Adamantane and memantine derivatives as peripheral NMDA receptor antagonists

Abstract

The present invention relates to cationic compounds of formula (I) for use as peripheral NMDA receptor antagonists. ##STR00001##

Claims

1. Cationic compound of formula (I): ##STR00035## wherein: R.sub.1 and R.sub.2 represent, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group; the group (CH.sub.2).sub.n-A is linked to the cycle in position (a) or (b); n is 0, 1, 2 or 3; A represents a NR.sub.3R.sub.4 group or a N.sup.+R.sub.3R.sub.4R.sub.5 group; R.sub.3, R.sub.4 and R.sub.5 represent, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.10)alkyl group, a (C.sub.1-C.sub.10)alkoxy group, a (C.sub.1-C.sub.10)alkyl-C(NH)(OH) group, a (C.sub.3-C.sub.8)cycloalkane group, a 6- to 10-membered aryl group or a 5- to 12-membered heteroaryl group; said alkyl or alkoxy groups being optionally substituted with one or more NR.sub.6R.sub.7 group, N.sup.+R.sub.6R.sub.7R.sub.8 group, (C.sub.3-C.sub.8)cycloalkane group, 6- to 10-membered aryl group or 5- to 12-membered heteroaryl group; with R.sub.6, R.sub.7 and R.sub.8 represent, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl; and the compound of formula (I) contains at least one positive charged nitrogen atom; provided that R.sub.1 and R.sub.2 are not both a hydrogen atom; and provided that when R.sub.1 and R.sub.2 are a methyl group, the group (CH.sub.2).sub.n-A is linked to the cycle in position (a), and n is 0, then A is not a group N.sup.+H.sub.3.

2. Cationic compound according to claim 1, wherein R.sub.1 and R.sub.2 are chosen among a hydrogen atom or a methyl group.

3. Cationic compound according to claim 1, wherein the group (CH.sub.2).sub.n-A is linked to the cycle in position (a).

4. Cationic compound according to claim 1, wherein n is 0 or 1.

5. Cationic compound according to claim 1, wherein said compound is of formula (Ia): ##STR00036## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are as defined in claim 1.

6. Cationic compound according to claim 1, wherein R.sub.3, R.sub.4 and R.sub.5 represent, independently of each other, a (C.sub.1-C.sub.10)alkyl group.

7. Cationic compound according to claim 1, wherein at least one of R.sub.3, R.sub.4 and R.sub.5 represents a methyl group.

8. Cationic compound according to claim 1, wherein R.sub.3, R.sub.4 and R.sub.5 are simultaneously a methyl group.

9. Cationic compound according to claim 1, wherein R.sub.3 and R.sub.4 are a methyl group and R.sub.5 represent a (C.sub.1-C.sub.10)alkyl group substituted with a (C.sub.3-C.sub.8)cycloalkane group.

10. Cationic compound according to claim 1, chosen among: ##STR00037## ##STR00038##

11. Medicament comprising as pharmaceutical active agent at least one compound as defined in claim 1.

12. A pharmaceutical composition comprising at least one compound as defined in claim 1, and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition as claimed in claim 12, wherein said compound is in combination with at least one other therapeutic agent.

14. Cationic compound of formula (I) according to claim 1 for use as a peripheral NMDA receptor antagonist.

15. Cationic compound according to claim 1, for use for treating a disease or a condition chosen among pulmonary hypertension, pulmonary diseases involving inflammation, fibrosis and remodeling, non-neuronal cancers, diabetes, atherosclerosis, sickle cell disease, diseases involving thrombosis, acute infections, chronic infectious diseases, inflammatory disease, autoimmune disease, heart failure, arrhythmias, renal disorders, pain, psoriasis, atopic dermatitis, and osteoporosis.

16. Cationic compound according to claim 15, wherein the disease is pulmonary arterial hypertension.

Description

FIGURES

(1) FIG. 1: Effect of NMDAR knockout in PASMCs on hemodynamics and cardiac remodeling in pulmonary hypertension in the hypoxic mouse model of PH (NS means not significant, and results are expressed as meanSEM).

(2) FIG. 2: Effect of NMDAR knockout in PASMCs on vascular remodeling in pulmonary hypertension in the hypoxic mouse model of PH (NS means not significant, and results are expressed as meanSEM; Statistical significance is indicated; *p<0.05, **p<0.01, ***p<0.001).

EXAMPLES

(3) Methods

(4) Animal Models of Pulmonary Hypertension

(5) 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.

(6) Following procedures performed on mice, were approved by the ethical committee CEEA26 (Animal experimentation ethic committee N.sup.o26) and the French ministry of higher education and research.

(7) Transgenic mice strains used are B6.12954-Grin1tm2Stl/J (further named as GRIN1fl/fl mice), B6.12956-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).

(8) 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-creGRIN1fl/fl mice and male Tagln-cre mice were used as controls. For NMDAR knocked out in endothelial cells, experiments were performed on male Tek-creGRIN1fl/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.

(9) Morphometric Analysis

(10) 6 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).

(11) For morphometric analysis performed on mouse lungs, intrapulmonary arterioles were divided in four groups based on their external diameter: less than 30 m, from 30 m to 50 m, from 50 m to 75 m and from 75 m to 125 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.

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

(13) The femoral vein of male Sprague-Dawley rats (CRL) weighing around 250 g was surgically catheterized at least 72 hours prior to the experiment. The drug was administered as 3.75 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.

(14) 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).

(15) Cultures of Hippocampal Neurons

(16) 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 l glutamine 200 mM 100 (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 (3-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.

(17) Electrophysiology

(18) 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 MQ) 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 M TTX, 20 M picrotoxin and 20 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, Calif., 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 M NMDA and 20 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.

