WO1997028157A1

WO1997028157A1 - NOVEL PIPERIDINE DERIVATIVES 4-SUBSTITUTED BY AN IMIDAZOLIDIN-2-ON-1-YL-ETHYL, TETRAHYDROPYRIMIDIN-2-ON-1-YL-ETHYL AND 1,3-DIAZEPIN-2-ON-1-YL-ETHYL GROUP, AND USE THEREOF AS α2-ADRENERGIC RECEPTOR ANTAGONISTS

Info

Publication number: WO1997028157A1
Application number: PCT/FR1997/000179
Authority: WO
Inventors: Jean-Louis Vidaluc; Thierry Imbert; Marc Marien; Michael Briley
Original assignee: Pierre Fabre Medicament
Priority date: 1996-02-01
Filing date: 1997-01-30
Publication date: 1997-08-07
Also published as: AU1606197A; FR2744451B1; FR2744451A1

Abstract

Novel cyclic urea derivatives of 4-ethyl piperidine having general formula 1, wherein R1 is a (1,4-benzodioxan-2-yl)methyl group, a (2-H)-benzopyrane-3-yl methyl group or a 4-(chromanone-2-yl)methyl group; R4 is a hydrogen atom, a C1-4 alkyl chain or an optionally substituted aryl, heteroaryl, aralkyl or naphthyl ring; n is 0, 1 or 2; and R2 and R3 are either hydrogen atoms or a benzo residue fused to the cyclic urea system; salts thereof and preparation methods therefor, are disclosed. The use of such compounds as a drug, pharmaceutical compositions containing same, and preparation methods therefor, are also disclosed.

Description

NEW PIPERIDINE DERIVATIVES SUSTITUTED IN POSITION 4 BY AN IMIDAZ0LIDIN-2-0N-1-YL-ETHYL GROUP, TETRAHYDROPYRIMIDIN-2-ON-1-YL-ETHYL, AND 1,3-DIA-ZEPIN-2-ON-1 -YL-ETHYL, AND THEIR APPLICATIONS AS RECEPTOR ANTAGONISTS

.ALPHA.2 ADRENER.GIQUES.

The present invention relates to new cyclic urea derivatives of 4-ethyl piperidine and their preparation methods. It also relates to the use of these compounds as a medicament, as well as for the preparation of a medicament used as an antagonist agent for 0: 2 adrenergic receptors, and intended for treating various pathologies such as neurodegenerative diseases, such as Parkinson's or Alzheimer's, depression, attention deficit, hyperactivity disorders, male sexual dysfunctions, ischemic myocardial or cerebral disorders, cerebral attacks, peripheral myopathies.

It has been shown (Mavridis, Neuroscience 41, 507, 1991) that the locus coeruieus plays a major role in the recovery of impaired dopaminergic functions by administration of MPTP in monkeys. Its destruction resulted in reduced recovery. Furthermore, compounds having a 0.2 antagonist action are shown to reduce parkinsonian symptoms in monkeys (Colpaert, Brain Res. Bull., 26, 627, 1991) or in rats (Colpaert, Neuropharmacology, 26, 1431, 1987) by elevated dopamine release (Marien, M., Noradrenergic mechanisms in PD, p.139, 1994, CRC Press, Boca Raton; Marien, M., Colpaert, F. Effect of (+) - efaroxan on mouse striatal dopamine in vivo metabolism. DOPAMINE 94-Satellite Meeting of the Xllth Int. Congr. Pharmacology, Quebec City, Canada, July 20-24, 1994). In addition, a co-antagonist, Idazoxan, is shown to have a beneficial action on the deleterious effects of cerebral ischemia (Gustafson, Exp. Brain Res., 86, 555, 1991 and J. Cereb. Blood Flow Metab. , 1990, 10, 885) as well as in progressive supranuclear palsy, a neurodegenerative disease (Ghika, Neurology, 41, 986, 1991).

Thus, a substance activating the noradrenergic system may have the property of opposing the progression of degeneration of neurons by reactivating systems of different localizations and, therefore, being useful in cases of neurodegenerative diseases, ischemia, depression . Certain compounds make it possible to respond to the problem such as, for example, the compounds described in patent applications EP-0 486 385, GB-2 244 431, WO 93/13074, EP-0 199 400, WO 94/00841 and WO 94 / 00715.

The compounds of the present invention differ from the prior art in that they have a cyclic urea motif, of the imidazolidinone, tetrahydropyrimidinone, quinazolinone, benzodiazepinone, benzimidazolone type, which is linked by a chain of 2 carbons in position 4 of piperidine.

The present invention therefore relates to new compounds of cyclic urea structure of 4-ethyl piperidine, with antagonistic ct2 activity, corresponding to the general formula 1

in which Rj represents a 1,4-benzodioxane-2-yl methyl residue (2-H) - benzopyran-3-yl methyl, 4-chromanone-2-yl methyl,

R2 and R3 represent either hydrogen atoms or constitute a benzene ring fused with the cyclic urea system,

R4 represents a hydrogen atom, a C1.4 alkyl radical, an aryl, heteroaryl, aralkyl radical, optionally substituted by one or more substituents such as halogens, or alkyls or alkoxy, n can take the values 0, 1 or 2, and their pharmaceutically acceptable salts.

