NOVEL DIZOCILPINE DERIVATIVES AS PERIPHERAL NMDA RECEPTOR ANTAGONISTS

Abstract

The present invention relates to compounds of formula (I);

##STR00001##

for use as peripheral NMDA receptor antagonists.

Claims

1. A compound of the following formula (I): ##STR00156## wherein R.sub.1 represents —OH; R.sub.2 represents a (C.sub.1-C.sub.10)alkyl group; n is 2, 3 or 4; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 each represent a hydrogen atom; and X.sup.- is an anionic counterion selected from the group consisting of I.sup.-, Cl.sup.-, Br.sup.-, and OH.sup.-.

2. The compound of claim 1, wherein R.sub.2 represents a methyl group or an ethyl group.

3. The compound of claim 1, wherein R.sub.2 represents a methyl group.

4. The compound of claim 1, wherein R.sub.2 represents an ethyl group.

5. The compound of claim 1, wherein n is 2.

6. The compound of claim 1, wherein n is 3.

7. The compound of claim 1, wherein n is 4.

8. The compound of claim 1, wherein the anionic counterion X.sup.- is selected from the group consisting of I.sup.- and Cl.sup.-.

9. The compound of claim 1, wherein the anionic counterion X.sup.- is I.sup.-.

10. The compound of claim 1, wherein the anionic counterion X.sup.- is Cl.sup.-.

11. The compound of claim 1, wherein the anionic counterion X.sup.- is Br.sup.-.

12. The compound of claim 1, wherein the anionic counterion X.sup.- is OH.sup.-.

13. The compound of claim 1, wherein the compound is selected from the group consisting of the following compounds: ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## .

14. A pharmaceutical composition, comprising: at least one compound of claim 1, and at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition of claim 14, further comprising at least one other therapeutic agent.

16. The pharmaceutical composition of claim 14, further comprising at least one other therapeutic agent selected from the group consisting of a vasodilator agent and a glutamate receptor antagonist, wherein the glutamate receptor antagonist is ionotropic and/or metabotropic.

17. The pharmaceutical composition of claim 14, further comprising at least one other therapeutic agent selected from the group consisting of NMDAR antagonists.

18. A method for treating a disease or condition in a subject, the method comprising: administering the compound of claim 1 to the subject, wherein the disease or condition is pulmonary hypertension.

19. A method for treating a disease or condition in a subject, the method comprising: administering the compound of the claim 1 to the subject, wherein the disease or condition is selected from the group consisting of pulmonary arterial hypertension and thromboembolic pulmonary hypertension.

20. A method for treating a disease in a subject, the method comprising: administering the compound of claim 1 to the subject, wherein the disease is pulmonary arterial hypertension.

Description

FIGURES

[0159] FIG. 1: Effect of NMDAR knockout in smooth muscle cells on the development of pulmonary hypertension. NMDAR knockout in smooth muscle cells attenuates hemodynamic and cardiac parameters of pulmonary hypertension as assessed by measurement of right ventricular systolic pressure and Fulton index. Right ventricular systolic pressure (RVSP) measurement in wild-type mice (n=8-14) and mice with a knockout of NMDAR in SMCs (n=7-13) after 3 weeks of normoxia or chronic hypoxia (FiO.sub.2: 10%). Ratio of right ventricle weight to left ventricle plus septum weight (Fulton index) for wild-type mice (n=12) and mice with a knockout of NMDAR in SMCs (n=8-12) after 3 weeks of normoxia or chronic hypoxia (FiO.sub.2: 10%).

[0160] FIG. 2: Effect of NMDAR knockout in smooth muscle cells on the development of pulmonary hypertension. NMDAR knockout in smooth muscle cells attenuates vascular remodeling of pulmonary hypertension as assessed by morphometric analysis. Morphometric analysis of pulmonary vessels in wild-type mice (n=5) and mice with a knockout of NMDAR in SMCs (n=5) after 3 weeks of normoxia or chronic hypoxia (FiO2: 10%). Same experiment as in FIG. 1. Pulmonary vessels were assigned to four groups on the basis of external vessel diameter (<30 .Math.m, 30 .Math.m to 50 .Math.m, 50 .Math.m to 75 .Math.m and 75 .Math.m to 125 .Math.m). Each vessel was classified as non-muscularized (VWF+, a-smooth muscle actin-), partially muscularized (VWF+, a-smooth muscle actin+/-), or fully muscularized (VWF+, a-smooth muscle actin+). Statistical significance was determined by a Mann-Whitney test (a), regular two-way ANOVA followed by Bonferonni’s tests (b-d), a one-way ANOVA followed by Bonferroni’s multiple comparison tests (e). *P < 0.05, **P < 0.01, ***P < 0.001 versus WT/control (a-d) or §§§P < 0.001 versus control, ***P < 0.001 versus PDGF (e). The values shown are means ± SEM (a-e).

[0161] FIG. 3: Measures of brain/plasma ratio (Kp.sub.“brain”) of MK801, Compound N°1 and Compound N°26 in rat. The results are expressed as the mean values obtained from 3 rats for each compound. Bars represent standard deviations. Kp.sub.“brain” MK-801= 17.7 ± 1.75. Kp.sub.“brain” Compound N°1 = 0.3 ± 0.03. Kp.sub.“brain” Compound N°26 = 0.4 ± 0.08.

EXAMPLES

Methods

Animal Models of Pulmonary Hypertension

[0162] All animals were used in strict accordance to the European Union regulations (Directive 2010/63/UE) for animal experiments. All animals were maintained in a temperature and humidity-controlled room with a 12 hours/12 hours light/dark cycle with access to a standard chow and water ad libitum.

[0163] Following procedures performed on mice, were approved by the ethical committee CEEA26 (Animal experimentation ethic committee N°26) and the French ministry of higher education and research.

[0164] Transgenic mice strains used are B6.129S4-Grin1tm2Stl/J (further named as GRIN1fl/fl mice), B6.129S6-Taglntm2(cre)Yec/J (further named as Tagln-cre mice) (both from JACKSON LABORATORY) and B6.Cg-Tg(Tek-cre/ERT2)1Arnd/ArndCnrm (further named as Tek-cre mice) (EUROPEAN MOUSE MUTANT ARCHIVE).

[0165] Briefly, GRIN1fl/fl mice were crossed with either Tek-cre mice or tagln-cre mice. For NMDAR knocked out in smooth muscle cells, experiments were performed on male Tagln-cre x GRIN1fl/fl mice and male Tagln-cre mice were used as controls. For NMDAR knocked out in endothelial cells, experiments were performed on male Tek-cre x GRIN1fl/fl mice and male Tek-cre mice were used as controls after 5 weeks of Tamoxifen-containing chow (HARLAN LABORATORIES) administration followed by 1 week of standard chow. In both experiments, pulmonary hypertension was induced exposing mice to 3 weeks of hypoxia (10% FiO.sub.2). Then, mice were submitted to anesthesia induced by inhalation of isoflurane 3% mixed with air and maintained decreasing isoflurane concentration between 1% and 1.5%. The heart was taken out the thoracic cage, auricles were removed and right ventricles were separated from left ventricles associated to septa. The weight of each part was measured and the ratio of the right ventricle weigh to the left ventricle with septum weigh was calculated for each mouse. Lungs were processed inflating them with 10 mL of a mixture of saline and OCT 1/1 ratio (Shandon™Cryomatrix™, THERMOFISCHER SCIENTIFIC). Ventricles and inflated lungs were then frozen in cooled isopentane (VWR) and stored at -80° C.

Morphometric Analysis

[0166] 6 .Math.m thick sections of mouse lungs were cut with a cryomicrotome (LEICA MICROSYSTEMS). Sections were allowed to dry during 1 hour under a hood. Then, they were fixed in cold acetone for 10 minutes. 10% goat serum plus 5% mouse serum were incubated for 1 hour to prevent unspecific binding of antibodies. Anti-VWF and Anti-alpha smooth muscle cell-FITC antibodies were incubated in presence of 2% mouse serum during 1 hour at room temperature. A negative control was performed omitting primary antibodies. The secondary antibody was incubated during 30 minutes in presence of 2% mouse serum DAPI (LIFE TECHNOLOGIES) diluted at 1/500 was incubated during 1 minute. Glass slides were finally mounted using Dako Fluorescent mounting medium (DAKO). Sections were then analyzed using Eclipse 80i microscope coupled to Nis Elements BR2.30 software (NIKON).

[0167] For morphometric analysis performed on mouse lungs, intrapulmonary arterioles were divided in four groups based on their external diameter: less than 30 .Math.m, from 30 .Math.m to 50 .Math.m, from 50 .Math.m to 75 .Math.m and from 75 .Math.m to 125 .Math.m. 20 arterioles per category identified with the VWF staining were qualified as non muscularized, partially muscularized or fully muscularized based on the alpha smooth muscle actin staining. 5 mice/group were included in the study.

In Vivo Brain Penetration Measurement: Drug Administration and Sampling of Brain and Plasma

[0168] The femoral vein of male Sprague-Dawley rats (CRL) weighing around 250 g was surgically catheterized at least 72 hours prior to the experiment. 3 animals were performed for each compound tested. The drug was administered as 3.45 h constant-rate intravenous infusion to approach steady state, using a flow rate of 0.8 mL/h, corresponding to dosage of 4 mg/kg (1.067 mg/kg/h, i.e. 1 mg / rat of ~250 g). The vehicle used was saline.

[0169] At the end of the infusion, the rats were anesthetized by inhalation of isoflurane, and blood was collected in a heparinized tube from the abdominal aorta, followed by immediate rinsing of the bloodstream for 2 minutes with saline at a rate of 15 mL/min using a peristaltic pump and left intraventricle cannula (flowing via right atrium). The brain (without cerebellum) was removed, and transferred in a tube and homogenized in two volumes of deionized water using a tissue homogenizer (Precellys24). All samples were stored at -20° C. until analysis. Plasma and brain homogenate sample preparation was performed using solid phase extraction on OASIS® WCX (Waters) and compounds were quantified by reversed phase liquid chromatography and positive electrospray ionization and multiple reaction monitoring mass spectrometry (LC-MS/MS).

Cultures of Hippocampal Neurons

[0170] For hippocampal neurons isolation and culture, all animals were used in strict accordance to the European Union regulations (Directive 2010/63/UE) for animal experiments. 18 day-pregnant female Wistar rats were decapitated, and fetuses were rapidly extracted from uterus and transferred in dissection solution (50 ml PBS (LIFE TECHNOLOGIES) + 50 units/ml penicillin-streptomycin (Abx) (THERMOFISCHER SCIENTIFIC) + 0.6% glucose. The rat fetus brains were quickly removed and placed in dissection solution before hippocampus extraction. Hippocampus were collected in HBSS (43.5 ml PBS, 0.6% glucose, 100 mM HEPES (LIFE TECHNOLOGIES), 100 units/ml Abx) and digested by addition of 0.25% trypsin (LIFE TECHNOLOGIES) and 0.1% DNAse I. After 10 minutes incubation at 37° C., 10% FBS (THERMOFISCHER SCIENTIFIC) was added to stop digestion. Cells were then mechanically dissociated by gentle pipetting to obtain uniform suspension. After centrifugation (10 minutes, 100 G) supernatant was removed and cell pellet was suspended in HC medium (50 ml neurobasal medium, 1 ml B27 supplement, 500 .Math.l glutamine 200 mM 100X (all from LIFE TECHNOLOGIES), 50 units/ml Abx) plus 10% FBS and without Abx. Cells were counted and 630,000 cells were dispatched in each poly-D-lysine-coated 35 mm petri dishes (BD Falcon, CORNING) containing 2 ml HC for culture. After 6 days of culture, cytosine β-D-arabinofuranoside (Ara-C) was added to inhibit proliferation of glial cells. Cells were then used from DIV 14. Cells were cultured at 37° C. in a humidified atmosphere of 5% CO.sub.2 and 95% air.

Electrophysiology

[0171] Chemicals used for patch-clamp solutions were provided by Sigma-Aldrich. TTX was provided by R&D, CNQX by Abcam. Whole-cell voltage clamp recordings from rat hippocampal neurons were made with patch pipettes (5-6 MΩ) filled with intracellular solution (in mM): 150 CsCl, 5 EGTA, 10 HEPES; its pH was adjusted to 7.2 with NaOH. The external bath solution contained (in mM): 140 NaCl, 3 KCl, 2 CaCl.sub.2, 10 HEPES, 10 glucose, 0.5 .Math.M TTX, 20 .Math.M picrotoxin and 20 .Math.M CNQX; its pH was adjusted to 7.4 with CsOH. The membrane potential was clamped at -60 mV. Currents were monitored using an AxoPatch200B patch clamp amplifier (Axon Instruments, Sunnyvale, CA, USA) filtered at 2 kHz and digitized at 100 Hz. Experiments were controlled by data acquisition board (National Instruments). Data were analyzed by Exel and GraphPad software. Liquid junction potentials were measured with the patch clamp amplifier. Transmembrane currents were evoked in acutely isolated neurons by the application of 100 .Math.M NMDA and 20 .Math.M D-serine. Antagonists of NMDA receptors were applied at increasing concentration. Cells were constantly perfused using gravity-fed bath at 1-2 ml/min. To calculate the percentage block by antagonist, residual desensitization of NMDA-induced currents was compensated by fitting exponentials to the pre-antagonist portion of traces.

Statistical Analysis

[0172] Results are expressed as mean+SEM of measurement unless otherwise indicated. Gaussian distribution of all data was assessed using Kolmogorov-Smirnov test or Shapiro-Wilk depending on sample size. To compare two groups of data, either unpaired t test or Mann-Whitney test were used depending on the data distribution. For multiple comparisons, one-way analysis of variance followed by Bonferroni test or Kruskal-Wallis followed by Dunn’s tests were used when it was appropriate. Results from transgenic mice were analyzed with a two-way analysis of variance followed by a Bonferroni test. Differences were considered significant with a P value < 0.05. Statistical analysis was performed with Prism 6 (GRAPHPAD SOFTWARE) and Excel softwares.