(19) Statistical Analysis

(20) 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

(21) Preparation of the Compounds According to the Invention

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

General Procedure A for the Preparation of 3,5-dimethyladamantan-1-amide

(23) 200 L of 1-bromo-3,5-dimethyladamantane (1 mmol) and 10 equivalent of the corresponding amide were mixed neat in a microwave type tube. The vial is sealed. The mixture was heated at the fusion point of the amide, and stirred at this temperature during 10 to 20 hours. After cooling at room temperature, 100 mL of dichloromethane was added to the reaction mixture. The solution obtained was washed successfully with 25 mL of water, and 25 mL of brine. 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 the Preparation of 3,5-dimethyladamantan-1-amide

(24) 400 L of 1-bromo-3,5-dimethyladamantane (2 mmol) and 5 equivalent of the appropriate nitrile were mixed neat in a microwave type tube. After addition of 200 L of sulfuric acid 96% (4 mmol), the vial is sealed and the mixture was heated at 50 C. under agitation during 6 hours. After cooling at room temperature, 40 mL of ice water was added to the reaction mixture, and the aqueous phase was extracted with 100 mL of dichloromethane. Organic layers were washed with 20 mL of a saturated solution of sodium bicarbonate then with 20 mL of water. After drying over Na.sub.2SO.sub.4 and evaporation of the solvent under reduce pressure, at 10 mbar, the crude product was purified by column chromatography on silica gel.

General Procedure C for Reduction of 3,5-dimethyladamantan-1-amide

(25) To 1 equivalent of a solution of adamantanamide derivative in 0.2 M of anhydrous THF was added 5 equivalent of LiAlH.sub.4 under nitrogen atmosphere at 0 C. After stirring at room temperature for an additional period of 30 minutes, the mixture was heated at reflux for 5 to 18 hours (reaction monitored by TLC). After being allowed to cool to room temperature, the mixture was treated with drop-to-drop addition of water 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 with Na.sub.2SO.sub.4, evaporation of the solvent under reduced pressure, at 10 mbar, the amine was directly engaged in the next step without purification.

General Procedure D for Permethylation of 3,5-dimethyladamantan-1-amine

(26) To a solution of 1 mmol of the corresponding amine in 3 mL of dioxane in a microwave-type tube, were added 1.3 g of cesium carbonate (4 mmol) and 5 mL of methyl iodide (80 mmol). The vial is sealed, and the mixture was heated at 100 C. under stirring for 24 hours. After being allowed to cool to room temperature, the precipitate formed was filtered on sintered filter and washed successively with 100 mL of ethyl acetate, then 50 mL of dichloromethane. The organic layers were concentrated under reduced pressure, at 10 mbar, to give the desired quaternarized ammonium iodide salt.

N,N,N,3,5-Pentamethyladamantan-1-ammonium iodide (Compound No1)

(27) Compound N.sup.o1 is prepared according to the general procedure D.

(28) To a solution of 108 mg of 3,5-dimethyladamantan-1-amine hydrochloride (0.5 mmol) in 2 mL of dioxane were added 648 mg of cesium carbonate (2 mmol) and 2.5 mL of methyl iodide (40.2 mmol) to give 122 mg of Compound N.sup.o1 as a white solid without purification.

(29) Yield: 70%.

(30) Melting point=290-293 C.

(31) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.3 (s, 9H), 2.43 (m, 1H), 1.93 (br s, 2H), 1.67 (dd, J=20.8 Hz, 10.9 Hz, 4H), 1.45-1.31 (m, 4H), 1.28-1.14 (m, 2H), 0.99 (s, 6H).

(32) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 74.9, 49.4, 49.1, 41.5, 41.2, 41.4, 34.1, 34.0, 30.6, 30.1.

(33) IR (neat) (cm.sup.1): .sub.max=3452, 2954, 2924, 2902, 2849, 1489, 1457, 1415, 1365, 1341, 1181, 987, 904, 841, 827, 717, 642.

(34) HRMS (ESI positive): Calculated for C.sub.15H.sub.28N [M-I].sup.+222.2222; Found 222.2213.

N-Ethyl-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No2)

(35) Compound N.sup.o2 is prepared according to the general procedure D.

(36) To a solution of 245 mg of N-Ethyl-3,5-dimethyladamantan-1-amine (1.2 mmol) in 2 mL of dioxane were added 1.53 g of cesium carbonate (4.7 mmol) and 6 mL of methyl iodide (96.4 mmol) to give 317 mg of Compound N.sup.o2 as a white solid without purification.

(37) Yield=73%.

(38) Melting point=248-250 C.

(39) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.52 (q, J=7.2 Hz, 2H), 3.1 (s, 6H), 2.48 (m, 1H), 2.03 (br s, 2H), 1.75 (dd, J=22.5 Hz, 10.8 Hz, 4H), 1.56 (t, J=7.2 Hz, 3H), 1.50-1.36 (m, 4H), 1.32-1.20 (m, 2H), 1.24 (br s, 2H), 1.22 (s, 3H), 1.19 (s, 3H), 1.02 (s, 6H).

(40) .sup.13C NMR (75 MHz; CDCl.sub.3) (ppm): 54.2, 49.5, 44.8, 41.5, 41.4, 34.3, 34.2, 30.8, 30.1, 9.9.

(41) IR (neat) (cm.sup.1): .sub.max=3420, 2949, 2903, 2864, 2847, 1485, 1454, 1366, 1349, 1266, 1015, 987, 815, 905.

(42) HRMS (ESI positive): Calculated for C.sub.16H.sub.30N [M-I].sup.+236.2378; Found 236.2384.

N-Propyl-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No3)

(43) Compound N.sup.o3 is prepared according to the general procedure D.

(44) To a solution of 221 mg of N-propyl-3,5-dimethyladamantan-1-amine (1 mmol) in 2 mL of dioxane were added 1.3 g of cesium carbonate (4 mmol) and 5 mL of methyl iodide (80 mmol) to give 264 mg of Compound N.sup.o3 as a white solid without purification.

(45) Yield=70%.

(46) Melting point=204-206 C.