Preferably, the group R \ is a group 1, 4-benzodioxane-2-yl methyl or (2-H) -benzopyrane-3-yl methyl, n = 0 or 1, R4 is a hydrogen atom, a aromatic or heteroaromatic nucleus optionally substituted by one or more Cl,

OCH3, OC2H5, CH3 a phenethyl chain, R2 and R3 are hydrogen atoms and correspond to the following compounds:

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl 1] -3-phenyl-tetrahydro-pyrimidin- 2-one (Compound No. 1) l- [2- [l- (1,4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3-phenyl-imidazolidin-2-one

(Compound # 2)

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -imidazolidin-2-one (Compound

No. 4) 1 - [2- [1 - (1, 4-Benzodioxan-2-y ι) methyl-4-piperidiny] ethyl] -3-methyl-imidazolidin-2-one

(Compound N ° 5)

1 - [2- [l - (1.4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3- (2-phenyl) ethyl- imidazolidin-2-one (Compound No. 6) l- [2 - [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3- (4-fluoro) phenyl-imidazolidin-2-one (Compound No. 7)

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3- (4-pyridyl) -imidazolidin-2- one (Compound No. 9)

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3- (2,6-dimethoxy) phenylimidazolidin-2-one (Compound No. 10) 1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl 1-4-piperidiny] ethyl] -3- (2,6-diethoxy) phenylimidazolidin-2-one (Compound No. 1 1) 1- [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3- (2,6-dimethyl) phenyl-imidazolidin-2-one (Compound No 12)

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl 1-4-piperidiny] ethyl] -3- (2,6-dichloro) phenylimidazolidin-2-one (Compound No. 13 )

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3- (2,4,6-trimethoxy) phenylimidazolidin-2-one (Compound No 15)

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny] ethyl] -3-ethyl- 1, 3-dihydro- (2H) - benzimidazol-2-one (Compound N ° 16) 3- [2- [1- (2H-1-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -1,4,5,5-tetrahydro-2H-1,3-benzodiazepin-2 -one (Compound # 17)

3- [2- [1- (2H-1-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -1,3-dihydro-2H-quinazolin-

2-one (Compound No. 18) l- [2- [l- (2H-1 -Benzopyran-3-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-imidazolidin-2-one (Compound No. 19) The present invention also relates to their optical isomers, their salified forms and their preparation methods.

By alkyl is preferably meant linear or branched C1-C4 alkyl radicals, in particular methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl radicals.

The term “aryl” preferably means the phenyl or naphthyl radicals. The term “heteroaryl” preferably means heteroaromatic radicals having one or more heteroatoms chosen from nitrogen, oxygen or sulfur, in particular heteroaromatic radicals comprising 5 or 6 atoms, such as the azole, pyridyl or piperidyl radicals.

The compounds of the invention of general formula 1 can be prepared according to the following general scheme:

12

13 Method B

In method A, preferably used in the case where R \ is the group "(1,4-benzodioxan-2-yl) methyl" (group "A") and where the cyclic ureas are of the 2-imidazolidinone type or tetrahydro-2 (1H) -pyrimidinones type, the compounds 1 of the invention are obtained by an N-alkylation of the cycloureas 7 with the chlorinated derivative 2 in a strong basic medium (eg NaH).

Intermediate 2 can be obtained by conventional routes such as chlorination with thionyl chloride (SOCI2) of precursor alcohol 3 resulting from the selective N-alkylation of 4- (2-hydroxyethyl) piperidine with 2- ( bromomethyl) -1,4-benzodioxane in carbonate medium (eg K2CO3) in solvents such as acetone or acetonitrile. In method B, used in the case where R \ is the group "(1,4-benzodioxan-2-yl) methyl" (group "A") and where the cycloureas are of the 3,4-dihydro-2 type ( 1H) - quinazolinones or of type 1, 3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-ones, the compounds 1 of the invention are synthesized by terminal cyclization of the triamines 10 by action of agents " carbonylants "such as phosgene (or its diphosgene or triphosgene derivatives), ethyl carbonate, or by carbonyidiimidazole (CDI).

The triamines 10 are obtained by standard reduction of their nitrated precursors 1 1, themselves prepared by N-alkylation of the primary amine 12 by 2-nitroaryl-ω-alkanol tosylates. Diamine 12 is synthesized by reduction with LiAlH4 of the precursor nitrile 13 obtained from 4-cyanomethylpiperidine (see J.L. Vidaluc et al. J. Med. Chem. 1994, 37 (5), 689-95).

In method C, preferably used in the case where Rj is the group "(2M-1 - benzopyran-3-yl) methyl" (group "B") or the group "(2,3-dihydro-4-oxo -4H-1 - benzopyran-2-yl) methyl "(group" C "), the compounds 1 of the invention are synthesized using a terminal N-alkylation of the intermediates 4 by activated derivatives, in particular halogens, of the type RIX (where RI is B or C) in a carbonate medium in common solvents such as acetone or acetonitrile.

Intermediates 4 are obtained by N-debenzylation of precursors 5 using conventional conditions such as hydrogenation catalyzed by palladium carbon or 1-chloroethyl chloroformate (see RA Olofson and JP Senet in J. Org. Chem. 1984 , 49 (1 1), 2081-2). The chlorinated derivative 6 is prepared from alcohol precursor, according to the method used by H. Sugimoto et al. in J. Med. Chem. 1992, 35 (24), 4542-8).