Example 1

Preparation of the Compounds According to the Invention

[0173] In accordance with the invention, the preparation of compounds of general formula (I) is illustrated below.

General Procedure A for the Preparation of 1-((5S,10R)-5-Methyl-10,11-Dihydro-5H-5,10-Epiminodibenzo[a,d][7]Annulen-12-yl)Ketone

[0174] To a solution of 258 mg of MK801 hydrochloride (1 mmol) in 10 mL of dry DCM were added 1.5 equivalent of the corresponding acyl chloride, 20 mol% of DMAP and 3 equivalent of TEA under argon. The mixture was stirred at room temperature for 12 hours to 20 hours (reaction monitored by TLC). 50 mL of diethyl ether was added to the reaction mixture. The solution obtained was washed two times with 15 mL of saturated aqueous solution of NH.sub.4Cl. Organic layers were dried over sodium sulfate, concentrated under reduce pressure, at 10 mbar, and the crude product was purified by column chromatography on silica gel.

General Procedure B for Reduction of 1-((5S,10R)-5-Methyl-10,11-Dihydro-5H-5,10-Epiminodibenzo[a,d][7]Annulen-12-yl)Ketone

[0175] To 1 equivalent of a solution of MK801 amide derivative in 0.2 M of anhydrous THF was added 5 equivalent of LiAlH.sub.4 under argon atmosphere at 0° C. After stirring at room temperature for an additional period of 30 minutes, the mixture was heated at reflux for 12 hours to 24 hours (reaction monitored by TLC). After being allowed to cool to room temperature, the mixture was treated with drop-to-drop addition of water at 0° C. till complete destruction of excess LAH. The mixture was then filtered on celite pad, washed with diethyl ether and the resultant solution was washed with brine. After drying over sodium sulfate, evaporation of the solvent under reduced pressure, at 10 mbar, the amine was directly engaged in the next step without purification.

General Procedure C for Preparation of (5S,10R)-12-CH.SUB.2.R-5-Methyl-10,11-Dihydro-5H-5,10-Epiminodibenzo[a,d][7]Annulene

[0176] To 1 equivalent of a solution of MK801 maleate in 0.1 M of anhydrous acetonitrile were added 3.5 equivalent of K.sub.2CO.sub.3 and 1.1 equivalent of RCH.sub.2X under argon atmosphere, at room temperature. After stirring at reflux for 12 hours (reaction monitored by TLC), and after being allowed to cool to room temperature, the mixture was filtered on celite pad and washed with ethyl acetate. After evaporation of the solvents under reduced pressure, at 10 mbar, the amine was directly engaged in the next step without purification.

General Procedure D for Quaternarization of (5S,10R)-12-CH.SUB.2.R-5-Methyl-10,11-Dihydro-5H-5,10-Epiminodibenzo[a,d][7]Annulene

[0177] To a solution of 1 equivalent of the corresponding amine in 0.2 M of dioxane in a microwave-type tube, was added 80 equivalent of alkyl iodide. The vial is sealed, and the mixture was heated at 50° C. or 100° C. under stirring for 12 hours/or stirred at room temperature for four days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure, at 10 mbar, to give the desired quatemarized ammonium iodide salt, eventually purified over preparative plate.

Compound N°1

[0178] Compound N°1 is prepared according to the general procedure D.

[0179] To a solution of 674 mg of (+)-MK801 maleate (2 mmol) in 5 mL of dioxane were added 2.59 g of cesium carbonate (8 mmol) and 5 mL of methyl iodide (80.3 mmol) to give 720 mg of Compound N°1 as a white solid without purification.

[0180] Yield: 98%.

[0181] Melting point = 270-280° C.

[0182] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.52 (br d, J = 6.9 Hz, 1H), 7.41-7.27 (m, 5H), 7.15-7.09 (m, 2H), 6.37 (d, J = 5.0 Hz, 1H), 3.99 (dd, J = 18.8 Hz, 5.9 Hz, 1H), 3.55 (s, 3H), 3.44 (s, 3H), 3.11 (d, J = 18.8 Hz, 1H), 2.19 (s, 3H).

[0183] .sup.13C NMR δ (75 MHz, MeOH d4) (ppm): 144.8, 137.4, 136.1, 131.5, 131.2 (2C), 131.0, 130.6, 129.3, 125.1, 124.9, 122.2, 82.8, 75.9, 42.7, 32.4 (2C), 12.6.

[0184] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3042, 3007, 2949, 1612, 1478, 1461, 1429, 1391, 1318, 1262, 1237, 1167, 1084, 1006, 971, 932, 809, 787, 768, 718.

[0185] HRMS (ESI positive):

[0186] Calculated for C.sub.18H.sub.20N [M-I].sup.+ 250.1596; Found 250.1592.

[00001]${\left[\alpha \right]}_{\text{D}}{}^{20}+190°\left(c0.50,\text{MeOH}\right).$

Compound N°2

[0187] Compound N°2 is prepared according to the general procedure D.

[0188] To a solution of 122 mg of (5S,10R)-12-ethyl-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2 mL of dioxane were added 2.5 mL of methyl iodide (40.2 mmol) to give 128 mg of Compound N°2 as a white solid without purification.

[0189] Yield: 64%.

[0190] Melting point = 230-232° C.

[0191] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.7-7.63 (m, 1H), 7.41-7.35 (m, 1H), 7.35-7.23 (m, 4H), 7.14-7.06 (m, 2H), 6.07 (d, J = 5.3 Hz, 1H), 3.77-3.6 (m, 2H), 3.5-3.36 (m, 1H), 3.29 (s, 3H), 3.15 (d, J = 19.0 Hz, 1H), 2.26 (s, 3H), 1.65 (t, J = 7.2 Hz, 3H).

[0192] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.2, 135.2, 134.4, 130.4, 130.1, 130.0 (2C), 129.2, 128.4, 124.4, 123.8, 120.6, 82.7, 71.2, 49.7, 45.9, 31.6, 14.1, 10.5.

[0193] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3010, 2944, 2839, 1613, 1478, 1452, 1425, 1398, 1307, 1275, 1252, 1132, 1088, 1042, 1028, 9b5, 903, 811, 768, 751, 667.

[0194] HRMS (ESI positive):

[0195] Calculated for C.sub.19H.sub.22N [M-I].sup.+ 264.1752; Found 264.1749.

[00002]${\left[\alpha \right]}_{\text{D}}{}^{20}+178°\left(c0.50,\text{MeOH}\right).$

Compound N°3

[0196] Compound N°3 is prepared according to the general procedure D.

[0197] To a solution of 70 mg of (5S,10R)-12-butyl-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.25 mmol) in 1 mL of dioxane were added 1.25 mL of methyl iodide (20 mmol) to give 104 mg of Compound N°3 as a yellow solid without purification.

[0198] Melting point = 200-203° C.

[0199] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.69-7.63 (m, 1H), 7.39-7.33 (m, 1H), 7.33-7.21 (m, 4H), 7.12-7.04 (m, 2H), 6.04 (d, J = 5.2 Hz, 1H), 3.67-3.46 (m, 2H), 3.29 (s, 3H), 3.28-3.20 (m, 1H), 3.15 (d, J = 18.7 Hz, 1H), 2.25 (s, 3H), 2.14-1.96 (m, 2H), 1.48-1.18 (m, 2H), 0.9 (t, J = 7.4 Hz, 3H).

[0200] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.1, 135.3, 134.4, 130.29, 130.22, 130.1 (2C), 129.2, 128.4, 124.5, 123.8, 120.6, 82.9, 71.6, 54.1, 46.5, 31.7, 26.1, 20.4, 14.1, 13.8.

[0201] IR (neat) (cm.sup.-1): λ.sub.max = 3467, 3008, 2960, 2932, 2873, 1612, 1479, 1461, 1425, 1395, 1275, 1233, 1159, 1083, 1059, 1042, 917, 897, 810, 786, 767, 677.

[0202] HRMS (ESI positive):

[0203] Calculated for C.sub.21H.sub.26N [M-I].sup.+ 292.2065; Found 292.2061.

[00003]${\left[\alpha \right]}_{\text{D}}{}^{20}+151°\left(c0.5,\text{MeOH}\right).$

Compound N°4

[0204] Compound N°4 is prepared according to the general procedure D.

[0205] To a solution of 85 mg of (5S,10R)-12-isobutyl-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.3 mmol) in 1.5 mL of dioxane were added 1.5 mL of methyl iodide (24.1 mmol) to give 100 mg of Compound N°4 as a white solid without purification.

[0206] Yield = 75%.

[0207] Melting point = 216-217° C.

[0208] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.70 (br d, J = 6.9 Hz, 1H), 7.37-7.31 (m, 1H), 7.31-7.20 (m, 4H), 7.11-7.02 (m, 2H), 6.22 (d, J = 5.2 Hz, 1H), 3.60 (dd, J= 18.5 Hz, 5.4 Hz, 1H), 3.30 (s, 3H), 3.21 (d, J = 18.5 Hz, 1H), 3.16-3.07 (m, 2H), 2.63 (sept, J = 6.3 Hz, 1H), 2.23 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H), 1.12 (d, J = 6.6 Hz, 3H).

[0209] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.4, 135.3, 134.8, 130.3, 130.25, 130.1, 130.0, 129.0, 128.4, 124.6, 123.8, 120.6, 84.1, 72.0, 61.2, 46.6, 32.0, 25.0, 23.7, 23.3, 14.2.

[0210] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3011, 2966, 2931, 2875, 1613, 1479, 1458, 1426,1393,1277,1233,1158,1080,1044, 971, 919, 908, 789, 717, 679, 640.

[0211] HRMS (ESI positive):

[0212] Calculated for C.sub.21H.sub.26N [M-I].sup.+ 292.2065; Found 292.2060.

[00004]${\left[\alpha \right]}_{\text{D}}{}^{20}+178°\left(c0.54,\text{MeOH}\right).$

Compound N°5

[0213] Compound N°5 is prepared according to the general procedure D.

[0214] To a solution of 70 mg of (5S,10R)-12-(cyclopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.25 mmol) in 1 mL of dioxane were added 1.25 mL of methyl iodide (20 mmol) to give 113 mg of Compound N°5 as a white solid without purification.

[0215] Yield = 90%.

[0216] Melting point = 103-105° C.

[0217] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.62 (br d, J = 6.7 Hz, 1H), 7.37-7.31 (m, 1H), 7.31-7.21 (m, 4H), 7.10-7.03 (m, 2H), 6.12 (d, J = 5.1 Hz, 1H), 3.84-3.70 (m, 2H), 3.37 (s, 3H), 3.23-3.10 (m, 2H), 2.26 (s, 3H), 1.51-1.38 (m, 1H), 0.94-0.83 (m, 1H), 0.80-0.69 (m, 2H), 0.51-0.42 (m, 1H).

[0218] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.1, 135.3, 134.7, 130.4, 130.2, 130.0 (2C), 129.3, 128.4, 124.2, 123.7, 120.6, 82.3, 72.2, 58.4, 46.1, 31.8, 14.6, 7.8, 6.7, 3.9.

[0219] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3077, 3000, 2939, 1613, 1478, 1460, 1426, 1391, 1359, 1275, 1173, 1084, 1059, 1032, 991, 917, 840, 788, 767, 717, 639.

[0220] HRMS (ESI positive):

[0221] Calculated for C.sub.21H.sub.24N [M-I].sup.+ 290.1909; Found 290.1909.

[00005]${\left[\alpha \right]}_{\text{D}}{}^{20}+126°\left(c0.54,\text{MeOH}\right).$

Compound N°6

[0222] Compound N°6 is prepared according to the general procedure D.

[0223] To a solution of 50 mg of (5S,10R)-12-(cyclopentyhnethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.16 mmol) in 1 mL of dioxane were added 0.8 mL of methyl iodide (13 mmol) to give 56 mg of Compound N°6 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0224] Yield = 74%.

[0225] Melting point = 125-127° C.

[0226] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.68 (br d, J = 6.8 Hz, 1H), 7.38-7.31 (m, 1H), 7.31-7.21 (m, 4H), 7.12-7.04 (m, 2H), 6.23 (d, J = 4.9 Hz, 1H), 3.62 (dd, J = 18.9 Hz, 5.4 Hz, 1H), 3.42-3.35 (m, 2H), 3.29 (s, 3H), 3.15 (d, J = 18.7 Hz, 1H), 2.79-2.65 (m, 1H), 2.24 (s, 3H), 2.10-1.98 (m, 1H), 1.76-1.50 (m, 5H), 1.43-1.32 (m, 1H), 1.27-1.15 (m, 1H).

[0227] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.8, 135.4, 134.6, 130.3, 130.2, 130.1, 130.0, 129.1, 128.4, 124.5, 123.7, 120.6, 83.3, 71.9, 59.5, 46.9, 35.8, 33.8, 33.6, 31.8, 25.3, 24.9, 14.1.

[0228] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3075, 3010, 2960, 2945, 2906, 2869, 1612, 1478, 1459, 1426, 1395, 1359, 1275, 1175, 1081, 1059, 918, 787, 726, 639.

[0229] HRMS (ESI positive):

[0230] Calculated for C.sub.23H.sub.28N [M-I].sup.+ 318.2222; Found 318.2220.

[00006]${\left[\alpha \right]}_{\text{D}}{}^{20}+125°\left(c0.51,\text{MeOH}\right).$

Compound N°7

[0231] Compound N°7 is prepared according to the general procedure D.

[0232] To a solution of 85 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)acetimidic acid (0.31 mmol) in 1.5 mL of dioxane was added 1.5 mL of methyl iodide (24.1 mmol) to give 90 mg of Compound N°7 as a white solid without purification.

[0233] Yield: 69%.