(47) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.29-3.20 (m, 2H), 3.1 (s, 6H), 2.46 (m, 1H), 2.00 (br s, 2H), 1.99-1.89 (m, 2H), 1.72 (dd, J=22.6 Hz, 11.0 Hz, 4H), 1.59-1.52 (m, 4H), 1.48-1.34 (m, 4H), 1.31-1.18 (m, 2H), 1.1 (t, J=7.2 Hz, 3H), 1.01 (s, 6H). .sup.13C NMR (75 MHz; CDCl.sub.3) (ppm): 63.4, 62.4, 35.6, 33.3, 22.4, 19.0, 18.2, 12.2.

(48) IR (neat) (cm.sup.1): .sub.max=3452, 2962, 2946, 2909, 2898, 2864, 2844, 1481, 1454, 1416, 1365, 1342, 1263, 1181, 920, 813, 787, 761, 725, 641.

(49) HRMS (ESI positive): Calculated for C.sub.17H.sub.32N [M-I].sup.+250.2535; Found 250.2532.

N-Butyl-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No4)

(50) Compound N.sup.o4 is prepared according to the general procedure D.

(51) To a solution of 235 mg of N-propyl-3,5-dimethyladamantan-1-amine (1 mmol) in 2 mL of dioxane were added 1.3 g of cesium carbonate (4 mmol) and 5 mL of methyl iodide (80 mmol) to give 282 mg of Compound N.sup.o4 as a white solid without purification.

(52) Yield=72%.

(53) Melting point=200-204 C.

(54) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.32-3.24 (m, 2H), 3.1 (s, 6H), 2.46 (m, 1H), 2.00 (br s, 2H), 1.91-1.79 (m, 2H), 1.72 (dd, J=22.2 Hz, 11.1 Hz, 4H), 1.55-1.44 (m, 4H), 1.44-1.37 (m, 4H), 1.31-1.18 (m, 2H), 1.03 (t, J=7.3 Hz, 3H), 1.00 (s, 6H).

(55) .sup.13C NMR (75 MHz; CDCl.sub.3) (ppm): 62.5, 62.4, 35.6, 33.3, 23.5, 22.4, 19.0, 18.2, 13.8.

(56) IR (neat) (cm.sup.1): .sub.max=3457, 2951, 2903, 2866, 2845, 1479, 1455, 1414, 1364, 1342, 1261, 1180, 920, 899, 839, 784, 724, 640.

(57) HRMS (ESI positive): Calculated for C.sub.18H.sub.34N [M-I].sup.+264.2691; Found 264.2687.

N,N-3,5-Tetramethyl-N-neopentyladamantan-1-ammonium iodide (Compound No5)

(58) Compound N.sup.o5 is prepared according to the general procedure D.

(59) To a solution of 67 mg of N-neopenthyl-3,5-dimethyladamantan-1-amine (0.25 mmol) in 1 mL of dioxane were added 330 mg of cesium carbonate (1 mmol) and 1.2 mL of methyl iodide (19.3 mmol) to give 20 mg of Compound N.sup.o5 as a pale yellow solid without purification.

(60) Yield: 20%.

(61) Melting point=198-200 C.

(62) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.21 (s, 6H), 3.15 (s, 2H), 2.47 (m, 1H), 2.03 (br s, 2H), 1.73 (dd, J=24.7 Hz, 11.0 Hz, 4H), 1.41 (dd, J=26.8 Hz, 12.9 Hz, 4H), 1.31 (s, 9H), 1.24 (br s, 2H), 1.02 (s, 6H).

(63) .sup.13C NMR (75 MHz; CDCl.sub.3) (ppm): 80.5, 67.9, 49.6, 46.5, 41.5, 40.9, 34.6, 33.7, 31.2, 30.1.

(64) IR (neat) (cm.sup.1): .sub.max=3400, 2952, 2921, 2903, 2867, 2848, 1486, 1455, 1414, 1375, 1363, 1262, 956, 919, 807, 776, 726, 641.

(65) HRMS (ESI positive): Calculated for C.sub.19H.sub.36N [M-I].sup.+278.2848; Found 278.2843.

N-isoPentyl-N,N-3-5-tetramethyladamantan-1-ammonium iodide (Compound No6

(66) Compound N.sup.o6 is prepared according to the general procedure D.

(67) To a solution of 135 mg of N-isopentyl-3,5-dimethyladamantan-1-amine (0.54 mmol) in 1.5 mL of dioxane were added 700 mg of cesium carbonate (2.16 mmol) and 2.7 mL of methyl iodide (43.4 mmol) to give 140 mg of Compound N.sup.o6 as a white solid without purification.

(68) Yield: 60%.

(69) Melting point=77-79 C.

(70) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.28-3.20 (m, 2H), 3.10 (s, 6H), 2.46 (m, 1H), 2.01 (br s, 2H), 1.81-1.64 (m, 7H), 1.41 (dd, J=20.3 Hz, 12.5 Hz, 4H), 1.27-1.22 (m, 2H), 1.02 (d, J=4.1 Hz, 6H), 1.01 (s, 6H).

(71) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 77.8, 57.6, 49.5, 45.5, 41.5, 41.4, 34.4, 34.2, 32.0, 30.8, 30.1, 26.7, 22.8.

(72) IR (neat) (cm.sup.1): .sub.max=3420, 3024, 2951, 2904, 2866, 2846, 1477, 1454, 1416, 1367, 817.

(73) HRMS (ESI positive): Calculated for C.sub.19H.sub.36N [M-I].sup.+278.2848; Found 278.2849.

N-isoButyl-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No7

(74) Compound N.sup.o7 is prepared according to the general procedure D.

(75) To a solution of 40 mg of N-isobutyl-3,5-dimethyladamantan-1-amine (0.17 mmol) in 1 mL of dioxane were added 200 mg of cesium carbonate (6.2 mmol) and 850 L of methyl iodide (13.7 mmol) to react during 3 hours to give 30 mg of Compound N.sup.o7 as a yellow solid without purification.

(76) Yield: 45%.

(77) Melting point=197-200 C.