Cycloureas 7 are prepared using conventional routes such as, for example, 1) in the case of imidazolidinones and tetrahydropyrimidinones, the cyclization of aminoalkylcarbamates by the action of ethylmagnesium bromide (see A. Basha in Tetrahedron Lett 1988, 29 ( 21), 2525-6), or the cyclization of Nw-haloalkyl-N'-arylureas by the action of strong bases such as NaH / THF or tBuOK / tBuOH as reported by DJ Cram et al. (J. Am. Chem. Soc. 1984, 106, 7150-67).

2) in the case of quinazolinones and 1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-ones by the action of "carbonylating" agents, phosgene (or its diphosgene or triphosgene derivatives), carbonyldiimidazole ( CDI) or ethyl or N, N'-disuccinimide carbonates, on type 9 diamines in solvents such as acetonitrile (see K. Takeda et al. Synth. Comm. 1982, 12, 213).

The halogenated intermediates of the RIX type were prepared according to methods reported by G. Mouysset et al., Respectively in Eur. J. Med. Chem. 1987, 22, 539-44 for RI = B and in Eur. J. Med. Chem. 1988, 23, 199-202 for RI = C.

The NMR and IR spectra as well as the elementary analyzes confirm the structure of the compounds obtained according to the invention. Experimental part

The following examples illustrate the invention without, however, limiting its scope. Method A

Example 1 l- [2- [l- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-tetrahydro-pyrimidin- 2-one (Compound No. 1) (RI = A, n = 1, R2 = R3 = H, R4 = Ph) Stage 1: 1 - [(1, 4-Benzodioxan-2-yl) methyl] -4-piperidineethanol (3)

A suspension containing 9.8 g (75.9 mmol) of 4- (2-hydroxyethyl) piperidine, 10 g (72.3 mmol) of finely ground potassium carbonate and 12 g (72.3 mmol) of iodide potassium in 100 ml of acetonitrile is brought to room temperature with stirring. A solution of 16.5 g (72.3 mmol) of 2-bromomethyl-1,4-benzodioxane in 20 ml of acetonitrile is introduced dropwise and the medium is brought to reflux for 6 h. After cooling, the insolubles are filtered and the filtrate is evaporated to dryness. The oily residue is taken up in dichloromethane and washed with water and then with brine. The residual organic phase is dried and evaporated to give an orange oil which is purified by chromatography on silica gel eluted with a dichloromethane-methanol mixture (95/5, then 90/10). After evaporation of the fractions concerned, 13.9 g (69%) of a yellow-orange oil are obtained which is pure enough to be used directly in stage 2. 1H NMR (CDCI3): δ 1.18-1.70 (M, 8H), 2.00-2.18 (qd, 2H), 2.48-2.69 (qd, 2H), 2.84- 3.01 (dd, 2H), 3.62-3 , 71 (m, 2H), 3.90-4.00 (dd, 1H), 4.24-4.35 (m, 2H), 6.78-6.89 (M, 4H). Stage 2: 1 - [(1,4-Benzodioxan-2-yl) methyl] -4- (2-chloroethyl) piperidine (2)

To a solution of 10.5 g (37.8 mmol) of l - [(1,4-benzodioxan-2-yl) methyl] -4- piperidineethanol, previously obtained, in 100 ml of dichloromethane are added 7 ml (96 , 0 mmol) of thionyl chloride with stirring at 0 ° C. The medium is left with stirring with return to ambient temperature, then brought to reflux for 4 h. After cooling, the solvent is evaporated to leave a crystalline residue which is taken up in ethyl ether. After filtration and drying, 10.6 g (94%) of off-white crystals are obtained (m.p .: 174-6 ° C).

Stage 3: 1- [2- [1- (I, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-phenyl- tetrahydropy midin-2-one (Compound No. 1) Formula 1 ( RI = A, n = l, R2 = R3 = H, R4 = Ph)

To a suspension of 0.18 g (3.8 mmol) of NaH (in 50% suspension in mineral oil and previously washed with petroleum ether) in 2 ml of dimethylacetamide (DMAC) is introduced a solution of 0.70 g (4.0 mmol) of 1 - phenyl-tetrahydro-2 (1H) -pyrimidinone in solution in 1 ml of DMAC. After stirring at room temperature for 30 min, a solution of 1 g (3.8 mmol) of 1- [(1,4-benzodioxan-2-yl) methyl] -4- (2-chloroethyl) piperidine is added (after alkalinization of the hydrochloride obtained in stage 2) in 2 ml DMAC, then the medium is heated at 100 ° C for 4 h. After cooling, the reaction crude is poured into a water-ice mixture and extracted with ethyl acetate. The organic phase is washed with water and then with brine, dried with anhydrous sodium sulfate, and evaporated to give white crystals which are taken up in isopropyl ether. 0.72 g (43%) of pure crystals are finally obtained, melting at

129-30 ° C. 1H NMR (CDCI3): δ 1.28-2.10 (M, 1 1H), 2.47-2.69 (M, 2H), 2.83-3.00 (M, 2H), 3.34 -

3.45 (M, 4H), 3.65-3.71 (t, 2H), 3.90-4.00 (m, 1H), 4.27-4.32 (M, 2H), 6, 78-6.85 (M, 4H),

7.12-7.32 (M, 5H).