[0234] Melting point = 189-192° C.

[0235] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 8.49 (br s, 1H), 7.49-7.28 (m, 6H), 7.20-7.14 (m, 1H), 7.13-7.06 (m, 1H), 6.35 (br s, 1H), 5.79 (d, J = 5.0 Hz, 1H), 5.48 (d, J = 14.5 Hz, 1H), 3.97 (dd, J = 18.7 Hz, 5.0 Hz, 1H), 3.8 (d, J = 14.5 Hz, 1H), 3.29 (s, 3H), 3.13 (d, J = 18.7 Hz, 1H), 2.46 (s, 3H).

[0236] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 166.0, 141.9, 134.7, 134.1, 130.6, 130.4 (2C), 130.3, 129.1, 128.7, 124.3, 123.6, 121.0, 84.8, 73.6, 54.8, 45.9, 31.8, 14.6.

[0237] IR (neat) (cm.sup.-1): λ.sub.max = 3314, 3146, 3013, 1689, 1606, 1477, 1458, 1428, 1413, 1392, 1321, 1273, 1233, 1184, 1114, 1083, 1019, 983, 897, 776, 731.

[0238] HRMS (ESI positive):

[0239] Calculated for C.sub.19H.sub.21N.sub.2O [M-I].sup.+ 293.1654; Found 293.1662.

[00007]${\left[\alpha \right]}_{\text{D}}{}^{20}+90°\left(c0.52,\text{MeOH}\right).$

Compound N°8

[0240] Compound N°8 is prepared according to the general procedure D.

[0241] To a solution of 165 mg of (5S,10R)-12-(4-fluorobenzyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 108 mg of Compound N°8 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0242] Yield: 46%.

[0243] Melting point = 92-94° C.

[0244] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.61-7.51 (m, 3H), 7.50-7.31 (m, 5H), 7.31-7.23 (m, 1H), 7.15-7.05 (m, 3H), 6.24 (d, J = 5.6 Hz, 1H), 5.64 (d, J = 13.4 Hz, 1H), 4.74 (d, J= 13.4 Hz, 1H), 4.13 (dd, J = 18.8 Hz, 5.7 Hz, 1H), 3.34 (s, 3H), 3.26 (d, J = 18.8 Hz, 1H), 2.00 (s, 3H).

[0245] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 165.7, 162.4, 143.3, 135.5, 135.4, 135.0, 134.4, 130.9, 130.7, 130.2, 130.1, 129.6, 128.7, 124.2, 123.6, 120.7, 116.8, 116.5, 82.4, 73.6, 57.3, 44.2, 32.3, 15.2.

[0246] IR (neat) (cm.sup.-1): λ.sub.max = 3452, 3033, 2934, 1605, 1512, 1478, 1458, 1424, 1392, 1302, 1230, 1163, 1082, 1016, 919, 907, 862, 833, 763, 717, 641.

[0247] HRMS (ESI positive):

[0248] Calculated for C.sub.24H.sub.23NF [M-I].sup.+ 344.1815; Found 344.1812.

[00008]${\left[\alpha \right]}_{\text{D}}{}^{20}+153°\left(c0.49,\text{MeOH}\right).$

Compound N°9

[0249] Compound N°9 is prepared according to the general procedure D.

[0250] To a solution of 190 mg of (5S,10R)-5-methyl-12-(3-(trifluoromethyl)benzyl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]armulene (0.5 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 75 mg of Compound N°9 as a pale yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0251] Yield: 29%.

[0252] Melting point = 167-170° C.

[0253] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 8.04 (d, J = 7.9 Hz, 1H), 7.75-7.68 (m, 1H), 7.65-7.55 (m, 2H), 7.49-7.23 (m, 7H), 7.06 (d, J = 7.4 Hz, 1H), 6.31 (d, J = 5.5 Hz, 1H), 5.81 (d, J = 13.2 Hz, 1H), 4.8 (d, J= 13.2 Hz, 1H), 4.14 (dd, J = 19.0 Hz, 5.5 Hz, 1H), 3.37 (s, 3H), 3.26 (d, J = 19.0 Hz, 1H), 1.91 (s, 3H).

[0254] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.1, 137.2, 134.9, 134.3, 131.0, 130.9, 130.5, 130.4, 130.2 (2C), 129.7, 129.4, 128.8 (2C), 127.7, 123.6, 123.5, 120.7 (2C), 82.6, 74.1, 57.7, 44.1, 32.2, 153.

[0255] IR (neat) (cm.sup.-1): λ.sub.max = 3447, 3015, 2928, 1616, 1478, 1453, 1423, 1393, 1329, 1274, 1209, 1182, 1168, 1125, 1018, 971, 919, 871, 808, 728, 642.

[0256] HRMS (ESI positive):

[0257] Calculated for C.sub.25H.sub.23NF.sub.3 [M-I].sup.+ 394.1783; Found 394.1779.

[00009]${\left[\alpha \right]}_{\text{D}}{}^{20}+136°\left(c0.50,\text{MeOH}\right).$

Compound N°10

[0258] Compound N°10 is prepared according to the general procedure D.

[0259] To a solution of 90 mg of (5S,10R)-12-isopentyl-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.31 mmol) in 1 mL of dioxane were added 1.5 mL of methyl iodide (24.1 mmol) to give 100 mg of Compound N°10 as a yellow solid without purification.

[0260] Yield = 74%.

[0261] Melting point = 215-217° C.

[0262] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.67 (br d, J = 6.9 Hz, 1H), 7.41-7.35 (m, 1H), 7.35-7.25 (m, 4H), 7.13-7.05 (m, 2H), 6.06 (d, J = 5.0 Hz, 1H), 3.67-3.44 (m, 3H), 3.29 (s, 3H), 3.16 (d, J = 18.9 Hz, 1H), 2.26 (s, 3H), 2.06-1.90 (m, 2H), 1.62 (sept, J = 6.6 Hz, 1H), 0.9 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H).

[0263] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.0, 135.2, 134.4, 130.3, 130.2, 130.1, 130.0, 129.2, 128.4, 124.5, 123.8, 120.7, 83.0, 71.5, 53.1, 46.5, 32.4, 31.7, 26.7, 22.8, 22.3, 14.2.

[0264] IR (neat) (cm.sup.-1): λ.sub.max = 3467, 3010, 2958, 2872, 1613, 1481, 1462, 1425, 1393,1273,1234,1160,1084,1045, 919, 785, 765, 729, 639.

[0265] HRMS (ESI positive):

[0266] Calculated for C.sub.22H2.sub.8N [M-I].sup.+ 306.2222; Found 306.2220.

[00010]${\left[\alpha \right]}_{\text{D}}{}^{20}+137°\left(c0.54,\text{MeOH}\right).$

Compound N°11

[0267] Compound N°11 is prepared according to the general procedure D.

[0268] To a solution of 66 mg of (5S,10R)-5-methyl-12-propyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.25 mmol) in 1.25 mL of dioxane was added 1.25 mL of methyl iodide (20.1 mmol) to give 44 mg of Compound N°11 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0269] Yield: 42%.

[0270] Melting point = 214-217° C.

[0271] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.69 (br d, J = 6.4 Hz, 1H), 7.42-7.27 (m, 5H), 7.16-7.07 (m, 2H), 6.12 (d, J = 4.7 Hz, 1H), 3.69-3.51 (m, 2H), 3.34 (s, 3H), 3.25-3.10 (m, 2H), 2.27 (s, 3H), 2.23-2.07 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0272] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.1, 135.3, 134.5, 130.4, 130.2, 130.1, 130.0, 129.2, 128.4, 124.5, 123.8, 120.6, 82.9, 71.6, 55.7, 46.6, 31.7, 18.2, 14.0, 11.6.

[0273] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3008, 2968, 2877, 1612, 1480, 1459, 1425, 1395,1275,1261,1233,1104,1081,1041,1018, 947, 880, 841, 782, 766, 731, 697.

[0274] HRMS (ESI positive):

[0275] Calculated for C.sub.20H.sub.24N [M-I].sup.+ 278.1909; Found 278.1908.

[00011]${\left[\alpha \right]}_{\text{D}}{}^{14}+124°\left(c0.17,\text{MeOH}\right).$

Compound N°12

[0276] Compound N°12 is prepared according to the general procedure D.

[0277] To a solution of 82 mg of (5S,10R)-12-hexyl-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.26 mmol) in 1.5 mL of dioxane was added 1.3 mL of methyl iodide (21 mmol) to give 43 mg of Compound N°12 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0278] Yield = 36%.

[0279] Melting point = 200-203° C.

[0280] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.69 (m, 1H), 7.42-7.27 (m, 5H), 7.15-7.09 (m, 2H), 6.13 (d, J = 5.0 Hz, 1H), 3.63 (dd, J = 19.2 Hz, 5.0 Hz, 1H), 3.57-3.48 (m, 1H), 3.35 (s, 3H), 3.33-3.26 (m, 1H), 3.18 (d, J = 19.2 Hz, 1H), 2.27 (s, 3H), 2.16-2.03 (m, 2H), 1.46-1.19 (m, 6H), 0.83 (t, J = 6.3 Hz, 3H).

[0281] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.0, 135.3, 134.5, 130.31, 130.25, 130.1, 130.0, 129.2, 128.5, 124.5, 123.8, 120.6, 82.9, 71.6, 54.4, 46.5, 31.7, 31.3, 26.8, 24.4, 22.6, 14.1, 13.8.

[0282] IR (neat) (cm.sup.-1): λ.sub.max = 3462, 3075, 3010, 2956, 2927, 2871, 2856, 1614, 1480, 1460, 1425, 1395, 1308, 1275, 1233, 1159, 1082, 920, 809, 783, 748, 639.

[0283] HRMS (ESI positive):

[0284] Calculated for C.sub.23H.sub.30N [M-I].sup.+ 320.2378; Found 320.2378.

[00012]${\left[\alpha \right]}_{\text{D}}{}^{14}+150°\left(c0.26,\text{MeOH}\right)$

Compound N°13

[0285] Compound N°13 is prepared according to the general procedure D.

[0286] To a solution of 100 mg of (5S,10R)-5-methyl-12-(2-methylbutyl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.34 mmol) in 1.5 mL of dioxane were added 1.5 mL of methyl iodide (24.1 mmol) to give 46 mg of Compound N°13 as a white solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0287] Yield = 31%.

[0288] Melting point = 181-184° C.

[0289] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.74 (br t, J = 7.0 Hz, 1H), 7.44-7.29 (m, 5H), 7.15-7.09 (m, 2H), 6.36 (d, J = 5.3 Hz, 1H, dia 1), 6.31 (d, J = 5.3 Hz, 1H, dia 2), 3.72 (dd, J = 18.8 Hz, 5.3 Hz, 1H, dia 1), 3.67 (dd, J = 18.8 Hz, 5.3 Hz, 1H, dia 2), 3.41-3.37 (m, 1H), 3.35 (s, 3H, dia 1), 3.33 (s, 3H, dia 2), 3.32-3.15 (m, 3H), 2.53-2.35 (m, 1H), 2.29 (s, 3H, dia 1), 2.28 (s, 3H, dia 2), 1.66-1.53 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H, dia 1), 1.21 (d, J = 6.5 Hz, 3H, dia 2), 0.97-0.87 (m, 3H).

[0290] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.5 (dia 1), 142.3 (dia 2), 135.4 (dia 1), 135.3 (dia 2), 134.9 (dia 1), 134.8 (dia 2), 130.3, 130.1, 130.0, 129.1 (dia 1) 129.0 (dia 2), 128.5, 124.5, 123.8, 120.7, 120.6, 84.0 (dia 1), 83.9 (dia 2), 72.3 (dia 1), 72.1 (dia 2), 61.1 (dia 1), 60.1 (dia 2), 47.0 (dia 1), 46.1 (dia 2), 32.0 (dia 1), 31.9 (dia 2), 30.8 (dia 1), 30.7 (dia 2), 30.3 (dia 1), 29.6 (dia 2), 20.7 (dia 1), 19.7 (dia 2), 14.2, 11.4 (dia 1), 11.2 (dia 2).

[0291] IR (neat) (cm.sup.-1): λ.sub.max = 3452, 3011, 2964, 2933, 2876, 1614, 1479, 1460, 1425, 1395, 1341, 1307, 1274, 1250, 1233, 1191, 1158, 1081, 1045, 1018, 970, 940, 918, 871, 788, 765, 728, 717, 677, 639.

[0292] HRMS (ESI positive):

[0293] Calculated for C.sub.22H.sub.28N [M-I].sup.+ 306.2222; Found 306.2219.

[00013]${\left[\alpha \right]}_{\text{D}}{}^{20}+180°\left(c0.44,\text{MeOH}\right).$

Compound N°14

[0294] Compound N°14 is prepared according to the general procedure D.

[0295] To a solution of 84 mg of (+)-MK801 maleate (0.25 mmol) in 1 mL of dioxane were added 324 mg of cesium carbonate (1 mmol) and 1.6 mL of ethyl iodide (20 mmol) to give 80 mg of Compound N°14 as a white solid without purification.

[0296] Yield: 79%.

[0297] Melting point = 237-238° C.

[0298] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.63 (d, J = 6.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.33-7.21 (m, 4H), 7.12-7.04 (m, 2H), 6.07 (d, J = 5.3 Hz, 1H), 3.9 (dd, J = 19.5 Hz, 5.4 Hz, 1H), 3.86-3.72 (m, 2H), 3.68-3.53 (m, 1H), 3.38-3.24 (m, 1H), 3.14 (d, 19.5 Hz, 1H), 2.26 (s, 3H), 1.65 (td, J = 7.2 Hz, 2.2 Hz, 6H).

[0299] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.7, 135.5, 134.3, 130.4, 130.3, 130.1, 130.0, 129.9, 128.2, 123.7, 123.6, 120.4, 83.8, 68.7, 52.1, 48.0, 32.0, 15.5, 11.5, 11.2.