(78) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.15 (s, 6H), 3.08 (d, J=4.9 Hz, 2H), 2.46 (m, 2H), 2.00 (br s, 2H), 1.72 (dd, J=23.8 Hz, 11.4 Hz, 4H), 1.41 (dd, J=26.4 Hz, 13.6 Hz), 1.24 (br s, 2H), 1.22 (s, 3H), 1.19 (s, 3H), 1.01 (s, 6H).

(79) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 78.5, 66.1, 49.6, 45.7, 41.6, 41.3, 34.5, 34.1, 31.0, 30.1, 24.4, 24.2.

(80) IR (neat) (cm.sup.1): .sub.max=3420, 2951, 2922, 2903, 2847, 1482, 1456, 1414, 1364, 1342, 1261, 1093, 1014, 919, 806, 776, 722, 640.

(81) HRMS (ESI positive): Calculated for C.sub.18H.sub.34N [M-I].sup.+264.2691; Found 264.2688.

N-(Cyclopropylmethyl)-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No8)

(82) Compound N.sup.o8 is prepared according to the general procedure D.

(83) To a solution of 100 mg of N-(cyclopropylmethyl)-3,5-dimethyladamantan-1-amine (0.43 mmol) in 2 mL of dioxane were added 553 mg of cesium carbonate (1.7 mmol) and 2.1 mL of methyl iodide (33.7 mmol) to give 113 mg of Compound N.sup.o8 as a yellow solid by precipitation with pentane of ethyl acetate filtrate, without purification.

(84) Yield: 77%.

(85) Melting point=180-183 C.

(86) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.29 (d, J=6.9 Hz, 2H), 3.15 (s, 6H), 2.41 (m, 1H), 1.98 (d, J=2.8 Hz, 2H), 1.76 (m, 1H), 1.71 (dd, J=20.7 Hz, 10.8 Hz, 4H), 1.37 (dd, J=33.4 Hz, 13.1 Hz, 4H), 1.21 (br s, 2H), 0.96 (s, 6H), 0.9-0.82 (m, 2H), 0.67-0.59 (m, 2H).

(87) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 76.9, 63.2, 49.4, 45.6, 41.5, 41.2, 34.3, 34.1, 30.7, 30.0, 5.8, 5.4.

(88) IR (neat) (cm.sup.1): .sub.max=3464, 2948, 2922, 2903, 2864, 2845, 1614, 1478, 1456, 1413, 1365, 1343, 1264, 1180, 1033, 970, 811, 768, 731.

(89) HRMS (ESI positive): Calculated for C.sub.18H.sub.32N [M-I].sup.+262.2535; Found 262.2529.

N-(Cyclohexylmethyl)-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No9)

(90) Compound N.sup.o9 is prepared according to the general procedure D.

(91) To a solution of 100 mg of N-(cyclohexylmethyl)-3,5-dimethyladamantan-1-amine (0.36 mmol) in 2 mL of dioxane were added 470 mg of cesium carbonate (1.45 mmol) and 1.8 mL of methyl iodide (28.9 mmol) to give 124 mg of Compound N.sup.o9 as a white solid, without purification.

(92) Yield: 80%.

(93) Melting point=247-249 C.

(94) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.14 (s, 6H), 2.99 (d, J=4.4 Hz, 2H), 2.45 (m, 1H), 2.10 (m, 1H), 1.99 (br s, 2H), 1.89 (d, J=11.7 Hz, 2H), 1.89-1.63 (m, 7H), 1.40 (dd, J=27 Hz, 13.1 Hz, 6H), 1.28-1.11 (m, 5H), 1.00 (s, 6H).

(95) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 78.3, 65.2, 49.5, 45.6, 41.5, 41.2, 34.5, 34.0, 33.0, 30.9, 30.1, 26.1, 25.5.

(96) IR (neat) (cm.sup.1): .sub.max=3029, 2950, 2921, 2907, 2849, 1478, 1453, 1417, 1264, 951, 933, 905, 818, 786.

(97) HRMS (ESI positive): Calculated for C.sub.21H.sub.38N [M-I]+304.3004; Found 304.2998.

N-nHexyl-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No10)

(98) Compound N.sup.o10 is prepared according to the general procedure D.

(99) To a solution of 100 mg of N-nhexyl-3,5-dimethyladamantan-1-amine (0.38 mmol) in 2 mL of dioxane were added 490 mg of cesium carbonate (1.5 mmol) and 1.9 mL of methyl iodide (30.5 mmol) to give 130 mg of Compound N.sup.o10 as a yellow solid, without purification.

(100) Yield: 82%.

(101) Melting point=192-195 C.

(102) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.28-3.20 (m, 2H), 3.10 (s, 6H), 2.46 (m, 1H), 2.00 (br s, 2H), 1.91-1.80 (m, 2H), 1.72 (dd, J=22.7 Hz, 10.5 Hz, 4H), 1.48-1.32 (m, 10H), 1.26-1.22 (m, 2H), 1.0 (s, 6H), 0.9 (t, J=7.1 Hz, 3H).

(103) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 58.5, 49.4, 45.5, 41.5, 41.2, 34.3, 34.1, 31.4, 30.7, 30.0, 26.5, 23.7, 22.5.

(104) IR (neat) (cm.sup.1): .sub.max=3452, 3023, 2951, 2922, 2902, 2865, 2846, 1479, 1455, 1415, 1365, 1343, 1311, 1180, 968, 900, 839, 816, 730.

(105) HRMS (ESI positive): Calculated for C.sub.20H.sub.38N [M-I].sup.+292.3004; Found 292.3005.

N-nOctyl-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No11)

(106) Compound N.sup.o11 is prepared according to the general procedure D.

(107) To a solution of 100 mg of N-nOctyl-3,5-dimethyladamantan-1-amine (0.34 mmol) in 2 mL of dioxane were added 445 mg of cesium carbonate (1.37 mmol) and 1.7 mL of methyl iodide (27.3 mmol) to give 132 mg of Compound N.sup.o11 as a white solid, without purification.

