardiovascular diseases such as:

* myocardial ischemia and coronary artery disease and more particularly in chronic stable angina attacks of unstable angina and Prinzmetal silent ischemia, and in the prevention of reocclusions, restenosis, and reinfarction.

* platelet aggregation inhibitors as adjuvants to thrombolysis in the case of restenosis and reocclusions.

* cerebral ischemia and more precisely in cerebrovascular accident the transient ischemic attack neurodegenerative diseases.

* and finally in atherosclerosis.

The administration of these compounds can be carried out by oral, parenteral or rectal route, each dose consists of an inert adjuvant facilitating the preparation, the absorption of the drug and of the active principle which can also be combined with another. These medicines can be in the form of tablets, capsules, suspensions, emulsions, syrups, suppositories, solutions or others. The administration of the active principle is carried out at an average dose of between 0.1 and 10 mg / kg of body weight.

Two preparations are given by way of nonlimiting example. The ingredients as well as other therapeutically acceptable which can be introduced in other proportions without modifying the scope of the invention. Example: Solution for injection: 3- [3- [4- [4- [4-fluorobenzoyl] piperidino] propyl] hydrogen tararate

-6-methoxy-4H-Benzopyran-4-one 10 mg

Propylene glycol 100 mg

Dextrose anhydrous 50 mg

Sterile distilled water qs 2 ml Stored in an inactinic glass ampoule to keep away from heat. Example: Tablets:

3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] hydrogenomaleate

-6-methoxy-4H-Benzopyran-4-one 40 mg

Lactose hydrate 100 mg Microcrystalline cellulose 25 mg

Carboxymethyl cellulose Na salt 3 mg

Magnesium stearate 2 mg

Corn starch 20 mg

Talc 3 mg Polyvinyl pyrrolidone 7 mg Total weight: 200 mg

Shavable tablets keep away from heat and moisture.

Claims

CLAIMS:

1 °) News 3- (ω- (4-benzoylpiperidino) alcoyl) -4H-Benzopyran-4- ones of general formula I.

in which the radicals are defined as follows: Ri, R ₂ , R3, R5, R6 equal or different represent - a hydrogen

- a branched or unbranched alkyl containing from 1 to 4 carbon atoms

- a branched or non-branched alkyloxy containing from 1 to 4 carbon atoms

- a hydroxyl

- an acetoxy - a halo group

- a nitro group

- an amino group substituted or not by a branched alkyl or not containing from 1 to 4 carbon atoms

- an acetamido or methanesulfonamido and two radicals can merge to give a methylene dioxy. R4 represents

- hydrogen

- a branched or unalkylated alkyl containing from 1 to 6 carbon atoms

- a benzene substituted or not by one or more hydroxyl or methoxyl A represents a branched alkylene group or not containing from 2 to 12 carbon atoms.

When the compounds of formula I contain an asymmetric carbon, the present invention relates both to racemic mixtures and to the various enantiomers or diastereoisomers or their mixtures. The present invention also includes the therapeutically acceptable inorganic or organic salts of the compounds of general formula I and their possible hydrates.

2 °) Compounds according to Claim 1, characterized in that it is chosen from the following compounds: Hydrogenomaleate of 3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -6- methoxy-4H-Benzopyran- 4-one]. 3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -6-methoxy- hydrochloride

4H-Benzopyran-4-one.

Hydrogenomaleate of 3- [3- [4-benzoylpiperidino] propyl] -6-methoxy-4H

Benzopyran-4-one. 3- [3- [4- (4-methyl benzoyl) piperidino] propyl] -4-methoxy- hydrochloride

4-H-Benzopyran-4-one.

3- [3- [4- [4- (4-fluorobenzoyl) piperidino] propyl] -5,7-dimethoxy-4H-Benzopyran-4-one hydrochloride monohydrate.

3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -6,7-dimethoxy-4H-Benzopyran-4-one hydrochloride.

3- [3- (4-benzoylpiperidino) propyl] -6,7-dimethoxy-4H- hydrochloride

Benzopyran-4-one.

3- [3- [4- (2,4-difluorobenzoyl) piperidino] propyl] -6,7-dimethoxy-4H-Benzopyran-4-one hydrochloride hydrate. 6,7-Dimethoxy-3- [3- [4- [4-methoxy-benzoyl) piperidino] propyl] -4H-Benzopyran-4-one hydrochloride.