[0300] IR (neat) (cm.sup.-1): λ.sub.max = 3467, 3019, 2981, 2829, 1613, 1484, 1460, 1452, 1428, 1396, 1308, 1295, 1250, 1231, 1153, 1133, 1076, 1040, 918, 903, 804, 787, 717, 641.

[0301] HRMS (ESI positive):

[0302] Calculated for C.sub.20H.sub.24N [M-I].sup.+ 278.1909; Found 278.1919.

[00014]${\left[\alpha \right]}_{\text{D}}{}^{20}+200°\left(c0.50,\text{MeOH}\right).$

Compound N°15

[0303] Compound N°15 is prepared according to the general procedure D.

[0304] To a solution of 100 mg of (5S,10R)-12-(cyclohexylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.32 mmol) in 1.5 mL of dioxane was added 1.5 mL of methyl iodide (24.1 mmol) to give 33 mg of Compound N°15 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0305] Yield =18%.

[0306] Melting point = 220-222° C.

[0307] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.70 (d, J = 7.0 Hz, 1H), 7.42-7.27 (m, 5H), 7.15-7.07 (m, 2H), 6.33 (d, J = 5.0 Hz, 1H), 3.67 (dd, J = 19.1 Hz, 5.0 Hz, 1H), 3.35 (s, 3H), 3.24-3.12 (m, 3H), 2.44-2.33 (m, 1H), 2.26 (s, 3H), 2.05-1.92 (m, 2H), 1.80-1.41 (m, 4H), 1.30-0.97 (m, 4H).

[0308] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.5, 135.4, 134.9, 130.4, 130.3, 130.2, 130.0, 129.2, 128.5, 124.5, 123.8, 120.7, 83.8, 72.3, 60.9, 46.8, 34.0, 33.8, 33.5, 32.0, 26.0, 25.8, 25.0, 14.2.

[0309] IR (neat) (cm.sup.-1): λ.sub.max = 3437, 3009, 2953, 1613, 1478, 1461, 1448, 1425, 1396, 1357, 1275, 1183, 1018, 919, 788, 765, 728, 639.

[0310] HRMS (ESI positive):

[0311] Calculated for C.sub.24H.sub.30N [M-I].sup.+ 332.2378; Found 332.2385.

[00015]${\left[\alpha \right]}_{\text{D}}{}^{20}+126°\left(c0.27,\text{MeOH}\right).$

Compound N°16

[0312] Compound N°16 is prepared according to the general procedure D.

[0313] To a solution of 60 mg of (5S,10R)-12-benzyl-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.19 mmol) in 1 mL of dioxane was added 0.8 mL of methyl iodide (13 mmol) to give 24 mg of Compound N°16 as a white solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0314] Yield: 28%.

[0315] Melting point = 220-222° C.

[0316] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.57 (d, J = 7.2 Hz, 1H), 7.50-7.29 (m, 10H), 7.29-7.22 (m, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.28 (d, J = 5.5 Hz, 1H), 5.61 (d, J = 13.2 Hz, 1H), 4.71 (d, J= 13.2 Hz, 1H), 4.14 (dd, J = 18.8 Hz, 5.9 Hz, 1H), 3.33 (s, 3H), 3.23 (d, J = 18.8 Hz, 1H), 1.96 (s, 3H).

[0317] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.5, 135.2, 134.6, 133.4 (2C), 130.9 (2C), 130.6, 130.2, 130.1, 129.8, 129.4 (2C), 128.6, 128.3, 123.7, 123.6, 120.6, 82.2, 73.8, 58.5, 44.1, 32.2, 15.1.

[0318] IR (neat) (cm.sup.-1): λ.sub.max = 3457, 3067, 3008, 2959, 2921, 2851, 1605, 1584, 1498, 1458, 1422, 1393, 1303, 1273, 1250, 1180, 1134, 1078, 1049, 1033, 970, 919, 907, 761, 732 704, 639.

[0319] HRMS (ESI positive):

[0320] Calculated for C.sub.24H.sub.24N [M-I].sup.+ 326.1909; Found 326.1908.

[00016]${\left[\alpha \right]}_{\text{D}}{}^{15}+93°\left(c0.05,\text{MeOH}\right).$

Compound N°17

[0321] Compound N°17 is prepared according to the general procedure D.

[0322] To a solution of 80 mg of (5S,10R)-12-(cyclobutylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.28 mmol) in 1.5 mL of dioxane were added 1.4 mL of methyl iodide (22.5 mmol) to give 31 mg of Compound N°17 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0323] Yield = 25%.

[0324] Melting point = 159-162° C.

[0325] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.7 (br d, J = 6.9 Hz, 1H), 7.40-7.27 (m, 5H), 7.15-7.05 (m, 2H), 6.36 (d, J = 5.2 Hz, 1H), 3.64 (dd, J = 18.6 Hz, 5.2 Hz, 1H), 3.48-3.41 (m, 2H), 3.22 (s, 3H), 3.16 (d, J = 18.6 Hz, 1H), 2.51-2.41 (m, 1H), 2.25 (s, 3H), 2.11-2.00 (m, 2H), 1.91-1.77 (m, 2H).

[0326] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.8, 135.3, 134.5, 130.4, 130.2, 130.1, 130.0, 129.2, 128.4, 124.5, 123.7, 120.6, 82.6, 71.8, 58.9, 46.2, 31.7, 31.0, 30.6, 27.3, 18.8, 14.1.

[0327] IR (neat) (cm.sup.-1): λ.sub.max = 3430, 3075, 2960, 2933, 2906, 1613, 1478, 1459, 1426, 1394, 1341, 1256, 1234, 1159, 1076, 1058, 1041, 1017, 971, 918, 909, 840, 764, 727, 639.

[0328] HRMS (ESI positive):

[0329] Calculated for C.sub.22H.sub.26N [M-I].sup.+ 304.2041; Found 304.045.

[00017]${\left[\alpha \right]}_{\text{D}}{}^{20}+121°\left(c0.29,\text{MeOH}\right).$

Compound N°18

[0330] Compound N°18 is prepared according to the general procedure D.

[0331] To a solution of 140 mg of (5S,10R)-5-methyl-12-((1-phenylcyclopropyl)methyl) - 10,11 - dihydro - 5H - 5,10-epiminodibenzo[a,d][7]annulene (0.36 mmol) in 2 mL of dioxane were added 1.8 mL of methyl iodide (28.9 mmol) to give 80 mg of Compound N°18 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0332] Yield: 45%.

[0333] Melting point = 174-176° C.

[0334] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.48-7.26 (m, 9H), 7.25-7.20 (m, 2H), 7.04-6.93 (m, 2H), 4.99 (d, J = 5.4 Hz, 1H), 4.25 (d, J = 14.2 Hz, 1H), 3.58 (d, J= 14.2 Hz, 1H), 3.31 (s, 3H), 3.24 (dd, J = 18.9 Hz, 5.4 Hz, 1H), 2.65 (d, J = 18.9 Hz, 1H), 2.10 (s, 3H), 1.71-1.61 (m, 1H), 1.43-1.33 (m, 1H), 1.32-1.22 (m, 1H), 0.96-0.86 (m, 1H).

[0335] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.1, 141.9, 134.8, 134.7, 130.3, 130.2 (2C), 130.1 (2C), 130.0, 129.6 (2C), 129.0, 128.6, 128.4, 124.1, 123.3, 121.0, 83.9, 73.0, 62.7, 45.9, 31.6, 23.1, 15.5, 15.0, 14.9.

[0336] IR (neat) (cm.sup.-1): λ.sub.max = 3450, 3005, 2959, 2921, 1605, 1495, 1478, 1460, 1444, 1424, 1395, 1306, 1277, 1232, 1183, 1115, 1073, 1039, 990, 919, 905, 836, 764, 725, 703, 675, 640.

[0337] HRMS (ESI positive):

[0338] Calculated for C.sub.27H.sub.28N [M-I].sup.+ 366.2222; Found 366.2216.

[00018]${\left[\alpha \right]}_{\text{D}}{}^{15}+116°\left(c0.50,\text{MeOH}\right).$

Compound N°19

[0339] Compound N°19 is prepared according to the general procedure D.

[0340] To a solution of 163 mg of (5S,10R)-5-methyl-12-(4-methylbenzyl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 97 mg of Compound N°19 as a pale yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0341] Yield: 42%.

[0342] Melting point = 134-136° C.

[0343] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.55 (d, J = 7.0 Hz, 1H), 7.47-7.27 (m, 7H), 7.24-7.13 (m, 3H), 7.05 (d, J = 7.3 Hz, 1H), 6.15 (d, J = 5.2 Hz, 1H), 5.39 (d, J = 13.3 Hz, 1H), 4.64 (d, J= 13.3 Hz, 1H), 4.11 (dd, J = 19.1 Hz, 5.8 Hz, 1H), 3.26 (s, 3H), 3.23 (d, J = 19.1 Hz, 1H), 2.32 (s, 3H), 1.97 (s, 3H).

[0344] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.5, 141.1, 135.2, 134.6, 133.1 (2C), 130.8, 130.5, 130.11, 130.07 (2C), 130.0, 129.7, 128.5, 125.1, 123.6 (2C), 120.6, 82.1, 73.6, 58.3, 44.2, 32.3, 21.5, 15.1.

[0345] IR (neat) (cm.sup.-1): λ.sub.max = 3457, 3052, 3013, 2952, 2920, 1737, 1613, 1478, 1457, 1422, 1393, 1326, 1272, 12U6, 1176, 1083, 1U51, 920, 907, 887, 8U8, 787, 730, 638.

[0346] HRMS (ESI positive):

[0347] Calculated for C.sub.25H.sub.26N [M-I].sup.+ 340.2065; Found 340.2072.

[00019]${\left[\alpha \right]}_{\text{D}}{}^{20}+124°\left(c0.56,\text{MeOH}\right).$

Compound N°20

[0348] Compound N°20 is prepared according to the general procedure D.

[0349] To a solution of 184 mg of (5S,10R)-12-(4-(tert-butyl)benzyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 83 mg of Compound N°20 as a pale yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0350] Yield: 33%.

[0351] Melting point = 152-154° C.

[0352] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.56 (d, J = 7.0 Hz, 1H), 7.49-7.35 (m, 7H), 7.35-7.27 (m, 2H), 7.25-7.19 (m, 1H), 7.07 (d, J = 7.0 Hz, 1H), 6.11 (d, J = 5.5 Hz, 1H), 5.39 (d, J = 13.3 Hz, 1H), 4.67 (d, J= 13.3 Hz, 1H), 4.12 (dd, J = 18.9 Hz, 5.5 Hz, 1H), 3.29 (s, 3H), 3.24 (d, J = 18.9 Hz, 1H), 2.01 (s, 3H), 1.27 (s, 9H).

[0353] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 154.2, 143.5, 135.2, 134.5, 132.9 (2C), 130.7, 130.5, 130.1, 130.0, 129.7, 128.5, 126.4 (2C), 125.1, 123.7, 123.6, 120.7, 82.2, 73.5, 58.1, 44.4, 35.0, 32.3, 31.3 (3C), 15.2.

[0354] IR (neat) (cm.sup.-1): λ.sub.max = 3452, 3014, 2965, 2905, 2868, 1813, 1613, 1515, 1477, 1459, 1422, 1393, 1365, 1337, 1303, 1269, 1233, 1179, 1160, 1133, 1111, 1082, 1051, 1018, 970, 919, 907, 888, 860, 840, 820, 790, 772, 730, 718, 674, 639.

[0355] HRMS (ESI positive):

[0356] Calculated for C.sub.28H.sub.32N [M-I].sup.+ 382.2535; Found 382.2542.

[00020]${\left[\alpha \right]}_{\text{D}}{}^{20}+115°\left(c0.55,\text{MeOH}\right).$

Compound N°21

[0357] Compound N°21 is prepared according to the general procedure D.

[0358] To a solution of 200 mg of (5S,10R)-12-(4-methoxybenzyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.6 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 95 mg of Compound N°21 as a pale yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0359] Yield: 39%.

[0360] Melting point = 101-103° C.

[0361] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.55 (d, J = 7.0 Hz, 1H), 7.47-7.35 (m, 5H), 7.35-7.27 (m, 2H), 7.24-7.19 (m, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.12 (d, J = 5.4 Hz, 1H), 5.4 (d, J = 13.5 Hz, 1H), 4.64 (d, J= 13.5 Hz, 1H), 4.1 (dd, J = 18.9 Hz, 5.4 Hz, 1H), 3.79 (s, 3H), 3.26 (s, 3H), 3.22 (d, J = 18.9 Hz, 1H), 1.98 (s, 3H).

[0362] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 161.4, 143.5, 135.2, 134.7 (2C), 130.8, 130.5, 130.1, 130.0, 129.7, 128.5, 123.6 (2C), 120.6, 119.9, 114.7 (2C), 81.9, 73.4, 58.1, 55.6, 44.1, 32.2, 15.1.

[0363] IR (neat) (cm.sup.-1): λ.sub.max = 3447, 3011, 2936, 2888, 1813, 1815, 1610, 1582, 1515, 1478, 1459, 1421, 1392, 1337, 1282, 1257, 1182, 1111, 1083, 1051, 919, 905, 887, 825, 787, 762, 731, 640.

[0364] HRMS (ESI positive):

[0365] Calculated for C.sub.25H.sub.26NO [M-I].sup.+ 356.2014; Found 356.2021.

[00021]${\left[\alpha \right]}_{\text{D}}{}^{20}+115°\left(c0.52,\text{MeOH}\right).$

Compound N°22

[0366] Compound N°22 is prepared according to the general procedure D.

[0367] To a solution of 173 mg of (5S,10R)-12-(4-chlorobenzyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 70 mg of Compound N°22 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0368] Yield: 29%.

[0369] Melting point = 160-162° C.