(108) Yield: 87%.

(109) Melting point=173-175 C.

(110) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.28-3.19 (m, 2H), 3.10 (s, 6H), 2.46 (m, 1H), 2.00 (br s, 2H), 1.91-1.80 (m, 2H), 1.72 (dd, J=22.7 Hz, 10.5 Hz, 4H), 1.48-1.16 (m, 18H), 1.0 (s, 6H), 0.88 (t, J=6.7 Hz, 3H).

(111) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 58.4, 49.4, 45.5, 41.4, 41.2, 34.3, 34.0, 31.7, 30.7, 30.0, 29.3, 29.1, 26.8, 23.8, 22.6, 14.1.

(112) IR (neat) (cm.sup.1): .sub.max=3464, 2952, 2923, 2901, 2848, 1480, 1455, 1414, 1365, 1342, 1311, 1264, 1180, 990, 920, 900, 839, 814, 725, 617.

N-(Cyclopentylmethyl)-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No12)

(113) Compound N.sup. 12 is prepared according to the general procedure D.

(114) To a solution of 100 mg of N-(Cyclohexylmethyl)-3,5-dimethyladamantan-1-amine (0.38 mmol) in 2 mL of dioxane were added 490 mg of cesium carbonate (1.51 mmol) and 1.9 mL of methyl iodide (30.5 mmol) to give 24 mg of Compound N.sup.o12 as a white solid, without purification.

(115) Yield: 15%.

(116) Melting point=213-215 C.

(117) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.27 (d, J=5.9 Hz, 2H), 3.13 (s, 6H) 2.45 (m, 1H), 2.17-2.05 (m, 2H), 2.00 (br s, 2H), 1.99 (br s, 2H), 1.80-1.62 (m, 8H), 1.49-1.27 (m, 5H), 1.24 (br s, 2H), 1.00 (s, 6H).

(118) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 64.2, 49.5, 46.0, 41.5, 41.3, 35.5, 34.4, 34.1, 33.9, 30.9, 30.1, 25.2.

(119) IR (neat) (cm.sup.1): .sub.max=3441, 2949, 2904, 2865, 2845, 1477, 1454, 1414, 1365, 1344, 1263, 1180, 920, 900, 813, 785, 728, 640.

(120) HRMS (ESI positive): Calculated for C.sub.20H.sub.36N [M-I].sup.+290.2848; Found 290.2848.

N-(3-Phenylpropyl)-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No13)

(121) Compound N.sup.o13 is prepared according to the general procedure D.

(122) To a solution of 150 mg of N-(3-Phenylpropyl)-3,5-dimethyladamantan-1-amine (0.5 mmol) in 2 mL of dioxane were added 650 mg of cesium carbonate (2 mmol) and 2.5 mL of methyl iodide (40.2 mmol) to give 95 mg of Compound N.sup.o13 as a white solid, without purification.

(123) Yield: 42%.

(124) Melting point=180-182 C.

(125) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 7.33-7.27 (m, 4H), 7.25-7.18 (m, 1H), 3.44-3.35 (m, 2H), 3.04 (s, 6H), 2.81 (t, J=7.4 Hz, 2H), 2.41 (m, 1H), 2.27-2.14 (m, 2H), 1.93 (b s, 2H), 1.65 (dd, J=22.9 Hz, 11.0 Hz, 4H), 1.43-1.29 (m, 4H), 1.27-1.13 (m, 2H), 0.97 (s, 6H).

(126) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 140.0, 128.8, 128.7, 126.6, 57.7, 49.3, 45.4, 41.4, 41.2, 34.2, 34.0, 32.4, 30.7, 30.0, 25.7.

(127) IR (neat) (cm.sup.1): .sub.max=2955, 2904, 2842, 1477, 1454, 1366, 1341, 1260, 1181, 906, 833, 813, 781, 732, 716, 701, 638.

(128) HRMS (ESI positive): Calculated for C.sub.23H.sub.36N [M-I].sup.+326.2848; Found 326.2846.

N-(2-Hydroxethyl)-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No14)

(129) Compound N.sup. 14 is prepared according to the general procedure D.

(130) To a solution of 150 mg of 2-(3,5-Dimethyladamantan-1-yl)amino)ethan-1-ol (0.67 mmol) in 3 mL of dioxane were added 870 mg of cesium carbonate (2.7 mmol) and 3.3 mL of methyl iodide (53 mmol) to give 191 mg of Compound N.sup.o14 as a white solid, without purification.

(131) Yield: 75%.

(132) Melting point=220-223 C.

(133) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 4.23 (br s, OH), 4.25 (br s, 2H), 3.63-3.56 (m, 2H), 3.19 (s, 6H), 2.44 (m, 1H), 1.95 (br s, 2H), 1.76-1.62 (m, 4H), 1.46-1.32 (m, 4H), 1.29-1.16 (m, 2H), 0.99 (s, 6H).

(134) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 59.5, 56.3, 49.4, 45.9, 43.2, 41.5, 40.9, 34.2, 33.8, 30.7, 30.0.

(135) IR (neat) (cm.sup.1): .sub.max=3376, 2951, 2904, 2847, 1629, 1456, 1414, 1364, 1342, 1260, 1180, 1090, 1046, 918, 901, 811, 769, 727, 643.

(136) HRMS (ESI positive): Calculated for C.sub.16H.sub.30NO [M-I].sup.+252.2327; Found 252.2326.

N-(2-Hydroxy-2-iminoethyl)-N,N-3,5-tetramethyladamantan-1-ammonium iodide (Compound No15)

(137) Compound N.sup.o15 is prepared according to the general procedure D.

(138) To a solution of 50 mg of 2-(-3,5-Dimethyladamantan-1-yl-amino)-acetimidic acid (0.21 mmol) in 1 mL of dioxane were added 272 mg of cesium carbonate (0.84 mmol) and 1.1 mL of methyl iodide (17.7 mmol) to react during 14 hours to give 35 mg of Compound N.sup.o15 as a white solid, without purification.

