Patent Application
20070105961
New uses of 1-amino-alkylcyclohexanes.
The prior art is represented by our prior U.S. Pat. No. 6,034,134 of Mar. 7, 2000 and our published application WO 99/01416, PCT/EP98/04026, and Parsons et al. Neuropharmacology 38, 85-108 (1999), wherein the active compounds utilized according to the present invention are disclosed and disclosed to be NMDA receptor antagonists and anticonvulsants.
The present invention is directed to a new use of 1-amino-alkylcyclohexane compounds selected from the group consisting of those of the formula
Representative of these compounds are as follows:
Of particular interest are compounds of the foregoing formula wherein at least R1, R4, and R5 are lower-alkyl and those compounds wherein R1 through R5 are methyl, those wherein x is 4 or 5, and in particular the compound N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof.
In our U.S. Pat. No. 6,034,134 of Mar. 7, 2000, we disclosed compounds of the foregoing formula, pharmaceutical compositions thereof, and their use as NMDA-receptor antagonists and anticonvulsants. It has now been found that compounds of the foregoing formula and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof, in addition to their NMDA antagonist and anticonvulsant properties, quite unpredictably possess a high degree of 5HT3 and neuronal nicotinic receptor antagonism, making them useful in the treatment of diseases and conditions where blockade of these receptors is important.
What we therefore believe to be comprised by our present invention may be summarized, inter alia, in the following words:
A method-of-treating a living animal for inhibition of progression or alleviation of a condition which is alleviated by a 5HT3 or neuronal nicotinic receptor antagonist, comprising the step of administering to the said living animal an amount of a 1-aminoalkylcyclohexane compound selected from the group consisting of those of the formula
method wherein at least R1, R4, and R5 are lower-alkyl; such a
method wherein R1 through R5 are methyl; such a
method wherein R1 is ethyl; such a
method wherein R2 is ethyl; such a
method wherein R3 is ethyl; such a
method wherein R4 is ethyl; such a
method wherein R5 is ethyl; such a
method wherein R5 is propyl; such a
method wherein R6 or R7 is methyl; such a
method wherein R6 or R7 is ethyl; such a
method wherein X is 4 or 5; such a
method wherein the condition treated or inhibited is selected from the group consisting of emesis, anxiety disorders, schizophrenia, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, Alzheimer's disease, cerebella tremor, Parkinson's disease, Tourette's, pain, and appetite disorders; such a
method wherein the compound is selected from the group consisting of
method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound in combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers.
Moreover, a use of a 1-aminoalkylcyclohexane selected from the group consisting of those of the formula
use wherein at least R1, R4, and R5 are lower-alkyl; such a
use wherein R1 through R5 are methyl; such a
use wherein x is 4 or 5; such a
use wherein the compound is selected from the group consisting of
use wherein the condition treated is selected from the group consisting of emesis, anxiety disorders, schizophrenia, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, Alzheimer's disease, cerebella tremor, Parkinson's disease, Tourette's, pain, and appetite disorders.
Background and Pharmacology
5-HT3 Receptor Antagonists
5-HT3 receptors are ligand gated ionotropic receptors permeable for cations. In man 5-HT3 receptors show the highest density on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferents and the area postrema of the brain stem, which forms the chemoreceptor trigger zone.
Since 5-HT3 receptors not only have a high density in the area postrema but also in the hippocampal and amygdala region of the limbic system, it has been suggested that 5-HT3 selective antagonists may have psychotropic effects (Greenshaw & Silverstone, 1997).
Indeed, early animal studies suggested that the 5-HT3 receptor antagonists, in addition to their well recognized anti-emetic use, may well be clinically useful in a number of areas. These include anxiety disorders, schizophrenia, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, Alzheimer's disease, cerebella tremor, Parkinson's disease treatment-related psychosis, pain (migraine and irritable bowel syndrome), and appetite disorders.
Neuronal Nicotinic Receptors
At present nine α subunits (α1-α9) and four β (β1-β4) subunits for nicotinic are known. α4β2 receptors are probably the most common in the CNS, especially in the hippocampus and striatum. They form non-selective cation channels with slowly, incompletely desensitizing currents (type II). Homomeric α7 receptors are both pre- and postsynaptic and are found in the hippocampus, motor cortex and limbic system as well as in the peripheral autonomic nervous system. These receptors are characterized by their high Ca2+ permeability and fast, strongly desensitizing responses (type 1A).