[0370] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.56 (d, J = 7.1 Hz, 1H), 7.53-7.47 (m, 2H), 7.47-7.27 (m, 7H), 7.26-7.21 (m, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.17 (d, J = 5.3 Hz, 1H), 5.54 (d, J = 13.3 Hz, 1H), 4.7 (d, J= 13.3 Hz, 1H), 4.11 (dd, J = 19.2 Hz, 5.3 Hz, 1H), 3.29 (s, 3H), 3.25 (d, J = 19.2 Hz, 1H), 2.01 (s, 3H).

[0371] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.2, 137.2, 135.0, 134.7 (2C), 134.4, 130.9, 130.7, 130.3, 130.1, 129.7 (2C), 129.6, 128.7, 126.8, 123.6 (2C), 120.7, 82.5, 73.7, 57.3, 44.2, 32.3, 15.3.

[0372] IR (neat) (cm.sup.-1): λ.sub.max = 3452, 3049, 3019, 2929, 1813, 1596, 1493, 1477, 1455, 1424, 1392, 1338, 1297, 1248, 1181, 1084, 1050, 1015, 970, 919, 907, 837, 814, 789, 723, 691, 671, 640.

[0373] HRMS (ESI positive):

[0374] Calculated for C.sub.24H.sub.23NCl [M-I].sup.+ 360.1519; Found 360.1516.

[00022]${\left[\alpha \right]}_{\text{D}}{}^{15}+115°\left(c0.50,\text{MeOH}\right).$

Compound N°23

[0375] Compound N°23 is prepared according to the general procedure D.

[0376] To a solution of 173 mg of (5S,10R)-12-(2-chlorobenzyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 11 mg of Compound N°23 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0377] Yield: 5%.

[0378] Melting point = 129-131° C.

[0379] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 8.10 (d, J=7.7 Hz, 1H), 7.7 (d, J = 7.7 Hz, 1H), 7.51-7.44 (m, 1H), 7.43-7.18 (m, 8H), 7.18-7.13 (m, 1H), 6.55 (d, J = 5.5 Hz, 1H), 5.13 (d, J = 13.8 Hz, 1H), 4.73 (d, J= 13.8 Hz, 1H), 4.16 (dd, J = 19.3 Hz, 5.5 Hz, 1H), 3.34 (d, J = 19.3 Hz, 1H), 3.00 (s, 3H), 3.25 (d, J = 19.2 Hz, 1H), 2.07 (s, 3H).

[0380] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.6, 135.8, 135.2, 134.6, 134.4, 132.3, 130.7, 130.6, 130.4, 130.1, 129.9, 129.3, 129.0, 128.2, 126.2, 124.3, 124.0, 120.2, 83.1, 73.8, 53.9, 43.9, 32.5, 13.6.

[0381] IR (neat) (cm.sup.-1): λ.sub.max = 3452, 3038, 2929, 1593, 1477, 1457, 1421, 1391, 1271, 1233, 1206, 1161, 1134, 1057, 1041, 1018, 970, 918, 763, 715, 682, 639.

[0382] HRMS (ESI positive):

[0383] Calculated for C.sub.24H.sub.23NC1 [M-I].sup.+ 360.1519; Found 360.1519.

[00023]${\left[\alpha \right]}_{\text{D}}{}^{20}+121°\left(c0.55,\text{MeOH}\right).$

Compound N°24

[0384] Compound N°24 is prepared according to the general procedure D.

[0385] To a solution of 163 mg of (5S,10R)-5-methyl-12-(2-methylbenzyl)-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.5 mmol) in 2.5 mL of dioxane was added 2.5 mL of methyl iodide (40.2 mmol) to give 30 mg of Compound N°24 as a pale yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0386] Yield: 14%.

[0387] Melting point = 101-103° C.

[0388] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.61 (d, J = 7.1 Hz, 1H), 7.47-7.14 (m, 10H), 7.02 (d, J = 7.1 Hz, 1H), 6.66 (d, J = 5.4 Hz, 1H), 5.51 (d, J = 13.9 Hz, 1H), 4.64 (d, J= 13.9 Hz, 1H), 4.19 (dd, J = 19.5 Hz, 5.4 Hz, 1H), 3.22 (d, J = 19.5 Hz, 1H), 3.12 (s, 3H), 2.34 (s, 3H), 1.91 (s, 3H).

[0389] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.4, 140.1, 135.2, 134.6, 134.0, 132.2, 131.0 (2C), 130.6, 130.2, 130.0, 129.8, 128.5, 127.0, 126.9, 124.0, 123.7, 120.4, 82.4, 74.5, 56.4, 43.9, 32.4, 21.3, 14.6.

[0390] IR (neat) (cm.sup.-1): λ.sub.max = 3442, 3023, 2924, 1605, 1493, 1459, 1420, 1391, 1272, 1255, 1232, 1161, 1082, 1047, 1018, 906, 882, 785, 768, 751, 717, 640.

[0391] HRMS (ESI positive):

[0392] Calculated for C.sub.25H.sub.26N [M-I].sup.+ 340.2065; Found 340.2059.

[00024]${\left[\alpha \right]}_{\text{D}}{}^{20}+92°\left(c0.49,\text{MeOH}\right).$

Compound N°25

[0393] Compound N°25 is prepared according to the general procedure D.

[0394] To a solution of 115 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.43 mmol) in 2 mL of dioxane was added 2 mL of methyl iodide (32.1 mmol) to give 163 mg of Compound N°25 as a pale green solid without purification.

[0395] Yield: 93%.

[0396] Melting point = 216-219° C.

[0397] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.51 (br d, J = 7.2 Hz, 1H), 7.39-7.27 (m, 5H), 7.15-7.08 (m, 2H), 5.89 (d, J = 5.2 Hz, 1H), 4.57 (t, J = 5.0 Hz, 1H) 4.50-4.37 (m, 1H) 4.17 (dd, J = 18.9 Hz, 5.4 Hz, 1H), 4.13-4.03 (m, 1H), 3.66-3.48 (m, 2H), 3.39 (s, 3H), 3.04 (d, J = 18.9 Hz, 1H), 2.24 (s, 3H).

[0398] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.1, 135.5, 135.0, 130.7, 130.3, 130.1, 130.0, 129.5, 128.2, 123.8, 123.6, 120.7, 83.6, 73.5, 56.2, 55.0, 46.1, 32.2, 13.7.

[0399] IR (neat) (cm.sup.-1): λ.sub.max = 3313, 2969, 2871, 1610, 1478, 1458, 1393, 1276, 1258, 1231, 1078, 1041, 1018, 957, 883, 763, 727, 720.

[0400] HRMS (ESI positive):

[0401] Calculated for C.sub.19H.sub.22NO [M-I].sup.+ 280.1701; Found 280.1706.

[00025]${\left[\alpha \right]}_{\text{D}}{}^{14}+188°\left(c0.51,\text{MeOH}\right).$

Compound N°26

[0402] Compound N°26 is prepared according to the general procedure D.

[0403] To a solution of 115 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.4 mmol) in 2 mL of dioxane were added 2.7 mL of ethyl iodide (33.8 mmol) to give 134 mg of Compound N°26 as a pale green solid without purification.

[0404] Yield: 80%.

[0405] Melting point = 202-205° C.

[0406] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.52 (d, J = 6.7 Hz, 1H), 7.40-7.23 (m, 5H), 7.15-7.07 (m, 2H), 5.79 (d, J = 5.1 Hz, 1H), 4.50 (br s, 1H), 4.25-3.96 (m, 4H), 369-3.62 (m, 2H), 3.45-3.34 (m, 1H), 3.06 (d, J= 19.0 Hz, 1H), 2.31 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0407] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.1, 135.5, 134.9, 130.6, 130.2, 130.1 (2C), 129.6, 128.2, 123.7, 123.2, 120.5, 85.0, 69.0, 56.5, 54.5, 54.3, 32.2, 14.5, 11.9.

[0408] IR (neat) (cm.sup.-1): λ.sub.max = 3314, 3013, 2921, 2820, 1612, 1478, 1461, 1429, 1405, 1393, 1340, 1271, 1228, 1177, 1159, 1089, 1042, 1029, 975, 926, 789, 766, 731, 696, 654, 631.

[0409] HRMS (ESI positive):

[0410] Calculated for C.sub.20H.sub.24NO [M-I].sup.+ 294.1858; Found 294.1853.

[00026]${\left[\alpha \right]}_{\text{D}}{}^{20}+155°\left(c0.49,\text{MeOH}\right).$

Compound N°27

[0411] Compound N°27 is prepared according to the general procedure D.

[0412] To a solution of 110 mg of 2-(5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.4 mmol) in 2 mL of dioxane were added 2.7 mL of ethyl iodide (33.8 mmol) to give 71 mg of Compound N°27 after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0413] Yield: 42%.

[0414] Melting point = 205-208° C.

[0415] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.51 (br d, J = 6.7 Hz, 1H), 7.40-7.28 (m, 5H), 7.18-7.07 (m, 2H), 5.82 (d, J = 5.1 Hz, 1H), 4.63 (br s, 1H), 4.28-3.93 (m, 4H), 3.74-3.44 (m, 3H), 3.07 (d, J= 19.0 Hz, 1H), 2.29 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0416] .sup.13C NMR δ (75 MHz, MeOD) (ppm): 145.0, 137.5, 136.1, 131.3, 131.1 (2C), 131.0, 129.2, 125.3, 124.3, 121.9, 86.5, 71.7, 69.9, 57.6, 55.9, 55.0, 32.6, 13.7, 11.4.

[0417] IR (neat) (cm.sup.-1): λ.sub.max = 3279, 2916, 2886, 1614, 1476, 1455, 1424, 1405, 1380, 1339, 1314, 1271, 1224, 1169, 1090, 1028, 1011, 973, 949, 927, 898, 857, 789, 768, 753, 734, 717, 693, 652, 627.

[0418] HRMS (ESI positive):

[0419] Calculated for C.sub.20H.sub.24NO [M-I].sup.+ 294.1858; Found 294.1854.

[00027]${\left[\alpha \right]}_{\text{D}}{}^{20}+0°\left(c0.60,\text{MeOH}\right).$

Compound N°28

[0420] Compound N°28 is prepared according to the general procedure D.

[0421] To a solution of 98 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)acetonitrile (0.38 mmol) in 2 mL of dioxane was added 2 mL of methyl iodide (32.1 mmol) to give 126 mg of Compound N°28 as a beige solid without purification.

[0422] Yield: 82%.

[0423] Melting point = 147-149° C.

[0424] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.59 (br d, J = 7.0 Hz, 1H), 7.50-7.33 (m, 5H), 7.24-7.14 (m, 2H), 6.45 (d, J = 5.2 Hz, 1H), 6.23 (d, J = 16.6 Hz, 1H), 4.91 (d, J = 16.6 Hz, 1H), 4.0 (dd, J = 19.2 Hz, 1H), 3.65 (s, 3H), 3.23 (d, J = 19.2 Hz, 1H), 2.44 (s, 3H).

[0425] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 141.6, 133.8, 133.0, 131.2, 131.0, 130.7, 130.5, 129.0, 128.1, 124.1, 123.9, 120.7, 111.4, 84.9, 74.8, 46.2, 43.7, 31.4, 14.7.

[0426] IR (neat) (cm.sup.-1): λ.sub.max = 3450, 2890, 2810, 1611, 1478, 1460, 1394, 1341, 1276, 1255, 1235, 1115, 1083, 1056, 1019, 988, 962, 918, 905, 886, 839, 784, 765, 718, 677, 640.

[0427] HRMS (ESI positive):

[0428] Calculated for C.sub.19H.sub.19N.sub.2 [M-I].sup.+ 275.1548; Found 275.1547.

[00028]${\left[\alpha \right]}_{\text{D}}{}^{20}+129°\left(c0.54,\text{MeOH}\right).$

Compound N°29

[0429] Compound N°29 is prepared according to the general procedure D.

[0430] To a solution of 92 mg of N-(2-((5S,10R)-5-methyl-10,11-dihydro-SH-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethyl)acetamide (0.3 mmol) in 1.5 mL of dioxane was added 1.5 mL of methyl iodide (24.1 mmol) to give 90 mg of Compound N°29 as a yellow solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0431] Yield: 28%.

[0432] Melting point = 216-218° C.

[0433] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 8.03 (t, J = 5.2 Hz, 1H), 7.56 (br d, J = 6.9 Hz, 1H), 7.40-7.27 (m, 5H), 7.17-7.08 (m, 2H), 5.88 (d, J = 4.8 Hz, 1H), 4.03 (dd, J = 18.8 Hz, 5.2 Hz, 1H) 3.92 (q, J = 5.7 Hz, 2H), 3.83-3.70 (m, 1H), 3.52-3.40 (m, 1H), 3.36 (s, 3H), 3.09 (d, J = 18.8 Hz, 1H), 2.21 (s, 3H), 2.03 (s, 3H).

[0434] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 172.1, 142.3, 134.6, 134.5, 130.8, 130.5, 130.3 (2C), 128.9, 128.4, 124.0, 123.5, 120.8, 84.0, 72.0, 52.4, 46.5, 34.9, 31.7, 23.4, 13.3.

[0435] IR (neat) (cm.sup.-1): λ.sub.max = 3250, 3043, 2939, 1666, 1479, 1461, 1442, 1392, 1370, 1276, 1020, 905, 784, 764, 716, 644.

[0436] HRMS (ESI positive):

[0437] Calculated for C.sub.21H.sub.25N.sub.2O [M-I].sup.+ 321.1967; Found 321.1964.

[00029]${\left[\alpha \right]}_{\text{D}}{}^{20}+130°\left(c0.20,\text{MeOH}\right).$

Compound N°30

[0438] Compound N°30 is prepared according to the general procedure D.