(139) Yield: 42%.

(140) Melting point=216-219 C.

(141) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 8.88 (br s, OH), 5.86 (br s, NH), 4.42 (s, 2H), 3.22 (s, 6H), 2.50 (m, 1H), 2.08 (br s, 2H), 1.82 (dd, J=24.0 Hz, 10.6 Hz, 4H), 1.43 (dd, J=27.2 Hz, 12.9 Hz, 4H), 1.27 (br s, 2H), 1.03 (s, 6H).

(142) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 165.7, 80.6, 58.5, 49.4, 45.1, 41.4, 41.3, 34.8, 34.1, 31.1, 30.1.

(143) IR (neat) (cm.sup.1): .sub.max=3331, 3238, 3156, 2950, 2907, 2845, 1693, 1607, 1446, 1418, 1360, 1311, 1261, 785, 697.

(144) HRMS (ESI positive): Calculated for C.sub.16H.sub.29N.sub.2O [M-I].sup.+265.2280; Found 265.2274.

N1-(3,5-Dimethyladamantan-1-yl)-N1,N1,N2,N2,N2-pentamethylethane-1,2-diammonium iodide (Compound No16)

(145) Compound N.sup.o16 is prepared according to the general procedure D.

(146) To a solution of 100 mg of N-ethanol-memantine (0.45 mmol) in 2 mL of dioxane were added 600 mg of cesium carbonate (1.85 mmol) and 2.3 mL of methyl iodide (37 mmol). The crude solid obtained is purified over preparative plates to deliver 55 mg of Compound N.sup.o16 as an orange amorphous solid.

(147) Yield: 22%.

(148) .sup.1H NMR (300 MHz, DMSO-d6) (ppm): 3.95 (m, 2H), 3.57 (m, 2H), 3.20 (s, 9H), 2.92 (s, 6H), 2.32 (m, 1H), 1.95 (br s, 2H), 1.80-1.68 (m, 4H), 1.46-1.36 (m, 2H), 1.33-1.15 (m, 4H), 0.94 (s, 6H).

(149) .sup.13C NMR (75 MHz, DMSO-d6) (ppm): 78.9, 57.9, 53.3, 50.1, 48.5, 47.8, 33.8, 32.3, 30.4, 29.7.

(150) IR (neat) (cm.sup.1): .sub.max=3440, 3009, 2950, 2921, 2904, 2865, 2846, 1486, 1455, 1416, 1364, 1343, 1311, 1180, 963, 953, 920, 785, 748.

3,5-dimethyladaman-1-yl-N,N,N-trimethylmethanamonium iodide (Compound No17)

(151) Compound N.sup.o17 is prepared according to the general procedure D.

(152) To a solution of 60 mg of 3,5-dimethyladamantan-1-yl-methanamine (0.3 mmol) in 2 mL of dioxane were added 400 mg of cesium carbonate (12 mmol) and 1.5 mL of methyl iodide (24 mmol) to give 80 mg of Compound N.sup.o17 as a white solid without purification.

(153) Yield: 71%.

(154) Melting point=288-292 C.

(155) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.6 (s, 9H), 3.44 (s, 2H), 2.15 (br s, 1H), 1.69 (br s, 2H), 1.42 (dd, J=25.2 Hz, 11.5 Hz, 4H), 1.38-1.33 (m, 4H), 1.24-1.10 (m, 2H), 0.85 (s, 6H).

(156) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 77.7, 56.7, 50.4, 48.0, 42.4, 40.5, 38.0, 31.3, 30.5, 29.2.

(157) IR (neat) (cm.sup.1): .sub.max=3442, 2997, 2946, 2895, 2842, 1491, 1453, 1420, 1376, 1360, 1344, 1265, 972, 943, 925, 895, 874, 734, 701.

(158) HRMS (ESI positive): Calculated for C.sub.16H.sub.30N [M-I].sup.+236.2378; Found 236.2381.

N-3,5-dimethyladaman-1-yl-methyl-N,N-trimethylethananamonium iodide (Compound No18)

(159) Compound N.sup.o18 is prepared according to the general procedure D.

(160) To a solution of 110 mg of 3,5-dimethyladamantan-1-yl-methanamine (0.5 mmol) in 2 mL of dioxane were added 675 mg of cesium carbonate (2.1 mmol) and 2.5 mL of methyl iodide (40 mmol) to give 130 mg of Compound N.sup.o18 as a white solid without purification.

(161) Yield: 69%.

(162) Melting point=261 C.

(163) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.82 (q, J=7.2 Hz, 2H), 3.44 (s, 6H), 3.35 (s, 2H), 2.16 (br s, 1H), 1.70 (br s, 2H), 1.24-1.10 (m, 11H), 1.38-1.33 (m, 2H), 0.85 (s, 6H).

(164) .sup.13C NMR (75 MHz; CDCl.sub.3) (ppm): 74.7, 63.0, 53.3, 50.4, 48.2, 42.4, 40.6, 38.0, 31.4, 30.5, 29.3, 9.4.

(165) IR (neat) (cm.sup.1): .sub.max=3442, 2946, 2919, 2898, 2863, 2842, 1487, 1455, 1420, 1376, 1360, 1267, 1020, 972, 893, 732, 699.

(166) HRMS (ESI positive): Calculated for C.sub.17H.sub.32N [M-I].sup.+250.2535; Found 250.2533.

N-3,5-dimethyladaman-1-yl-methyl-N,N, 2-trimethylpropan-1-anamonium iodide (Compound No19)

(167) Compound N.sup.o19 is prepared according to the general procedure D.

(168) To a solution of 75 mg of N-3,5-dimethyladamantan-1-yl-methyl-2-methylpropan-1-amine (0.3 mmol) in 1 mL of dioxane were added 390 mg of cesium carbonate (1.2 mmol) and 1.5 mL of methyl iodide (24 mmol) to give 130 mg of Compound N.sup.o19 as a white solid without purification.