Elementary analyzes for C26H33N3O3

Theor. C (71.70), H (7.64), N (9.65); Expl. C (71, 45), H (7.68), N (9.66). By the same sequence of reactions as in the case of Example 1 at stage 3, and using the appropriate imidazolidin-2-ones in place of the 1-phenyl-tetrahydro-2 (1 H) - pyrimidinone, one obtains the following compounds: Example 2 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-imidazolidin-2-one (Compound No. 2)

(RI = A, n = 0, R2 = R3 = H, R4 = Ph)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = Ph)

M.p .: 155-6 ° C (Fumarate)

Elementary analyzes for C29H35N3O7 Theor. C (64.79), H (6.56), N (7.82); Expl. C (64.71), H (6.53), N (7.77). Example 3 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (phenylmethyl) - imidazolidin-2-one (Compound No. 3)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = CH ₂ Ph) PF: 147-8 ° C (Oxalate)

Elementary analyzes for C28H35N3O7

Theor. C (63.98), H (6.71), N (7.99); Expl. C (63.47), H (6.64), N (7.82). Example 4 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -imidazolidin-2-one (Compound No. 4)

Formula 1 (RI = A, n = 0, R2 = R3 = R4 = H) PF: 188-90 ° C (Oxalate) Elementary analyzes for C21H29N3O7

Theor. C (57.92), H (6.71), N (9.65); Expl. C (57.37), H (6.70), N (9.38). Example 5 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-methyl-imidazolidin-2-one

(Compound N ° 5)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = Me)

M.p .: 173-4 ° C (Oxalate)

Elementary analyzes for C22H31N3O7 Theor. C (58.78), H (6.95), N (9.35); Expl. C (58.46), H (6.88), N (9.17). Example 6 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2-phenyl) ethyl-imidazolidin-2-one (Compound No. 6)

Formula 1 (RI = A, n = 0, R2 = R3 ≈ H, R4 = CH ₂ CH ₂ Ph) PF: 179-80 ° C (hydrochloride)

Elementary analyzes for C27H35CIN3O3

Theor. C (66.72), H (7.46), N (8.65), Cl (7.29); Expl. C (66.94), H (7.51), N (8.66), Cl

(7.39).

Example 7 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (4-fluoro) phenyl-imidazolidin-2-one (Compound No. 7)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = 4-F-Ph)

M.p .: 148-50 ° C (Base)

Elementary analyzes for C25H30FN3O3 Theor. C (68.31), H (6.88), N (9.56),; Expl. C (68.19), H (6.98), N (9.70). Example 8

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methy l-4-piperidinyl] ethy l] -3- (4-trifluoromethoxy) phenyl-imidazolidin-2-one (Compound No. 8)

Formula 1 (R1 = A, n = 0, R2 = R3 = H, R4 = 4-OCF ₃ -Ph) PF: 1 12-3 ° C (Base)

Elementary analyzes for C26H30F3N3O4 Theor. C (61.77), H (5.99), N (8.32); Expl. C (61, 75), H (6.02), N (8.30). Example 9 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (4-pyridyl) -imidazolidin-2- one (Compound No. 9) Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 ≈ 4-Pyridyl)

M.p .: 198-200 ° C (Oxalate)

Elementary analyzes for C24H30N4O3, 1,5 oxalate, H2O

Theor. C (56.34), H (6.08), N (9.73); Exp. C (56.26), H (5.86), N (9.53). Example 10 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-dimethoxy) phenylimidazolidin-2-one (Compound No. 10)

Formula 1 (RI - A, n = 0, R2 = R3 = H, R4 - 2,6-diOMe-Ph)

M.p .: 108-9 ° C (Base)

Elementary analyzes for C27H35N3O5 Theor. C (67.33), H (7.32), N (8.72); Expl. C (67.45), H (7.31), N (8.68). Example 1 1 l- [2- [l - (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-diethoxy) phenylimidazolidin-2-one (Compound N ° 1 1)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = 2,6-diOEt-Ph) m.p .: 95-6 ° C (Base)

Elementary analyzes for C29H39N3O5

Theor. C (68.34), H (7.71), N (8.25); Expl. C (68.30), H (7.78), N (8.26). Example 12 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-dimethyl) phenylimidazolidin-2-one (Compound No. 12)

Formula 1 (R1 = A, n ^≈ O, R2 = R3 = H, R4 = 2,6-diMe-Ph)

M.p .: 141-2 ° C (Oxalate)

Elementary analyzes for C29H37N3O7, 1/2 H2O

Theor. C (63.5), H (6.93), N (7.66); Exp. C (63.63), H (6.86), N (7.58). Example 13 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-dichloro) phenyl-imidazoiidin-2-one (Compound No. 13)

Formula 1 (R1 = A, n = 0, R2 = R3 = H, R4 = 2,6-diCl-Ph) m.p .: 216-8 ° C (hydrochloride)

Elementary analyzes for C25H30CIN3O3

Theor. C (56.99), H (5.74), N (7.97), Cl (20.18); Expl. C (56.51), H (5.70), N (7.84), Cl

(19.83).