7-methoxy-3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] hydrochloride -

4H-Benzo- pyran-4 one.

7-methoxy-3- [3- (4-benzoylpiperidino) propyl] -4H hydrochloride-Benzopyran-4-one.

3- [3- [4- (2,4-difluorobenzoyl) piperidino] propyl] -7-methoxy-4H-Benzopyran-4-one hydrochloride.

3- [3- [4- (4-fluorobenzoyl) piperidino] propyl) -6-methyl-4H- hydrochloride

Benzopy ran-4-one. 3- [3- [4- (4-fluorobenzoyl) piperidino] propyl) -6-chloro-4H- hydrochloride

Benzopy ran-4-one.

3- [3- (4-benzoyl piperidino) propyl] -6-chloro-4H- hydrochloride

Benzopyran-4-one.

3- [3- [4- (2,4-difluorobenzoyl) piperidino] propyl] -6-chloro-4H-Benzo-pyran-4-one hydrochloride.

7,8-Dimethoxy-3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -4H-Ben-zopyran-4-one hydrochloride.

Sesquihydrate of 3- [3- [4- (4- fluorobenzoyl) piperidino] propyl] -5,7,8-trimethoxy-4H-Benzopyran-4-one hydrochloride. 3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -6,7-methylenedioxy-4H-Benzopyran-4-one hydrochloride.

3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -4H- hydrochloride

Benzopyran-4-one.

3- [3- [4- [4- (4-fluorobenzoyl) piperidino] propyl] hydrochloride hydrate -8- Methoxy-4H-Benzopyran-4-one.

3- [2- [4- (4-fluorobenzoyl) piperidino] ethyl] -6-methoxy-4H-Benzopyran-4-one hydrogenomaleate. 3- [2- [4- (4-fluorobenzoyl) piperidino] ethyl] -6-fluoro-4H- hydrochloride

Benzopyran-4-one.

3- [4- [4- (4-fluorobenzoyl) piperidino] butyl] -6-methoxy- hydrochloride

4H-Benzopy ran-4-one. Hydrogenomaleate of 3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl] -7- methoxy-4H- Benzopyran-4-one.

Hydrogenomaleate of 6-Fluoro-3- [4- [4- (4- fluorobenzoyl) piperidino] butyl] -4H- Benzopyran-4-one.

6-chloro-3- [4- [4- (4-fluorobenzoyl) piperidino] butyl] -4H hydrochloride-Benzopyran-4-one.

Hydrogenomaleate of 3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl] -6- methyl-4H-Benzo-pyran-4-one.

6,7-Dimethoxy-3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl) -4H-Benzopyranone hydrogenomaleate. 5,7-Dimethoxy-3- [4- [4- (4- (4-fluorobenzoyl) piperidino] butyl) -4H-Benzopyran-4-one hydrogenomaleate.

6,7-Dimethoxy-3- [4- (4-benzoylpiperidino) butyl] -4H- hydrogenomaleate

Benzopy ran-4-one.

3- [5- [4- (4-fluorobenzoyl) piperidino] pentyl] -6-mehoxy-4H-Benzo-pyran-4-one hydrochloride.

3- [6- [4- [4-fluorobenzoyl] piperidino] hexyl] -6-methoxy- hydrochloride

4H-Benzo- pyran-4-one.

3- [7- [4- (4-fluorobenzoyl) piperidino] heptyl] -6-methoxy- hydrochloride

4H-Benzo- pyran -4-one. 3- [9- [4- [4-fluorobenzoyl] piperidino] nonyl] -6- methoxy-4H-Benzopy ran-4-one hydrochloride hydrate.

6,7-Dimethoxy-3- [5- [4- [4- [fluorobenzoyl] piperidino] pentyl] -4H-Benzopyran-4-one hydrochloride hemihydrate.

Sesquihydrate of 6,7-dimethoxy-3- [6- [4- [4-fluorobenzoyl] piperidino] hexyl] -4H-Benzopyran-4-one hydrochloride.

6,7-Dimethoxy-3- [9- [4- [4-fluorobenzoyl] piperidino] nonyl] -4H-Benzo-pyran-4-one hydrochloride.