[0439] To a solution of 343 mg of (5S,10R)-5-methyl-12-((1-phenylcyclopropyl)methyl) - 10,11 - dihydro - 5H - 5,10 -epiminodibenzo[a,d][7]annulene (0.89 mmol) in 3 mL of dioxane were added 4.6 mL of methyl iodide (73.9 mmol) to give 260 mg of Compound N°30 as a beige solid after purification over preparative plate (eluent: 90% DCM/10% MeOH).

[0440] Yield: 55%.

[0441] Melting point = 62-164° C.

[0442] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.53-7.27 (m, 10H), 7.07-6.99 (m, 2H), 5.25 (d, J = 5.1 Hz, 1H), 4.38 (d, J = 14.2 Hz, 1H), 3.66 (d, J= 14.2 Hz, 1H), 3.34 (s, 3H), 3.31 (dd, J = 18.9 Hz, 5.0 Hz, 1H), 2.77 (d, J = 18.9 Hz, 1H), 2.14 (s, 3H), 1.71-1.61 (m, 1H), 1.51-1.41 (m, 1H), 1.32-1.22 (m, 1H), 1.00-0.90 (m, 1H).

[0443] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.1, 140.7, 134.8, 134.7, 134.2, 131.6 (2C), 130.4, 130.2, 130.11, 130.07, 129.8 (2C), 129.0, 128.5, 124.0, 123.5, 120.9, 83.8, 73.1, 62.5, 45.9, 31.7, 22.6, 15.7, 15.4, 15.1.

[0444] IR (neat) (cm.sup.-1): λ.sub.max = 3423, 3013, 2959, 2851, 1605, 1494, 1479, 1459, 1425, 1396, 1306, 1275, 1232, 1183, 1114, 1092, 1039, 1013, 991, 919, 905, 832, 764, 718, 677, 640.

[0445] HRMS (ESI positive):

[0446] Calculated for C.sub.27H.sub.27NCI [M-I].sup.+ 400.1832; Found 400.1826.

[00030]${\left[\alpha \right]}_{\text{D}}{}^{15}+102°\left(c0.50,\text{MeOH}\right).$

Compound N°31

[0447] Compound N°31 is prepared according to the general procedure D.

[0448] To a solution of 170 mg of (5S,10R)-12-(cydopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.62 mmol) in 3 mL of dioxane was added 4 mL of iodoethane (50 mmol) to give 55 mg of Compound N°31 as a white solid after purification over preparative plate (eluent: 95% DCM/5% MeOH).

[0449] Yield = 21%.

[0450] Melting point = 189-191° C.

[0451] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.62 (br d, J = 7.0 Hz, 1H), 7.43-7.26 (m, 5H), 7.14-7.07 (m, 2H), 6.06 (d, J = 5.3 Hz, 1H), 4.14 (dd, J = 14.1 Hz, 4.6 Hz, 1H), 4.07 (dd, J = 14.1 Hz, 7.5 Hz, 1H), 3.99 (dd, J = 19.4 Hz, 5.4 Hz, 1H), 3.32-3.18 (m, 1H), 3.14 (d, J = 19.4 Hz, 1H), 3.12-3.03 (m, 1H), 2.38 (s, 3H), 1.58 (t, J = 7.2 Hz, 3H), 1.31-1.20 (m, 1H), 0.86-0.69 (m, 2H), 0.47-0.37 (m, 1H), 0.35-0.26 (m, 1H).

[0452] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.8, 135.5, 134.2, 130.5, 130.3, 130.1, 130.0, 129.9, 128.2, 123.5 (2C), 120.4, 83.2, 68.0, 57.4, 51.8, 31.9, 15.4, 11.0, 7.8, 6.9, 5.5.

[0453] IR (neat) (cm.sup.-1): λ.sub.max = 3452, 2998, 2929, 1614, 1461, 1428, 1394, 1340, 1295, 1272, 1250, 1230, 1157, 1113, 1077, 1058, 1030, 919, 840, 788, 764, 718, 639.

[0454] HRMS (ESI positive):

[0455] Calculated for C.sub.22H.sub.26N [M-I].sup.+ 304.2065; Found 304.2059.

[00031]${\left[\alpha \right]}_{\text{D}}{}^{20}+113°\left(c0.51,\text{MeOH}\right).$

Compound N°32

[0456] To a solution of 90 mg of Compound N°26 (0.22 mmol) in 5 mL of methanol was added amberlite IRA-400 chloride (440 mg) and the mixture was stirred at room temperature for 2 h. After filtration, the solution was concentrated under vacuum to give 70 mg of Compound N°32 as a pale pink solid without any purification.

[0457] Melting point = 115-120° C.

[0458] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.51 (br d, J = 7.1 Hz, 1H), 7.40-7.27 (m, 5H), 7.13 (d, J = 7.1 Hz, 1H), 7.08 (br d, J = 7.1 Hz, 1H), 5.93 (d, J = 4.9 Hz, 1H), 4.26 (dd, J = 19 Hz, 5.6 Hz, 2H), 4.11-4.01 (m, 1H), 3.99-3.90 (m, 1H), 3.76-3.55 (m, 3H), 3.46-3.38 (m, 1H), 3.05 (d, J = 19.0 Hz, 1H), 2.26 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).

[0459] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.1, 135.6, 135.3, 130.6, 130.2, 130.1, 130.0, 128.1, 123.5, 123.3, 120.3, 84.6, 70.8, 69.7, 56.6, 54.6, 54.3, 32.2, 14.2, 11.8.

[0460] IR (neat) (cm.sup.-1): λ.sub.max = 3378, 2918, 2851, 1648, 1479, 1462, 1430, 1396, 1341, 1273, 1229, 1178, 1U91, 1043, 928, 789, 751, 716, 653, 630.

[0461] HRMS (ESI positive):

[0462] Calculated for C.sub.20H.sub.24NO [M-I].sup.+ 294.1858; Found 294.1847.

[00032]${\left[\alpha \right]}_{\text{D}}{}^{20}+177°\left(c0.27,\text{MeOH}\right).$

Compound N°33

[0463] To a solution of 7.1 g of Compound N°31 (16.4 mmol) in 220 mL of methanol were added of amberlite IRA-400 chloride (56 g) and the mixture was stirred at room temperature for 2 h. After filtration, the solution was concentrated under vacuum to give 5.1 g of Compound N°33 as a white solid without any purification.

[0464] Yield: 92%.

[0465] Melting point: 180-181° C.

[0466] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.57 (d, J = 6.8 Hz, 1H), 7.33 (dt, J = 13.5, 7.9 Hz, 5H), 7.16 - 7.04 (m, 2H), 6.21 (d, J = 5.4 Hz, 1H), 4.43 (dd, J = 14.4, 4.4 Hz, 1H), 4.05 (m, 2H), 3.30 - 3.05 (m, 3H), 2.37 (s, 3H), 1.62 (t, J= 7.2 Hz, 3H), 1.18 -0.98 (m, 1H), 0.85 - 0.59 (m, 2H), 0.47 - 0.32 (m, 1H), 0.24 (m, 1H).

[0467] IR (neat) (cm.sup.-1): λ.sub.max = 3387, 3001, 1627, 1459, 1430, 1395, 1247, 1158, 1108, 1024, 758, 713, 634.

[0468] HRMS (ESI positive): Calculated for C.sub.22H.sub.26N [M-C1].sup.+ 304.2065; Found 304.2061.

Compound N°34

[0469] Compound N°34 was prepared according to the procedure described for the synthesis of Compound N°33. To a solution of 5.3 g of Compound N°14 (13.1 mmol) in 177 mL of methanol were added amberlite IRA-400 chloride (42.5 g) to give 5.1 g of Compound N°34 as a white solid without purification.

[0470] Yield: 93%.

[0471] Melting point = 218-219° C.

[0472] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.62 (d, J = 7.0 Hz, 1H), 7.42 - 7.26 (m, 5H), 7.13 (d, J= 7.0 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.24 (d, J= 5.2 Hz, 1H), 4.08 (m, 2H), 3.80 (m, 1H), 3.65 (m, 1H), 3.39 (m, 1H), 3.17 (d, J= 19.5 Hz, 1H), 2.29 (s, 3H), 1.62 - 1.46 (m, 6H).

[0473] IR (neat) (cm.sup.-1): λ.sub.max = 3347, 3016, 2972, 1455, 1405, 1237, 1044, 1015, 762, 743.

[0474] HRMS (ESI positive): Calculated for C.sub.20H.sub.24N [M-Cl].sup.+ 278.1909; Found 278.1904.

Compound N°35

[0475] To a solution of 100 mg of (5S,10R)-12-(cyclopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.36 mmol) in 2 mL of acetonitrile in a microwave-type tube, were added 2.81 mL of propyl iodide (28.8 mmol). The vial is sealed, and the mixture was heated at 75° C. under stirring for 4 days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 137 mg of Compound N°35 as a yellow solid after purification by silica-gel column chromatography (eluent 90% DCM/10% MeOH).

[0476] Yield: 85%.

[0477] Melting point = 203-204° C.

[0478] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.62 (d, J = 6.1 Hz, 1H), 7.47 - 7.22 (m, 5H), 7.12 (d, J = 6.3 Hz, 2H), 6.08 (d, J = 4.9 Hz, 1H), 4.07 (m, 1H), 3.79 (t, J = 12.6 Hz, 1H), 3.28 - 3.01 (m, 3H), 2.39 (s, 3H), 2.23 (m, 1H), 1.89 (m, 1H), 1.24 (dd, J= 9.6, 4.7 Hz, 2H), 0.93 (t, J= 6.2 Hz, 3H), 0.79 (m, 2H,), 0.40 (m, 2H).

[0479] IR (neat) (cm.sup.-1): λ.sub.max = 3481, 3001, 1454, 1420, 1384, 1024, 926, 753.

[0480] HRMS (ESI positive): Calculated for C.sub.23H.sub.28N [M-I].sup.+ 318.2222; Found 318.2213.

Compound N°36

[0481] To a solution of 100 mg of (5S,10R)-12-(cyclopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.36 mmol) in 2 mL of acetonitrile in a microwave-type tube, were added 2.81 mL of butyl iodide (28.8 mmol). The vial is sealed, and the mixture was heated at 75° C. under stirring for 4 days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 131 mg of Compound N°36 as a yellow solid after purification by silica-gel column chromatography (eluent 90% DCM/10% MeOH).

[0482] Yield: 79%.

[0483] Melting point = 171-172° C.

[0484] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.61 (d, J = 7.2 Hz, 1H), 7.34 (dd, J = 13.6, 5.3 Hz, 5H), 7.16 - 7.05 (m, 2H), 6.10 (d, J = 4.7 Hz, 1H), 4.28 (dd, J = 14.3, 4.8 Hz, 1H), 4.09 (m, 1H), 3.81 (t, J = 10.9 Hz, 1H), 3.14 (m, 3H), 2.37 (s, 3H), 2.21 (m, 1H)1.91 (s, 1H), 1.44 - 1.14 (m, 3H), 0.93 (t, J= 7.3 Hz, 3H), 0.78 (d, J = 22.6 Hz, 2H), 0.51 - 0.41 (m, 1H), 0.39 - 0.29 (m, 1H).

[0485] IR (neat) (cm.sup.-1): λ.sub.max = 3441, 2962, 2932, 1726, 1449, 1424, 1237, 1024, 758, 738.

[0486] HRMS (ESI positive): Calculated for C.sub.24H.sub.30N [M-I].sup.+ 332.2378; Found 332.2386.

Compound N°37

[0487] To a solution of 56 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.21 mmol) in 1.2 mL of acetonitrile in a microwave-type tube, were added 1.6 mL of propyl iodide (16.8 mmol). The vial is sealed, and the mixture was heated at 90° C. under stirring for 4 days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 55 mg of Compound N°37 as a yellow solid without purification.

[0488] Yield: 60%.

[0489] Melting point = 221-222° C.

[0490] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.50 (d, J = 7.9 Hz, 1H), 7.35 (dd, J = 19.9, 12.5 Hz, 5H), 7.12 (dd, J = 13.1, 6.6 Hz, 2H), 5.82 (d, J = 4.8 Hz, 1H), 4.55 (t, J = 5.4 Hz, 1H), 4.21 (m, 3H), 3.73 (t, J= 12.4 Hz, 2H), 3.58 (d, J = 15.1 Hz, 1H), 3.34 (s, 1H), 3.05 (d, J= 19.1 Hz, 1H), 2.28 (s, 3H), 2.12 (m, 1H), 1.70 - 1.60 (m, 1H), 0.92 (t, J= 7.2 Hz, 3H).

[0491] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.9, 135.3, 134.9, 130.6, 130.3, 130.1, 130.0, 129.5, 128.1, 123.4, 123.1, 120.3, 84.8, 69.7, 60.2, 56.5, 54.9, 32.3, 19.5, 14.3, 11.3.

[0492] IR (neat) (cm.sup.-1): λ.sub.max = 3328, 2957, 2349, 1445, 1034, 748.

Compound N°38

[0493] To a solution of 63 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.23 mmol) in 1.3 mL of acetonitrile in a microwave-type tube, were added 2.0 mL of butyl iodide (18.4 mmol). The vial is sealed, and the mixture was heated at 90° C. under stirring for 4 days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 47 mg of Compound N°38 as a yellow solid without purification.

[0494] Yield: 45%.

[0495] Melting point = 196-197° C.

[0496] .sup.1H NMR δ (300 MHz, Acetone) (ppm): 7.72 (d, J= 6.7 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.48 - 7.31 (m, 5H), 7.21 (s, 1H), 5.86 (d, J= 5.2 Hz, 1H), 5.01 (t, J = 5.4 Hz, 1H), 4.28 - 4.01 (m, 3H), 3.83 (t, J = 11.1 Hz, 1H), 3.68 (m, 2H), 3.53 - 3.37 (m, 1H), 3.19 (d, J= 19.0 Hz, 1H), 2.46 (s, 3H), 2.14 (m, 1H), 1.67 (m, 1H), 1.47 - 1.21 (m, 2H), 0.89 (t, J= 7.3 Hz, 3H).