Example 14 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-diisopropyl) phenyl-imidazolidin-2-one (Compound No. 14)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = 2,6-diiPr-Ph)

M.p .: 138-40 ° C (Base)

Elementary analyzes for C31H43N3O3 Theor. C (73.63), H (8.57), N (8.31); Expl. C (73.54), H (8.64), N (8.33). Example 15

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,4,6-trimethoxy) phenylimidazolidin-2-one (Compound No 15)

Formula 1 (RI = A, n = 0, R2 = R3 = H, R4 = 2,4,6-triOMe-Ph) M.P .: 1 10-2 ° C (Base)

Elementary analyzes for C28H37N3O6

Theor. C (65.73), H (7.29), N (8.21); Expl. C (65.01), H (7.23), N (8.38). Example 16

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-ethyl- 1, 3-dihydro- (2H) - benzimidazol-2-one (Compound N ° 16)

Formula 1 (RI = A, n = 0, R2, R3 = benzo, R4 = Et)

M.p .: 142-3 ° C (Oxalate)

Elementary analyzes for C27H33N3O7

Theor. C (63.39), H (6.50), N (8.21); Expl. C (63.00), H (6.44), N (8.12). Method B

Example 17 3- [2- [1- (2H-1-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -1,4,5,5-tetrahydro-2H-1,3-benzodiazepin-2- one (Compound N ° 17) Formula 1 (RI = A, n = 2, R2, R3 = benzo, R4 = H)

Stage 1: l - [(1,4-Benzodioxan-2-yl) methyl] -4-piperidineacetonitrile (13)

After alkalinization of 25 g (0.155 mole) of 4-piperidineacetonitrile hydrochloride (obtained according to RA Olofson and JP Senet in J. Org. Chem. 1984, 49 (11), 2081-2 and previously described in J. Med. Chem. 1994, 37 (5), 689-95) by NaOH IN under an ice bath and extraction with dichloromethane, an oil is obtained. This is brought into contact with 50 g (0.156 mole) of 2-hydroxymethyl 1-1,4-benzodioxane tosylate and the mixture brought to 140 ° C. for 20 h. The medium obtained is treated with a sodium carbonate solution and extracted with dichloromethane. The organic phase is washed with water, then dried with anhydrous sodium sulfate and evaporated to dryness. A brown residual oil is obtained which is purified by chromatography on silica gel eluted with a dichloromethane-methanol mixture (98/2). After evaporation of the fractions concerned, 27 g (64%) of a yellow oil are obtained which is directly used in the next step. 1H NMR (CDC1): δ 1.44-1.85 (M, 5H), 2.05-2.31 (M, 4H), 2.52-2.73 (M, 2H), 2.91- 3.05 (M, 2H), 3.93-4.03 (m, 1H), 4.24-4.35 (M, 2H), 6.80-6.91 (M, 4H). Stage 2: l - [(], 4-Benzodioxan-2-yl) methyl] -4-piperidineethanamine (12)

To a suspension of 9.3 g (0.24 mole) of lithium aluminum hydride (LiAlH4) in 200 ml of anhydrous THF is added a solution of 27 g (0.10 mole) of the oil obtained in the previous stage in 100 ml of anhydrous THF. The medium is brought to reflux for 3 h. After cooling, the excess LiAlH4 is destroyed by slow addition of a saturated solution of sodium sulfate and the medium obtained filtered through celite. The filtrate is evaporated to give 26.3 g (95%) of a colorless oil sufficiently pure to be used directly in the next stage.

1H NMR (CDCI3): δ 1.23-1.67 (M, 9H), 1.98-2.16 (M, 2H), 2.47-3.00 (M, 6H), 3.90- 4.00 (m, 1H), 4.23-4.33 (M, 2H), 6.78-6.90 (M, 4H). Stage 3: l - [(1,4-Benzodioxan-2-yl) methyl] -N- [2- (2-nitrophenyl) ethyl] -4- piperidineethanamine (1 1)

In a solution of 1.7 g (6.15 mmol) of amine (obtained in the preceding stage 2) in 2 ml of dimethyl sulfoxide (DMSO) with stirring at 140 ° C., a solution of 2 is added dropwise, 0 g (6.22 mmol) of 2- [2- (nitrophenyl)] ethanol tosylate in 3 ml of DMSO. The brown solution obtained is left with stirring at 140 ° C for 2 h. After cooling, the medium is poured into 20 ml of an ammonia-crushed ice mixture and extracted with ethyl acetate. The organic phase is washed with water, dried, filtered and evaporated to dryness. The residual brown oil is purified by chromatography on silica gel eluted with ethyl acetate-methanol (1/1). 0.5 g (19%) of a yellow oil is finally obtained.

1H NMR (CDC1 ₃ ): δ 1.27-1.67 (M, 9H), 1.99-2.16 (M, 2H), 2.49-2.70 (M, 4H), 2.85 -3.12 (M, 5H), 3.92-4.02 (m, 1H), 4.25-4.34 (M, 2H), 6.80-6.91 (M, 4H), 7 , 27-7.40 (M, 2H), 7.50-7.58 (td, 1H), 7.89-7.94 (d, 1H). Stage 4: 1 - [(1, 4-Benzodioxan-2-yl) methyl] -N- [2- (2-aminophenyl) ethyl] -4- piperidineethanamine (10)