(169) Yield: 84%.

(170) Melting point=165-168 C.

(171) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.59 (d, J=5.3 Hz, 2H), 3.48 (s, 6H), 3.42 (s, 2H), 2.31 (m, 1H), 2.15 (m, 1H), 1.70 (br s, 2H), 1.43 (dd, J=27 Hz, 11.1 Hz, 4H), 1.36 (br s, 4H), 1.19 (d, J=6.5 Hz, 6H), 1.19-1.10 (m, 2H), 0.85 (s, 6H).

(172) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 76.1, 75.4, 53.8, 50.3, 48.4, 42.4, 40.7, 38.1, 31.3, 30.5, 29.3, 24.5, 23.4.

(173) IR (neat) (cm.sup.1): .sub.max=3400, 2945, 2894, 2863, 2838, 1487, 1454, 1373, 1361, 1344, 1262, 994, 969, 888, 876, 843, 737.

(174) HRMS (ESI positive): Calculated for C.sub.19H.sub.36N [M-I].sup.+278.2848; Found 278.2848.

N,N,N-Trimethyladamantan-1-ammonium iodide (Compound No20, not According to the Invention)

(175) Compound N.sup.o20 is prepared according to the general procedure D.

(176) To a solution of 188 mg of adamantan-1-amine hydrochloride (1 mmol) in 3 mL of dioxane were added 1.3 g of cesium carbonate (4 mmol) and 5 mL of methyl iodide (80 mmol) to give 240 mg of Compound N.sup.o20 as a white solid without purification.

(177) Yield: 75%.

(178) Melting point=325 C.

(179) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.32 (s, 9H), 2.41 (br s, 3H), 2.06 (br d, J=2.6 Hz, 6H), 1.72 (dd, J=24.4 Hz, 13.1 Hz, 6H).

(180) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 73.3, 48.9, 35.2, 35.1, 30.2.

(181) IR (neat) (cm.sup.1): .sub.max=3442, 2955, 2909, 2854, 1491, 1477, 1448, 1416, 1370, 1347, 1265, 1039, 957, 939, 800, 733, 701.

(182) HRMS (ESI positive): Calculated for C.sub.13H.sub.24N [M-I].sup.+194.1909; Found 194.1905.

(183) Compound N.sup.o21, not According to the Invention

(184) Compound N.sup.o21 is prepared according to the general procedure D.

(185) To a solution of 94 mg of Adamantan-2-amine hydrochloride (0.5 mmol) in 2 mL of dioxane were added 0.81 g of cesium carbonate (2.5 mmol) and 2.5 mL of methyl iodide (40.2 mmol) to give 105 mg of Compound N.sup.o21 as a white solid, without purification.

(186) Yield: 66%.

(187) Melting point=344-346 C.

(188) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 4.0 (br s, 1H), 3.52 (s, 9H), 2.64 (br s, 2H), 2.17-1.94 (m, 8H), 1.89-1.75 (m, 4H).

(189) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 79.7, 54.3, 39.7, 37.3, 31.5, 29.0, 27.0, 26.0.

(190) IR (neat) (cm.sup.1): .sub.max=3400, 2998, 2924, 2907, 2862, 2849, 1491, 1476, 1420, 1352, 1274, 1099, 1039, 969, 941, 865, 819.

(191) HRMS (ESI positive): Calculated for C.sub.13H.sub.24N [M-I].sup.+194.1909; Found 194.1910.

(192) Compound N.sup.o22, not According to the Invention

(193) Compound N.sup.o22 is prepared according to the general procedure D.

(194) To a solution of 90 mg of N-ethyladamantan-2-amine (0.5 mmol) in 2 mL of dioxane were added 0.81 g of cesium carbonate (2.5 mmol) and 2.5 mL of methyl iodide (40.2 mmol) to give 117 mg of Compound N.sup.o22 as a white solid, without purification.

(195) Yield: 70%.

(196) Melting point=300 C.

(197) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.86 (q, J=7.3 Hz, 2H), 3.76 (br s, 1H), 3.40 (s, 6H), 2.61 (br s, 2H), 2.13-1.96 (m, 8H), 1.91-1.74 (m, 4H), 1.43 (t, J=7.3 Hz, 3H).

(198) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 77.2, 60.7, 54.5, 51.3, 40.1, 37.6, 32.2, 28.9, 27.3, 26.0, 9.5.

(199) IR (neat) (cm.sup.1): .sub.max=3400, 3006, 2923, 2908, 2862, 2851, 1493, 1460, 1354, 1270, 1099, 1039, 967, 944, 864, 811.

(200) HRMS (ESI positive): Calculated for C.sub.16H.sub.26N [M-I].sup.+208.2065; Found 208.2059.

N-isoButyl-N,N-dimethyladamantan-2-ammonium iodide (Compound No23, not According to the Invention)

(201) Compound N.sup.o20 is prepared according to the general procedure D.

(202) To a solution of 85 mg of N-isoButyladamantan-2-amine (0.41 mmol) in 2 mL of dioxane were added 0.53 g of cesium carbonate (1.64 mmol) and 1 mL of methyl iodide (16 mmol) to give 64 mg of Compound N.sup.o23 as a white solid, without purification.

(203) Yield: 40%.

(204) Melting point=227-229 C.

(205) .sup.1H NMR (300 MHz, CDCl.sub.3) (ppm): 3.90 (br s, 1H), 3.58 (d, J=5.1 Hz, 2H), 3.43 (br s, 6H), 2.61 (br s, 2H), 2.33-2.22 (m, 1H), 2.13-1.96 (m, 8H), 1.90-1.75 (m, 4H), 1.21 (d, J=6.7 Hz, 6H).

(206) .sup.13C NMR (75 MHz, CDCl.sub.3) (ppm): 78.1, 72.6, 60.7, 54.6, 51.9, 40.1, 37.6, 32.2, 29.0, 27.3, 26.1, 24.3, 23.6.