[0497] .sup.13C NMR δ (75 MHz, Acetone) (ppm): 145.0, 144.5, 137.1, 136.0, 131.0, 130.8, 130.5 (2C), 128.5, 124.9, 124.2, 121.5, 80.7, 7.7, 58.7, 57.0, 55.8, 32.4, 27.9, 20.5, 13.8, 13.5.

[0498] IR (neat) (cm.sup.-1): λ.sub.max = 3304, 2962, 1440, 1034, 736.

Compound N°39

[0499] Compound N°39 is prepared according to the general procedure D.

[0500] To a solution of 44 mg of 4-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)butan-1-ol (0.14 mmol) in 0.83 mL of dioxane were added 0.88 mL of ethyl iodide (11.2 mmol) to give 34 mg of Compound N°39 as a white solid without purification.

[0501] Yield: 53%.

[0502] Melting point = 201-202° C.

[0503] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.59 (d, J= 7.4 Hz, 1H), 7.43 - 7.29 (m, 5H), 7.16 (d, J= 6.6 Hz, 1H), 7.09 (d, J= 6.9 Hz, 1H), 5.91 (d, J= 4.9 Hz, 1H), 3.97 (d, J = 13.9 Hz, 2H), 3.68 (m, 4H), 3.37 (dd, J= 14.3, 6.7 Hz, 1H), 3.15 (d, J= 18.2 Hz, 1H), 3.01 (m, 1H), 2.31 (s, 3H), 2.25 (m, 1H), 2.12 - 1.99 (m, 1H), 1.54 (dd, J= 15.6, 8.2 Hz, 5H).

[0504] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 144.05, 141.55, 135.51, 134.26, 130.46, 130.35, 130.13, 130.04, 129.74, 128.29, 123.54, 120.33, 83.95, 68.58, 60.33, 53.06, 52.86, 31.82, 29.66, 22.12, 15.08, 11.76.

[0505] IR (neat) (cm.sup.-1): λ.sub.max = 3377, 2912, 1454, 1384, 1069, 1024, 1014, 1000, 767, 748.

[0506] HRMS (ESI positive): Calculated for C.sub.22H.sub.28NO [M-I].sup.+ 322.2171; Found 322.2167.

Compound N°40

[0507] Compound N°40 is prepared according to the general procedure D.

[0508] To a solution of 150 mg of (5S,10R)-12-(cydopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.54 mmol) in 3.2 mL of dioxane were added 0.21 mL of ethyl iodide (2.72 mmol) to give 38 mg of Compound N°40 as a yellow solid without purification.

[0509] Yield: 16%.

[0510] Melting point = 179-180° C.

[0511] .sup.1H NMR λ (300 MHz, CDCl.sub.3) (ppm): 7.59 (d, J = 6.9 Hz, 1H), 7.34 (td, J = 14.7, 7.3 Hz, 5H), 7.10 (dd, J = 15.7, 7.7 Hz, 2H), 6.48 (d, J= 5.8 Hz, 1H), 4.40 (d, J = 5.5 Hz, 1H), 4.28 (d, J = 14.4 Hz, 2H), 3.88 (dd, J = 18.8, 5.3 Hz, 1H), 3.37 - 3.21 (m, 1H), 3.05 (dd, J = 26.7, 17.3 Hz, 2H), 2.37 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.82 (td, J = 8.4, 4.0 Hz, 1H), 0.77 - 0.68 (m, 1H), 0.48 - 0.38 (m, 1H), 0.00 (dd, J= 9.5, 4.3 Hz, 1H).

[0512] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.3, 139.7, 135.1, 130.5, 130.4, 130.3, 129.8, 128.2, 126.4, 123.8, 123.3, 120.2, 70.1, 59.1, 55.8, 55.4, 49.2, 43.6, 31.6, 15.4, 7.8, 6.8, 5.9.

[0513] IR (neat) (cm.sup.-1): λ.sub.max = 3328, 2998, 2995, 1459, 1424, 1019, 758.

[0514] HRMS (ESI positive): Calculated for C.sub.22H.sub.26NO [M-I].sup.+ 320.2014; Found 320.1992.

Compound N°41

[0515] To a solution of 110 mg of (5S,10R)-12-(cyclopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.39 mmol) in 2.2 mL of dioxane were added 2.7 mL of propargyl bromide (31.2 mmol). The vial is sealed, and the mixture was heated at 45° C. under stirring for 15 hours. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 123 mg of Compound N°41 as a white solid without purification.

[0516] Yield: 79%.

[0517] Melting point = 168-169° C.

[0518] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.70 (d, J= 6.8 Hz, 1H), 7.37 (dd, J = 16.6, 9.8 Hz, 5H), 7.12 (dd, J= 11.6, 7.3 Hz, 2H), 6.62 (s, 1H), 4.81 (s, 2H), 3.87 (dd, J= 19.0, 5.2 Hz, 1H), 3.70 (dd, J= 13.9, 4.6 Hz, 1H), 3.50 (dd, J= 13.8, 8.8 Hz, 1H), 3.24 (d, J= 18.9 Hz, 1H), 2.92 (s, 1H), 2.40 (s, 3H), 1.49 (m, 1H), 1.02 - 0.81 (m, 3H), 0.45 (d, J = 5.6 Hz, 1H).

[0519] IR (neat) (cm.sup.-1): λ.sub.max = 3310, 2986, 2361, 2181, 2045, 1460, 1047, 767, 717.

[0520] HRMS (ESI positive): Calculated for C.sub.23H.sub.24N [M-Br].sup.+ 314.1909; Found 314.1909.

Compound N°42

[0521] To a solution of 146 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.55 mmol) in 2.9 mL of dioxane were added 3.9 mL of propargyl bromide (44.0 mmol). The vial is sealed, and the mixture was heated at 90° C. under stirring for 4 days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 177 mg of Compound N°42 as a white solid without purification.

[0522] Yield: 84%.

[0523] Melting point = 201-202° C.

[0524] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.61 - 7.50 (m, 1H), 7.35 (dt, J= 17.2, 8.3 Hz, 5H), 7.14 (d, J = 6.4 Hz, 2H), 6.43 (d, J= 5.1 Hz, 1H), 5.69 - 5.59 (m, 1H), 5.52 (dd, J= 17.4, 2.4 Hz, 1H), 4.75 - 4.59 (m, 1H), 4.37 (dd, J= 19.1, 5.4 Hz, 1H), 4.24 (d, J = 17.9 Hz, 1H), 3.98 (d, J= 14.4 Hz, 1H), 3.64 (t, J= 13.7 Hz, 2H), 3.06 (d, J= 18.8 Hz, 1H), 2.96 (d, J = 2.3 Hz, 1H), 2.35 (s, 3H).

[0525] IR (neat) (cm.sup.-1): λ.sub.max = 3169, 2962, 2117, 1445, 1400, 1346, 1089, 1094, 945, 846, 782, 767, 688.

Compound N°43

[0526] To a solution of 100 mg of (5S,10R)-12-(cyclopropylmethyl)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene (0.36 mmol) in 2 mL of acetonitrile were added 1.2 mL of allyl bromide (14.4 mmol). The vial is sealed, and the mixture was heated at 50° C. under stirring for 15 hours. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 97 mg of Compound N°43 as a white solid without purification.

[0527] Yield: 68%.

[0528] Melting point = 131-132° C.

[0529] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.48 (dd, J = 5.8, 2.5 Hz, 1H), 7.43 -7.38 (m, 1H), 7.36 - 7.25 (m, 4H), 7.17 - 7.08 (m, 2H), 6.47 - 6.26 (m, 1H), 5.91 (d, J= 5.0 Hz, 1H), 5.54 (d, J = 10.1 Hz, 1H), 5.21 (d, J= 16.7 Hz, 1H), 4.75 (dd, J= 13.4, 5.3 Hz, 1H), 4.19 - 4.10 (m, 1H), 3.97 (dd, J= 19.0, 5.4 Hz, 1H), 3.71 (dd, J= 13.5, 8.8 Hz, 1H), 3.29 (dd, J = 14.1, 8.8 Hz, 1H), 3.13 (d, J= 19.2 Hz, 1H), 2.41 (s, 3H), 1.32 - 1.18 (m, 1H), 0.85 - 0.69 (m, 2H), 0.45 (d, J= 3.2 Hz, 2H).

[0530] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 143.6, 135.4, 134.3, 130.3, 130.1, 130.0, 129.9, 128.1, 127.1, 126.2, 123.4, 123.3, 120.4, 82.9, 69.0, 59.2, 57.8, 31.8, 15.1, 7.9, 6.7, 5.4.

[0531] IR (neat) (cm.sup.-1): λ.sub.max = 3495, 3005, 1731, 1621, 1461, 1448, 1393, 1248, 1082, 994, 790, 768.

Compound N°44

[0532] To a solution of 50 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.18 mmol) in 1 mL of acetonitrile were added 0.65 mL of allyl bromide (7.2 mmol). The vial is sealed, and the mixture was heated at 90° C. under stirring for 4 days. After being allowed to cool to room temperature, the precipitate formed was increased by addition of pentane and filtered on sintered filter and washed with ethyl acetate, then recovered by dissolution in dichloromethane. The obtained solution was concentrated under reduced pressure (10 mbar) to give 61 mg of Compound N°44 as a white solid without purification.

[0533] Yield: 87%.

[0534] Melting point = 196-197° C.

[0535] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.34 (m, 6H), 7.17 - 7.07 (m, 2H), 6.20 (dt, J = 15.2, 9.7 Hz, 1H), 5.81 (d, J = 5.1 Hz, 1H), 5.45 (dd, J = 13.5, 7.7 Hz, 2H), 5.23 (d, J= 16.6 Hz, 1H), 4.65 (dd, J= 14.0, 4.5 Hz, 1H), 4.35 (dd, J = 12.6, 6.6 Hz, 1H), 4.22 (dd, J= 19.0, 5.6 Hz, 1H), 4.14 - 3.99 (m, 2H), 3.67 (s, 2H), 3.04 (d, J= 18.7 Hz, 1H), 2.32 (s, 3H).

[0536] IR (neat) (cm.sup.-1): λ.sub.max = 3246, 1461, 1434, 1082, 1434, 1082, 924, 766, 751.

Compound N°45

[0537] To a solution at 0° C. of 65 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethan-1-ol (0.24 mmol) in 1 mL of tetrahydrofuran were added 6 mg of sodium hydride (0.26 mmol). The solution was stirred for 30 min and 57 .Math.L of methyl iodide were added. The mixture was stirred at room temperature for 17 hours and then diluted in diethyl ether. The organic was washed with water and a saturated solution of sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure (10 mbar) to give Compound N°45 as a white solid after purification by silica-gel column chromatography (eluent 90% DCM/10% MeOH).

[0538] Yield: 28%.

[0539] Melting point = 162-163° C.

[0540] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.54 - 7.48 (m, 1H), 7.41 - 7.28 (m, 5H), 7.11 (dd, J= 12.9, 7.0 Hz, 2H), 5.61 (d, J = 5.3 Hz, 1H), 4.27 - 4.08 (m, 2H), 3.98 -3.85 (m, 2H), 3.56 (dd, J= 18.6, 8.2 Hz, 2H), 3.48 (s, 1H), 3.38 (s, 3H), 3.05 (d, J= 18.9 Hz, 1H), 2.33 (s, 3H).

[0541] .sup.13C NMR δ (75 MHz, CDCl.sub.3) (ppm): 142.26, 135.0 (2C), 130.3, 130.2, 130.1, 130.0, 129.0, 128.3, 123.8, 123.5, 120.9, 83.7, 74.1, 67.2, 59.7, 53.0, 45.6, 32.0, 14.1.

[0542] IR (neat) (cm.sup.-1): λ.sub.max = 3491, 2927, 1474, 1449, 1425, 1395, 1257, 1202, 1108, 1024, 950, 767, 743, 713.

[0543] HRMS (ESI positive): Calculated for C.sub.20H.sub.24NO [M-I].sup.+ 294.1858; Found 294.1852.

Compound N°46

[0544] To a solution of 900 mg of (+)-MK801 maleate (2.67 mmol) in 30 mL of acetonitrile were added 1.10 g of potassium carbonate (8.00 mmol) and 0.70 mL of allyl bromide (8.00 mmol). The resulting mixture was refluxed for 6 hours, allowed to cool down at room temperature and filtrated using dichloromethane as solvent. After evaporation, the crude product was purified by silica gel chromatography (dichloromethane/methanol : 97.5/2.5 to 95/5) to give 122 mg of Compound N°46 as a white brown solid.

[0545] Yield: 12%.

[0546] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.53-7.50 (m, 1 H), 7.42-7.28 (m, 5 H), 7.13-7.11 (m, 2 H), 6.35-6.11 (m, 2 H), 5.95 (d, J= 4.9 Hz, 1 H), 5.65-5.55 (m, 3 H), 5.27 (d, J = 16.7 Hz, 1 H), 4.67 (dd, J = 14.2, 6.3 Hz, 1 H), 4.53 (dd, J= 13.5, 5.4 Hz, 1 H), 4.36 (dd, J= 14.2, 7.9 Hz, 1 H), 4.06 (dd, J = 19.3, 5.1 Hz, 1 H), 3.73 (dd, J = 13.4, 8.7 Hz, 1 H), 3.17 (d, J= 19.2 Hz, 1 H), 2.35 (s, 3 H).

[0547] MS (ESI positive): 302 [C.sub.22H.sub.24N].sup.+

Compound N°47

[0548] Compound N°47 was prepared according to the procedure described for the synthesis of Compound N°33. To a solution of 122 mg of Compound N°46 (0.32 mmol) in 14 mL of methanol were added amberlite IRA-400 chloride (1.02 g) to give 100 mg of Compound N°47 as a white brown solid without purification.