Changes in nicotinic receptors have been implicated in a number of diseases. These include Alzheimer's disease, Parkinson's disease, Tourette's, schizophrenia, drug abuse, and pain.
Based on the observation that the nicotinic agonist nicotine itself seems to have beneficial effects, drug development so far aimed at the discovery of selective nicotinic agonists.
On the other hand, it is unclear whether the effects of nicotinic agonists in, e.g., Tourette's syndrome and schizophrenia, are due to activation or inactivation/desensitization of neuronal nicotinic receptors.
The effects of agonists on neuronal nicotinic receptors is strongly dependent on the exposure period. Rapid reversible desensitization occurs in milliseconds, rundown occurs in seconds, irreversible inactivation of α4β2 and α7 containing receptors occurs in hours and their upregulation occurs within days.
In other words: the effects of nicotinic “agonists” may in fact be due to partial agonism, inactivation and/or desensitization of neuronal nicotinic receptors. In turn, moderate concentrations of neuronal nicotinic receptor channel blockers could produce the same effects as reported for nicotinic agonists in the above mentioned indications.
Amino-Alkylcyclohexanes are 5-HT3 and Neuronal Nicotinic Receptor Antagonists
We speculated whether novel amino-alkylcyclohexane derivatives (U.S. Pat. No. 6,034,134), being there described as uncompetitive NMDA receptor antagonists and anticonvulsants, might possibly also act as 5HT3 and neuronal nicotinic antagonists. These properties would allow the use of the amino-alkylcyclohexanes in all diseases or conditions where blockade of 5HT3 or nicotinic receptors is important. Our findings were positive.
Synthesis
The synthesis of the novel amino-alkylcyclohexanes which are utilized according to the present invention has been described in U.S. Pat. No. 6,034,134 of Mar. 7, 2000.
Alternative Procedure
The 1-cyclic amino compounds may also be prepared by reacting the corresponding 1-free amino-alkylcyclohexane and the selected alpha, omega-dihaloalkyl compound, e.g., 1,3-dibromopropane, 1,4-dibromobutane, or 1,5-dibromopentane, according to the following representative example:
1,3,3,5,5-pentamethylcyclohexylamine hydrochloride (12 g, 58.3 mmol), potassium carbonate (48.4 g, 350 mmol) and 1,4-dibromobutane (7.32 ml, 61.3 mmol) were refluxed in acetonitrile (250 ml) for 60 h. After cooling to r.t., the mixture was filtered and the precipitate was washed with diethyl ether (600 ml). The filtrate was concentrated in vacuo by rotary evaporation and the residue was fractionally distilled at reduced pressure (11 mm/Hg). The fraction at 129° C. was collected to obtain colorless oil (8.95 g). This was dissolved in diethyl ether (120 ml) and 2.7 M HCl solution in diethyl ether (30 ml) was added. The resulting precipitate was filtered off, washed with diethyl ether (3*30 ml) and dried in vacuo over NaOH to give N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine hydrochloride hydrate (12.9 g, 68%) with m.p. 158° C. PMR spectrum: (DMSO-d6, TMS) d: 0.97 (6H, s, 3,5-CH3); 1.11 (6H, s, 3,5-CH3); 0.8-1.4 (2H, cyclohexane 4-CH2) 1.41 (3H, s, 1-CH3); 1.69 (4H, m, cyclohexane 2,6-CH2); 1.84 (4H, m, pyrrolidine 3,4-CH2); 3.20 (4H, m, pyrrolidine 2,5-CH2); 10.9 ppm (1H, br s, NH+).
Elemental analysis (C15H29n*HCl*H2O) Found (%) C 65.0; H 11.7; N5.0 Calculated (%) C 64.8; H 11.6; N 5.0.