(207) IR (neat) (cm.sup.1): .sub.max=3464, 2966, 2919, 2854, 1491, 1469, 1372, 1271, 1099, 1039, 968, 916, 641.

(208) HRMS (ESI positive): Calculated for C.sub.16H.sub.30N [M-I].sup.+236.2378; Found 236.2372.

(209) The table 1 below illustrates Compounds N.sup.o1 to N.sup.o19 of the invention:

(210) TABLE-US-00001 TABLE 1 (I) (a) or Coun- No Formula R.sub.1 R.sub.2 (b) n A R.sub.3 R.sub.4 R.sub.5 terion 1 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.3 I.sup. .sup.1 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.3 Cl.sup. 2 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 I.sup. 3 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 I.sup. 4 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2CH.sub.2CH.sub.3 I.sup. 5 0 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2C(CH.sub.3).sub.3 I.sup. 6 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2CH(CH.sub.3).sub.2 I.sup. 7 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH(CH.sub.3).sub.2 I.sup. 8 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2(C.sub.3H.sub.5) I.sup. 9 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2(C.sub.6H.sub.11) I.sup. 10 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 (CH.sub.2).sub.5CH.sub.3 I.sup. 11 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 (CH.sub.2).sub.7CH.sub.3 I.sup. 12 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2(C.sub.5H.sub.9) I.sup. 13 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 (CH.sub.2).sub.3(C.sub.6H.sub.5) I.sup. 14 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2OH I.sup. 15 0 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2C(NH)(OH) I.sup. 16 CH.sub.3 CH.sub.3 (a) 0 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3 I.sup. 17 CH.sub.3 CH.sub.3 (a) 1 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2N.sup.+(CH.sub.3).sub.3 I.sup. 18 CH.sub.3 CH.sub.3 (a) 1 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2N.sup.+(CH.sub.3).sub.2(CH.sub.2CH.sub.3) I.sup. 19 CH.sub.3 CH.sub.3 (a) 1 N.sup.+R.sub.3R.sub.4R.sub.5 CH.sub.3 CH.sub.3 CH.sub.2CH(CH.sub.3).sub.2 I.sup.

(211) The compounds according to the invention were the subject of pharmacological assays.

Example 2

(212) Role of NMDA Receptors in the Development of Pulmonary Hypertension

(213) To understand the functional importance of NMDARs in smooth muscle cells, the Grin1 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).

(214) 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.

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

(216) 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

(217) In Vivo Brain Penetration Measurements

(218) Compounds of the present invention provide a mean to prevent Blood-Brain Barrier. This assumption has been verified on rats.

(219) 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.

(220) 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 0.3-0.5 are considered to have sufficient access to the CNS, compounds with a value greater than 1 freely cross the BBB, whereas compounds with a brain/plasma ratio smaller than 0.1 may be unable to enter the CNS.

(221) Thus, the brain penetration of memantine and Compound N.sup.o1 was measured in rat by establishing the brain/plasma ratio, Kp.sub.brain in triplicate (3 rats/Compound). The three tables below (Tables 1-3) show the results on plasma concentration, brain concentration and calculation of the Kp.sub.brain for the two compounds memantine and Compound N.sup. 1.

(222) TABLE-US-00002 TABLE 1 Plasma concentration Plasma concentration Compounds Rat (ng/mL) Mean CV % Memantine 1 123.23 102.25 18.0 2 88.69 3 94.85 Compound No1 4 34.77 27.47 23.2 5 23.11 6 24.52

(223) Plasma concentration was measured in 3 rats for each compound memantine and Compound N.sup.o1. Compound N.sup.o1 still retains a good plasma concentration as compared to memantine.

(224) TABLE-US-00003 TABLE 2 Brain concentration Brain concentration Compounds Rat (ng/g) Mean CV % Memantine 1 3342 3185 5.9 2 2977 3 3237 Compound No1 4 3.03 2.5 56.5 5 0.90 6 3.57

(225) Brain concentration was measured in 3 rats for each compound memantine and Compound N.sup.o1. Compound N.sup.o1 presents a very low brain concentration as compared to memantine.

(226) TABLE-US-00004 TABLE 3 Calculation of Kp.sub.brain Compounds Rat Kp.sub.brain Mean Memantine 1 27.12 31.6 2 33.57 3 34.13 Compound No1 4 0.09 0.091 5 0.04 6 0.15

(227) The Kp.sub.brain value (defined as the total brain/plasma concentration ratio at steady state) was calculated in 3 rats for each compound memantine and Compound N.sup.o1. Compound N.sup.o1 presents a very low Kp.sub.brain value (below 0.1) as compared to memantine.

(228) In conclusion, as known and previously described, memantine 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 value found below 0.1, the Compound N.sup.o1 does not penetrate the CNS in rat.

Example 4

(229) In Vitro Activity

(230) Previous studies have shown that the NMDAR exists in the peripheral vasculature.

(231) 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).

(232) Thus, to provide the accuracy of a well-known and admitted screening system, the molecule described herein where tested in serial concentrations ranging from 1 nM to 100 M for their NMDAR blocking activity using patch-clamp. 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.

(233) TABLE-US-00005 TABLE 4 NMDAR antagonist activity of selected compounds Compound IC.sub.50 (M) Memantine 1.0 Compound No1 9.9 Compound No1 11.6 Compound No2 18.0 Compound No3 29.0 Compound No4 110 Compound No6 14.3 Compound No8 3.5 Compound No9 35.2

(234) Using this test the parent molecule memantine had an IC.sub.50 of 1 M, which is 5 consistent with its known antagonist activity (Traynelis S F et al Pharmacological reviews 2010). Compounds of the present invention have an activity ranging from 3.5 to 110 M (Table 4). Notably, Compounds N.sup.o1 and N.sup.o1 have an activity in the 10 M range in iodure or chlorure form. Of interest, results obtained with Compound N.sup.o8 (IC.sub.50=3.5 M) clearly demonstrate that structural modification on the nitrogen atom of memantine is not deleterious for activity.