[0549] Yield: 92%.

[0550] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.49-7.46 (m, 1 H), 7.39-7.25 (m, 5 H), 7.14-7.07 (m, 2 H), 6.40-6.26 (m, 1 H), 6.19-6.06 (m, 1 H), 5.99 (d, J= 5.0 Hz, 1 H), 5.63-5.54 (m, 3 H), 5.24 (d, J= 16.9, 1 H), 4.92 (dd, J= 14.1, 6.4, 1 H), 4.53 (dd, J= 5.4, 13.3 Hz, 1 H), 4.39 (dd, J = 14.2, 7.9 Hz, 1 H), 4.11 (dd, J= 5.4, 19.1 Hz, 1 H), 3.73 (dd, J = 13.5, 8.8 Hz, 1 H), 3.14 (d, J= 19.3 Hz, 1 H), 2.32 (s, 3 H).

Compound N°48

[0551] To a solution of 400 mg of 2-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulen-12-yl)ethanol (1.50 mmol) in 7.5 mL of dioxane were added 1.30 g of potassium carbonate (15.0 mmol) and 1.20 mL of 2-iodoethanol (15.3 mmol). The resulting mixture was stirred and heated in a sealed tube at 100° C. for 96 hours, allowed to cool down at room temperature and filtrated using dichloromethane as solvent. After evaporation, the crude product was purified by silica gel chromatography (dichloromethane/methanol: 97.5/2.5 to 95/5) to give 300 mg of Compound N°48 as a white solid.

[0552] Yield: 46%.

[0553] .sup.1H NMR δ (300 MHz, CDCl.sub.3) (ppm): 7.57-7.55 (m, 1 H), 7.40-7.26 (m, 5 H), 7.13-7.08 (m, 2 H), 5.99 (d, J = 4.9 Hz, 1 H), 4.34-3.89 (m, 9 H), 3.63-3.59 (m, 1 H), 3.43-3.37 (m, 1 H), 3.08 (d, J= 18.9 Hz, 1 H), 2.32 (s, 3 H).

[0554] The table 1 below illustrates Compounds N°1 to N°53 of the invention:

##STR00098##

TABLE-US-00002 N° Formula n R.sub.1 R.sub.2 Chirality Counterion X.sup.- 1 [00099] 1 —H —CH.sub.3 (+) I.sup.- 2 [00100] 1 —CH.sub.3 —CH.sub.3 (+) I.sup.- 3 [00101] 3 —CH.sub.3 —CH.sub.3 (+) I.sup.- 4 [00102] 1 —CH(—CH.sub.3).sub.2 —CH.sub.3 (+) I.sup.- 5 [00103] 1 -cyclopropyl —CH.sub.3 (+) I.sup.- 6 [00104] 1 -cyclopentyl —CH.sub.3 (+) I.sup.- 7 [00105] 1 —C(═NH)—OH —CH.sub.3 (+) I.sup.- 8 [00106] 1 -4-fluorophenyl —CH.sub.3 (+) I.sup.- 9 [00107] 1 -3-CF.sub.3-phenyl —CH.sub.3 (+) I.sup.- 10 [00108] 2 —CH(—CH.sub.3).sub.2 —CH.sub.3 (+) I.sup.- 11 [00109] 2 —CH.sub.3 —CH.sub.3 (+) I.sup.- 12 [00110] 5 —CH.sub.3 —CH.sub.3 (+) I.sup.- 13 [00111] 1 —CH(—CH.sub.3)—CH.sub.2—CH.sub.3 —CH.sub.3 (+) I.sup.- 14 [00112] 1 —CH.sub.3 —CH.sub.2—CH.sub.3 (+) I.sup.- 15 [00113] 1 -cyclohexyl —CH.sub.3 (+) I.sup.- 16 [00114] 1 -phenyl —CH.sub.3 (+) I.sup.- 17 [00115] 1 -cyclobutyl —CH.sub.3 (+) I.sup.- 18 [00116] 1 -cyclopropyl-phenyl —CH.sub.3 (+) I.sup.- 19 [00117] 1 -4-CH.sub.3-phenyl —CH.sub.3 (+) I.sup.- 20 [00118] 1 -4-C(-CH.sub.3).sub.3-phenyl —CH.sub.3 (+) I.sup.- 21 [00119] 1 -4-OCH.sub.3-phenyl —CH.sub.3 (+) I.sup.- 22 [00120] 1 -4-chlorophenyl —CH.sub.3 (+) I.sup.- 23 [00121] 1 -2-chlorophenyl —CH.sub.3 (+) I.sup.- 24 [00122] 1 -2-CH.sub.3-phenyl —CH.sub.3 (+) I.sup.- 25 [00123] 2 —OH —CH.sub.3 (+) I.sup.- 26 [00124] 2 —OH —CH.sub.2—CH.sub.3 (+) I.sup.- 27 [00125] 2 —OH —CH.sub.2—CH.sub.3 (±) I.sup.- 28 [00126] 1 —CN —CH.sub.3 (+) I.sup.- 29 [00127] 2 —NH—CO—CH.sub.3 —CH.sub.3 (+) I.sup.- 30 [00128] 1 -cyclopropyl-4-chlorophenyl —CH.sub.3 (+) I.sup.- 31 [00129] 1 -cyclopropyl —CH.sub.2—CH.sub.3 (+) I.sup.- 32 [00130] 2 —OH —CH.sub.2—CH.sub.3 (+) Cl.sup.- 33 [00131] 1 -cyclopropyl —CH.sub.2—CH.sub.3 (+) Cl.sup.- 34 [00132] 1 —CH.sub.3 —CH.sub.2—CH.sub.3 (+) Cl.sup.- 35 [00133] 1 -cyclopropyl —(CH.sub.2).sub.2— CH.sub.3 (+) I.sup.- 36 [00134] 1 -cyclopropyl —(CH.sub.2).sub.3— CH.sub.3 (+) I.sup.- 37 [00135] 2 —OH —(CH.sub.2).sub.2— CH.sub.3 (+) I.sup.- 38 [00136] 2 —OH —(CH.sub.2).sub.3— CH.sub.3 (+) I.sup.- 39 [00137] 4 —OH —CH.sub.2—CH.sub.3 (+) I.sup.- 40 [00138] 1 -cyclopropyl —(CH.sub.2).sub.2— OH (+) I.sup.- 41 [00139] 1 -cyclopropyl —CH.sub.2— C═CH (+) Br.sup.- 42 [00140] 2 —OH —CH.sub.2— C═CH (+) Br.sup.- 43 [00141] 1 -cyclopropyl —CH.sub.2— CH═CH.sub.2 (+) Br.sup.- 44 [00142] 2 —OH —CH.sub.2— CH═CH.sub.2 (+) Br.sup.- 45 [00143] 2 —O—CH.sub.3 —CH.sub.3 (+) I.sup.- 46 [00144] 1 —CH═CH.sub.2 —CH.sub.2— CH═CH.sub.2 (+) Br.sup.- 47 [00145] 1 —CH═CH.sub.2 —CH.sub.2— CH═CH.sub.2 (+) Cl.sup.- 48 [00146] 2 —OH —(CH.sub.2).sub.2— OH (+) I′ 49 [00147] 1 —CH.sub.3 —CH(—CH.sub.3)— CH.sub.2—OH (+) Cl.sup.- 50 [00148] 2 —O—CH.sub.3 —CH.sub.2—CH.sub.3 (+) Cl.sup.- 51 [00149] 2 —O—CH.sub.2—CH.sub.3 —CH.sub.2—CH.sub.3 (+) Cl.sup.- 52 [00150] 2 —F —CH.sub.2—CH.sub.3 (+) Cl.sup.- 53 [00151] 2 —N(CH.sub.3).sub.2 —CH.sub.2—CH.sub.3 (+) Cl.sup.-

[0555] The table 2 below illustrates Compounds N°54 to N°56 of the invention:

##STR00152##

TABLE-US-00003 N° Formula n R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5, R.sub.6, R.sub.7 et R.sub.8 R.sub.9 R.sub.10 Chirality Counter ion X.sup.- 54 [00153] 1 —H —CH.sub.3 —H —H —H —CH.sub.3 —H (+) I— 55 [00154] 2 —CH.sub.3 —CH.sub.2— CH.sub.3 —H —H —H —CH.sub.3 —H (+) I.sup.- 56 [00155] 1 —H —CH.sub.3 —H —O—CH.sub.3 —H —H —H (+) I.sup.-

[0556] The compounds according to the invention were the subject of pharmacological assays.

Example 2

Role of NMDA Receptors in the Development of Pulmonary Hypertension

[0557] To understand the functional importance of NMDARs in smooth muscle cells, the Grinl gene (encoding the obligatory GluN1 subunit) has been deleted from the smooth muscle cells of mice. These knock out mice for NMDAR in PASMC were produced breeding mice expressing Cre recombinase in smooth muscle cells with floxed GRIN1 mice (GRIN1: gene coding for GluN1 ubiquitous subunit of NMDARs).

[0558] Under chronic hypoxia (FiO.sub.2 10%, 3 weeks), KO mice develop an attenuated form of PH compared to control mice, with a decreased right ventricular pressure and cardiac hypertrophy (Fulton index) (FIG. 1). In FIG. 1, P < 0.01 and p < 0.001 in KO mice compared to wild type under hypoxia, for right ventricular systolic pressure and Fulton index, respectively.

[0559] After chronic hypoxia (FiO.sub.2 10%, 3 weeks), KO mice also have a decreased muscularization of small vessels (diameter < 50 .Math.m) compared to control mice (FIG. 2). Moreover, KO mice present less muscularized large vessels (75 .Math.m < diameter < 125 .Math.m) in both normoxic and hypoxic conditions compared to control mice (FIG. 2).

[0560] These results indicate that knocking out NMDAR in PASMC attenuates pulmonary vascular cell remodeling, cardiac remodeling and PH in hypoxic mice. Thus, PASMC NMDA receptors contribute to pulmonary vascular cell remodeling, cardiac remodeling and to pulmonary hypertension.

Example 3

In Vivo Brain Penetration Measurements

[0561] Compounds of the present invention provide a mean to prevent Blood-Brain Barrier. This assumption has been verified on rats.

[0562] Among methods addressing central nervous system penetration in drug discovery, in vivo equilibrium distribution between blood and brain in rodents is the most commonly used parameter to evaluate brain penetration.

[0563] This parameter is defined as the ratio of concentrations in brain and blood, Kp.sub.“brain” (C.sub.brain/C.sub.plasma) or log(BB). Log(BB) is the logarithm of the ratio of the steady-state total concentration of a compound in the brain to that in the blood/plasma, log(BB) = log(C.sub.brain/C.sub.plasma). This parameter depends upon the passive diffusion characteristics, the implication of membrane transporters at the BBB level and the relative drug binding affinity differences between the plasma proteins and brain tissue. Generally, compounds with a brain/plasma ratio of greater than 0.5 are considered to have sufficient access to the CNS. Thus, compounds with a value greater than 1 freely cross the BBB.

[0564] Thus, the brain penetration of MK801, Compound N°1 and Compound N°26 was measured in rat by establishing the brain/plasma ratio, Kp.sub.“brain” in triplicate (3 rats/Compound). The enclosed FIG. 3 shows the results on calculation of the Kp.sub.“brain” for the three compounds MK801, Compound N°1 and Compound N°26.

[0565] The Kp.sub.“brain” value (defined as the total brain/plasma concentration ratio at steady state) was calculated in 3 rats for each compound MK801, Compound N°1 and Compound N°26. Compounds N°1 and N°26 present a very low Kp.sub.“brain” value as compared to MK801 (0.3 ± 0.03 and 0.4 ± 0.08 versus 17.7 ± 1.75).

[0566] In conclusion, as known and previously described, MK801 penetrates freely across the BBB and intensively penetrate the CNS in rat. As we expected, due to the presence of a quaternary ammonium and as demonstrated by the Kp.sub.“brain” values, the Compounds N°1 and N°26 do not penetrate the CNS in rat.

Example 4

In Vitro Activity: Evaluation of NMDAR Blocking Activity Using Patch-Clamp

[0567] Previous studies have shown that the NMDAR exists in the peripheral vasculature.

[0568] All NMDAR subunits were examined by RT-PCR and sequencing in the peripheral endothelium and peripheral vascular smooth muscle cells. The sequences of these NMDAR subunits in both vascular cells showed a high similarity if not identity to the sequences of brain NMDAR (Chen H et al, J Vasc Surg 2005, Qureshi I et al Vasc Med 2005).

[0569] The molecules described herein were tested in serial concentrations ranging from 1 nM to 100 .Math.M for their NMDAR blocking activity using patch-clamp.

[0570] Whole-cell voltage clamp recordings from rat hippocampal neurons were then used to calculate IC.sub.50 for each molecule. The IC.sub.50 is the concentration of an inhibitor where the response (or binding) is reduced by half.

TABLE-US-00004 NMDAR antagonist activity of selected compounds Compound IC.sub.50 (.Math.M) Dizocilpine ((+)-MK801 maleate) 0.29 Compound N°1 0.65 Compound N°2 0.57 Compound N°3 0.50 Compound N°4 0.82 Compound N°5 0.40 Compound N°6 1.10 Compound N°26 0.4 Compound N°27 0.36 Compound N°31 0.27

[0571] The results show that the parent molecule dizocilpine had an IC.sub.50 of 0.29 .Math.M, which is consistent with its known antagonist activity. Compounds of the present invention have an activity ranging from 0.27 to 1.10 .Math.M. Of interest, results obtained with Compound N°31 (IC.sub.50 = 0.27 .Math.M), Compound N°27 (IC.sub.50 = 0.36 .Math.M), and Compounds N°5 and N°26 (IC.sub.50 = 0.4 .Math.M) clearly demonstrate that structural modification on the nitrogen atom of dizocilpine is not deleterious for activity.