1.35 g (6.0 mmol) of chloride are introduced into a solution of 0.5 g (1.2 mmol) of the oil (previously obtained in stage 3) in 20 ml of absolute ethanol. stannous bihydrate. The medium is brought to reflux with stirring for 4 h, then evaporated to dryness. The residue is taken up in an ice-cold soda solution and extracted with ethyl acetate. The organic phase is washed with water, brine, filtered and evaporated to dryness. 0.4 g (87%) of a yellow oil is obtained which is sufficiently pure to be used in the next stage. Stage 5: 3- [2- [1- (2H-1-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -1,4,5,5-tetrahydro-2H-1,3-benzodiazepin-2 -one (Compound No. 17) To a solution of 0.4 g (1 mmol) of the oil (obtained in stage 4 above) in 10 ml of acetonitrile is added 0.2 g (1.2 mmol) of carbonyldiimidazole (CDI) and the mixture is brought to reflux for 3 h followed by overnight with return to ambient temperature. The medium is evaporated, the residue taken up in dichloromethane and the organic solution washed with water, then with brine, and finally dried with anhydrous sodium sulfate. After evaporation of the dichloromethane, 0.4 g of a brown oil is obtained which is purified by chromatography on silica gel eluted with the dichloromethane-methanol mixture (95/5). We get, after evaporation of the pure fractions, 0.21 g (50%) of beige crystals which are treated with fumaric acid in an ethanol-ether mixture. 0.2 g of beige fumarate crystals is obtained, melting at 188 ° -90 ° C. 1H NMR (DMSO-d6): δ 1.10-2.17 (M, 9H), 2.62-2.66 (M, 2H), 2.90-3.06 (M, 2H), 3, 26- 3.36 (M, 2H), 3.89-3.99 (m, 1H), 4.25-4.36 (M, 4H), 6.60 (s, 2H), 6.73- 6.89 (M, 6H),

7.06-7.19 (M, 2H), 9.14 (s, 2H).

Elementary analyzes for C29H35N3O7

Theor. C (64.79), H (6.56), N (7.82); Expl. C (64.18), H (6.54), N (7.72).

By the same series of reactions as in the case of Example 17, and using the appropriate 2-nitro benzyl chlorides, bromides or tosylates, the corresponding quinazolinones are obtained, illustrated by the following example: Example 18

2-one (Compound N ° 18) Formula 1 (RI = A, n = 1, R2, R3 = benzo, R4 = H)

M.p .: 182-4 ° C (Fumarate)

Elementary analyzes for C28H33N3O7, 1/2 H2O

Theor. C (63.15), H (6.39), N (7.89); Expl. C (63.01), H (6.42), N (7.93).

Method C Example 19 1- [2- [1- (2H-1-Benzopyran-3-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-imidazolidin-2-one

(Compound No. 19)

Formula 1 (RI = B, n = 0, R2, R3 = benzo, R4 = Ph)

Stage 1: 1- [2- (1-Phenylmethyl-4-pipéήdinyl) ethyl] -3-phenyl-imidazolidin-2-one (5) In a stirred suspension, at room temperature and under a stream of nitrogen, 0, 75 g (18.7 mmol) of sodium hydride, previously washed with petroleum ether (suspension at

60% in mineral oil), in 3 ml of anhydrous dimethylformamide (DMF), a solution of 2.75 g (17.0 mmol) of l-phenyl-imidazolidin-2-one is introduced dropwise into

5 ml of DMF. The medium is left under stirring for 45 min at room temperature, then a solution of 4.04 g (17.0 mmol) of 1- is added dropwise. (phenylmethyl) -4- (2-chloroethyl) piperidine in 5 ml of DMF. The medium is stirred for 30 min at ambient temperature, then brought to 100 ° C. for 5 h.

It is then poured carefully into ice water to obtain a white precipitation which is filtered, washed twice with water, and dried under vacuum at 50 ° C. 5.0 g (81%) of white crystals are obtained, melting at 110-1 ° C, used directly in stage 2.

IH NMR (CDCI3): δ 1.28-1.98 (M, 9H), 2.82-2.87 (d, 2H), 3.26-3.46 (M, 6H), 3.74- 3.82

(t, 2H), 6.96-7.04 (t, 1H), 7.21-7.34 (M, 7H), 7.51-7.55 (d, 2H).

Stage 2: 1- [2- (4-piperidinyl) ethyl] -3-phenyl-imidazolidin-2-one (4)

In the solution of 3.6 g (10 mmol) of 1- [2- (1-phenylmethyl-4-piperidinyl) ethyl] -3-phenyl-imidazolidin-2-one in 50 ml of methanol, are successively introduced 1, 1 ml IN HCl and 0.35 g of 10% palladium on carbon. The medium is placed under a hydrogen atmosphere and with vigorous stirring. After absorption of 224 ml of hydrogen, the catalyst is filtered on Whatman paper and the filtrate evaporated to dryness. The residue is taken up in a dilute sodium hydroxide solution (0.1N) until basic (pH ~ 12) and extracted with dichloromethane. The organic phase is washed with water and then with brine, dried with anhydrous sodium sulfate, filtered and evaporated to dryness to give 2.5 g (92%) of white crystals. M.p .: 97-8 ° C used directly in stage 3.