5,7-Dimethoxy-3- [5- [4- [4- [4-fluorobenzoyl] piperidino] pentyl] -4H-Benzopyran-4-one hydrogenomaleate. 3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-methoxy-2- methyl 1-4H-Benzopyran-4-one hydrochloride.

Hydrogenomaleate of 3- [4- [4- [4- [4-fluorobenzoyl] piperidino] butyl] -6- methoxy-2-methyl-4H-Benzopyran-4-one.

Hydrogenomaleate of 6,7-dimethoxy-3- [3- [4- [4- fluorobenzoyl] piperidino] propyl] -2-Methyl-4H-Benzopyran-4-one.

3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-methoxy-4H-Benzopyran-4-one. 3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-hydroxy- hydrochloride

4H-Benzo-py ran-4-one.

3- [3- [4- (4-fluorobenzoyl) piperidino] propyl] -5-hydroxy-7-methoxy-4H-Benzopy ran-4-one hydrochloride. 3_ [3- [4- (4-methanesulfonamidobenzoyl) piperidino] propyl] -6-methoxy-4H-Benzopyran- hydrochloride

4-one.

3- [3- [4- [4-fluorobenzoyl] piperidino] propyl] -6-acetamido-4H-Benzopyran-4-one hydrogenomaleate. 3- [3- [4- [4- [4-fluorobenzoyl] piperidino] propyl] -5,7-dimethoxy-4H-Benzopyran-4-one hydrogenotartrate.

3- [5- [4- [4- [4-fluorobenzoyl] piperidino] pentyl] -6- methoxy-4H-Benzopy ran-4-one hydrogenotartrate.

3- [5- [4- [4- [4-fluorobenzoyl] piperidino] pentyl] -5,7-dimethoxy-4H-Benzopyran-4-one hydrogenotartrate.

Hydrogenomaleate of 3- [3- [4- [4-fluorobenzoyl] piρéridino] propyl] -6- methane-sulfonamido-4H-Benzopy ran-4-one.

3- [3- [4- [4-fluorobenzoyl] piperidincjpropyl] -6-nitro-4H- hydrochloride

Benzopy ran-4-one. Hydrogenomaleate of 3- [3- [4- [4- [4-fluorobenzoyl] piperidino] -3,3-dimethylpropyl] -6-methoxy-4H-Benzopyran-4-one.

Hydrogenomaleate of 6-acetoxy-3- [3- [4- [4- fluorobenzoyl] piperidino] propyl] -4H-Benzopyran-4-one.

3 °) Process for preparing the chemical compounds according to claims 1 and 2 characterized in that a compound of structure IV is reacted:

where Ri, R ₂ , R3, R5, R and A are as defined in 1.

* with dimethyl formamide dimethylacetal in the case where R4 = H in the presence or not of dimethyl formamide as solvent at a temperature between 20 and 80 °.

* or with dimethyl acetamide dimethyl acetal in the case where R4 = ÇH3 in the presence or not of dimethyl acetamide at a temperature between 20 and 100 °. 4) Process for the preparation of the chemical compounds according to Claims 1 and 2, characterized in that a compound of structure IV is reacted:

WHERE RI, R ₂ , R3, R5, Rg and A have the same meaning as in 1 with the compounds R4COX and R4COONa where R4 has the same meaning as in 1 with R4 ≠ H and where X represents either a chlorine or the group R4COO - at a temperature between 120 and 180 °.

5 °) As new drugs the compounds defined according to one of claims 1 and 2.

6 °) Pharmaceutical composition characterized in that it contains as active principle at least one compound according to one of claims 1,

2 and 5 associated with an inert pharmaceutical carrier or other pharmaceutically acceptable vehicles and which may or may not be associated with another drug.

7 °) Pharmaceutical composition according to claim 6 useful in the prophylactic treatment of myocardial ischemia such as attacks of chronic stable angina, unstable angina and Prinzmetal, silent ischemia, reinfarction, reocclusion and restenosis.

8 °) Pharmaceutical composition according to claim 6 useful as an antiplatelet agent as an adjuvant to thrombolysis and in the prevention of restenosis, reocclusions, and reinfarction

9 °) Pharmaceutical composition according to claim 6 useful in cerebral ischemia, stroke, transient ischemic attack and neurodegenerative diseases.

10 °) Pharmaceutical composition according to claim 6 characterized in that it allows to prevent and treat atherosclerosis.