IH NMR (CDCI3): δ 1.11-1.85 (M, 8H), 2.51-2.63 (td. 2H), 3.01-3.07 (d, 2H), 3.27- 3.47 (M, 4H), 3.75-3.83 (t, 2H), 6.96-7.04 (t, 1H), 7.25-7.34 (M, 2H), 7, 51 -7.56 (d, 2H). Stage 3 l- [2- [l- (2H-I-Benzopyran-3-yl) methyl-4-piperidinyl] ethyl] -3-phenyl- imidazolidin-2-one (Compound No. 19)

A suspension containing 0.7 g (2.5 mmol) of 2 - [(4-piperidinyl) ethyl] -3-phenylimidazolidin-2-one, 0.35 g (3.3 mmol) of finely sodium carbonate ground and a catalytic amount of potassium iodide in 5 ml of acetonitrile is brought to reflux with stirring for approximately 1 h. After cooling, a solution of 0.8 g (4.4 mmol) of 3-chloromethyl-2H-1-benzopyran is introduced dropwise (see G. Mouysset et al. Eur. J. Med Chem. 1987, 22, 539-44) in 5mL of acetonitrile. The medium is brought to reflux for 3 h and then evaporated to dryness. The solid residue is taken up in the water-dichloromethane mixture. The organic phase is washed with water, dried with anhydrous sodium sulfate, and evaporated to give 1.3 g of impure yellow crystals. These are purified by chromatography on a column of silica gel eluted with the dichloromethane mixture. methanol (95/5). 1.0 g of light yellow crystals are obtained which are recrystallized from absolute ethanol to give 0.65 g (59%) of off-white crystals which are treated with an equivalent of oxalic acid in the absolute ether-ethanol mixture. After filtration and drying, 0.65 g of white oxalate crystals are obtained. Fusion: 200-2 ° C.

IH NMR (DMSO-d6): δ 1.47-1.91 (M, 7H), 2.67 (M, 2H), 3.24-3.80 (M, 10H), 4.78 (s,

2H), 6.60 (s, 1H), 6.78-7.35 (M, 7H), 7.55-7.59 (d, 2H), 8.40 (si, 2H).

Elementary analyzes for C28H33N3O6

Theor. C (66.26), H (6.55), N (8.28); Expl. C (66.1 1), H (6.45), N (7.94). Example 19 1- [2- [1- (2,3-Dihydro-4-oxo-4H-1-benzopyran-2-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-imidazolidin-2-one ( Compound # 21)

0.8 g (2.9 mmol) of 1- [2- (4-piperidinyl) ethyl] -3-phenyl-imidazolidin-2-one (4) previously described, 0.31 g (2.9 mmol) of finely pulverized sodium carbonate and a catalytic amount of potassium iodide are suspended at room temperature in 5 ml of acetonitrile. A solution of 0.75 g (2.9 mmol) of 3-hydroxymethyl-4H-1-benzopyran-4-one mesylate (prepared according to G. Mouysset et al. Eur. J. Med. Chem. 1988, 23, 199-202) in 5 ml of acetonitrile and the medium is brought to reflux for 4 h. After evaporation of the solvent, the residue is taken up in the water-ethyl acetate mixture and the organic phase is washed with water, then with brine, and dried with anhydrous sodium sulfate. It is then evaporated to give 0.8 g of an orange oil which is purified by chromatography on a column of silica gel eluted with a dichloromethane-methanol mixture (98/2). 0.35 g (27%) of a yellow-orange oil is thus obtained. Treatment with oxalic acid in an ethanol-ether medium gives 0.30 g of oxalate in the form of white crystals. (M.p .: 222-3 ° C).

IH NMR (DMSO-d6): δ 1.47 (M, 5H), 1.84-1.89 (M, 2H), 2.64-2.98 (M, 4H), 3.22-3, 50 (M, 8H), 3.76-3.84 (t, 2H), 5.01 (m, 1H), 6.2 (si, 2H), 6.95-7.1 1 (M, 3H ), 7.27-7.35 (t, 2H), 7.55-7.59 (M, 3H), 7.75-7.79 (d, 1H). IR (KBr, C = O: 1694 cm ^"1 )

Elementary analyzes for C28H33N3O7 Theor. C (64.23), H (6.35), N (8.03); Expl. C (63.97), H (6.32), N (7.90).

Table I below shows some examples of synthesized products which illustrate the invention without however limiting its scope:

A = (1,4-benzodioxan-2-yl) methyl;

B = (2H-1-benzopyran-3-yl) methyl;

C = (2,3-dihydro-4-oxo-4H-1-benzopyran-2-yl) methyl.

Table I

1) Bindings to the alpha-2 adrenergic receptor.

Demonstration of the alpha-2 antagonist activity of the compounds belonging to the present invention is made on the basis of binding tests on the alpha-2 adrenergic receptor using the racemic 2-methoxy-idazoxan (RX 821002) as radioactive ligand selective for these receptors [method of NJ Mallard et al. Brit. J. Pharmacol. 102, 221 (1991)].

By way of examples, the specific binding values are indicated in Table II below:

Table II

It is thus shown that the compounds of the invention according to general formula I are potent antagonists of the α2 adrenergic receptors in vitro and increase the release of noradrenaline at the central level as shown in the following study. 2) In vivo study of the reversion of hypothermia induced by guanabenz.

The central noradrenergic effect of the products of the present invention is shown in vivo in the test of hypothermia induced by guanabenz (α2 agonist) in mice according to the test described by S.C. Dilsaver et al. in Pharmacol. Biochem. Behav. 1993, 45, 247-9.

The inhibitory capacities are expressed in ED50 which represent the doses producing an inhibition against guanabenz in 50% of the animals. These values are obtained using the method of JT Litchfield and F. Wilcoxon (J. Pharmacol. Exp. Ther. 96, 99-1 13, 1949) and are calculated only when inhibition occurs in more than 60% of the animals tested .

Table III below reproduces the values obtained by the intraperitoneal route and by the oral route for the products of the present invention:

Table III

The compounds of the invention according to general formula 1 are thus shown to be potent agents antagonists of the adrenergic ct2 receptors and thus cause an increased release of noradrenaline. They can be used in human therapy and are of interest for the treatment of neurodegenerative diseases and their progression such as Parkinson's disease, Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, cognitive disorders linked to age, attention and memory disorders, hyperactivity disorders, Creutzfeld-Jacob disease, Pick's disease, amyotrophic lateral sclerosis, myasthenia gravis, myopathies and peripheral neuropathies, neurodegeneration and brain damage due to central ischemic attacks, stroke, depression, myocardial ischemia and male sexual dysfunction.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula 1 and a suitable excipient. The pharmaceutical compositions can be presented, in a suitable manner, for oral, injectable or parenteral administration, in the form of capsules, capsules, tablets or injectable preparations at a dose of 0.1 to 200 g per day.

Claims

1 / A compound of general formula 1 where

in which R \ represents a 1,4-benzodioxane-2-yl methyl residue (2-H) - benzopyran-3-yl methyl, 4-chromanone-2-yl methyl,

R2 and R3 represent either hydrogen atoms or constitute a benzene ring fused with the cyclic urea system, R4 represents a hydrogen atom, an alkyl radical in Cj_4, an aryl, heteroaryl, aralkyl radical, optionally substituted by one or several substituents such as halogens, or alkyls or alkoxy, n can take the values 0, 1 or 2, and their pharmaceutically acceptable salts. 2 / A compound of general formula 1 according to claim 1, characterized in that

R \ represents a 1,4 benzodioxane -2-yl methyl or a (2H) -benzopyran3-yl methyl, R4 represents an atom of H, Me, phenyl, phenyl substituted by groups OCH3, OC ₂ H ₅ , Cl, Me.

3 / A compound of general formula 1 according to one of claims 1 or 2, characterized in that it is chosen from:

• l- [2- [l - (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-tetrahydro-pyrimidin-2-one

• 1- [2- [1- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-imidazolidin-2-one l- [2- [l- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (phenylmethyl) - imidazolidin-2-one l- [2- [l- (l, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -imidazolidin-2-one l- [2- [l- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] - 3-methyl-imidazolidin-2- one l- [2- [l- (1,4-Benzodioxan-2-yl) methyl! -4-piperidinyl] ethyl] -3- (2-phenyl) ethyl-imidazolidin-2 -one l- [2- [l- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (4-fluoro) phenyl- imidazolidin-2-one l- [2- [ l- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyI] ethyl] -3- (4-pyridyl) -imidazolidin- 2-one l- [2- [l- (1,4-Benzodioxan- 2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-dimethoxy) phenyl-imidazolidin-2-one l- [2- [l- (1,4-Benzodioxan-2-yl) methyl- 4-piperidinyl] ethyl] -3- (2,6-diethoxy) phenyl-imidazolidin-2-one l- [2- [l- (1,4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3- (2,6-dimethyl) phenylimidazolidin-2-one

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl 1] -3- (2,6-dichloro) phenyl- imidazolidin-2-one

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidiny l] ethyl] -3- (2,4,6-trimethoxy) phenyl-imidazolidin-2-one

1 - [2- [1 - (1, 4-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -3-ethyl- 1, 3-dihydro- (2H) - benzimidazol-2-one

3- [2- [1- (2H-1-Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] -1,4,5,5-tetrahydro-2H- 1,3-benzodiazepin-2-one

3- [2- [1 - (2H- 1 -Benzodioxan-2-yl) methyl-4-piperidinyl] ethyl] - 1, 3-dihydro-2H- quinazolin-2-one l- [2- [l- ( 2H-1-Benzopyran-3-yl) methyl-4-piperidinyl] ethyl] -3-phenyl-imidazolidin-2- one. 4 / A process for preparing the compound of general formula 1 according to one of claims 1 to 3, characterized in that the intermediate of formula 2 is reacted with a derivative of formula 7

in which R \, R2, R3, R4 and n are defined in one of claims 1 or 2, or else a compound of formula 4 is reacted

or in which R2, R3, R4 and n are defined in one of claims 1 or 2, with an activated derivative of benzodioxane methanol or di H benzopyran methanol.

5 / A process for preparing the compound of general formula 1 according to one of claims 1 to 3, characterized in that a derivative of formula 10 is reacted

n being defined according to one of claims 1 or 2 with a carbonylating group, such as phosgene, ethyl carbonate, or carbonyl diimidazole.

6 / As a medicament, the compounds of formula 1 according to one of claims l to 3. 11 Pharmaceutical composition characterized in that it comprises at least one compound of formula 1 according to one of claims 1 to 3 and a suitable excipient.

8 / Use of a compound of formula 1 according to one of claims 1 to 3, for the preparation of a medicament having an action c <2 antagonist intended for the treatment of neurodegenerative diseases and their progression such as Parkinson's disease, Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, age-related cognitive disorders, attention and memory disorders, hyperactivity disorders, Creutzfeld-Jacob disease, Pick's disease, amyotrophic lateral sclerosis, myasthenia gravis, myopathies and peripheral neuropathies, neurodegeneration and brain damage due to central ischemic attacks, stroke, depression, myocardial ischemia and male sexual dysfunction.