Electrophysiology
Hippocampi were obtained from rat embryos (E20 to E21) and were then transferred to Ca2+ and Mg2+ free Hank's buffered salt solution (Gibco) on ice. Cells were mechanically dissociated in 0.05% DNAase/0.3% ovomucoid (Sigma) following an 8 minute pre-incubation with 0.66% trypsin/0.1% DNAase (Sigma). The dissociated cells were then centrifuged at 18 G for 10 minutes, re-suspended in minimum essential medium (Gibco) and plated at a density of 150,000 cells cm−2 onto poly-DL-ornithine (Sigma)/laminin (Gibco)—precoated plastic Petri dishes (Falcon). The cells were nourished with NaHCO3/HEPES-buffered minimum essential medium supplemented with 5% foetal calf serum and 5% horse serum (Gibco) and incubated at 37° C. with 5% CO2 at 95% humidity. The medium was exchanged completely following inhibition of further glial mitosis with cytosine-β-D-arabinofuranoside (ARAC, 5 μM Sigma) after about 5 days in vitro.
Patch clamp recordings were made from these neurones after 15-21 days in vitro with polished glass electrodes (2-3 MΩ) in the whole cell mode at room temperature (20-22° C.) with the aid of an EPC-7 amplifier (List). Test substances were applied using a modified fast application system (SF-77B Fast Step, Warner Instruments) with 100 μM opening diameter theta glass (Clark TGC 200-10) pulled with a Zeiss DMZ (Augsburg, Munich) horizontal puller. The contents of the intracellular solution were normally as follows (mM): CsCl (95), TEACl (20), EGTA (10), HEPES (10), MgCl2 (1), CaCl2 (0.2), glucose (10), Tris-ATP (5), Di-Tris-Phosphocreatinine (20), Creatine Phosphokinase (50 U); pH was adjusted to 7.3 with CsOH or HCl. The extracellular solutions had the following basic composition (mM): NaCl (140), KCl (3), CaCl2 (0.2), glucose (10), HEPES (10), sucrose (4.5), tetrodotoxin (TTX 3*10−4).
N1E-115 cells were purchased from the European collection of cell cultures (ECACC, Salisbury, UK) and stored at −80° C. until further use. The cells were plated at a density of 100,000 cells cm−2 onto plastic Petri dishes (Falcon) and were nourished with NaHCO3/HEPES-buffered minimum essential medium (MEM) supplemented with 15% foetal calf serum (Gibco) and incubated at 37° C. with 5% CO2 at 95% humidity. The medium was exchanged completely daily. Once every three days, cells were re-seeded onto fresh Petri dishes following treatment with trypsin-EDTA (1% in PBS), resuspension in MEM, and centrifugation at 1000 for 4 mins.
Patch clamp recordings were made from lifted cells, 2-3 days following seeding with polished glass electrodes (2-3 MΩ) in the whole cell mode at room temperature (20-22° C.) with an EPC-7 amplifier (List). Test substances were applied as for hippocampal cells. The contents of the intracellular solution were as follows (mM): CsCl (130), HEPES (10), EGTA (10), MgCl2 (2), CaCl2 (2), K-ATP (2), Tris-GTP (0.2), D-Glucose (10); pH was adjusted to 7.3 with CsOH or HCl. The extracellular solutions had the following basic composition (mM): NaCl (124), KCl (2.8), HEPES (10), pH 7.3 with NaOH or HCl.
Only results from stable cells were accepted for inclusion in the final analysis, i.e., showing at least 75% recovery of responses to agonist (serotonin or Ach) following removal of the antagonist tested. Despite this, recovery from drug actions wasn't always 100% because of rundown in some cells (<=10% over 10 mins). When present, this was always compensated by basing the % antagonism at each concentration on both control and recovery and assuming a linear time course for this rundown. All antagonists were assessed at steady-state blockade with 3 to 6 concentrations on at least 5 cells. Equilibrium blockade was achieved within 2 to 5 agonist applications, depending on antagonist concentration.
Results
Table 1 shows the general structure of selected amino-alkylcyclohexanes used in the present study.
Substitutions in brackets represent alternatives in racemic mixtures, e.g., CH3(C3H7) means CH3 or C3H7.
A: Original data for a single N1E-115 cell—serotonin was applied as indicated by the bars. The left and right panels show control and recovery responses respectively. The middle three panels show equilibrium responses in the continuous presence of MRZ 2/633 1, 3, and 10 μM respectively.
B: Peak and steady-state (plateau) serotonin current responses were normalized to control levels and plotted as means (±SEM) against MRZ 2/633 concentration (n=8). Estimation of IC50s and curve fitting were made according to the 4 parameter logistic equation (GraFit, Erithacus Software).
A: Original data for a single hippocampal neurone—Ach was applied as indicated by the bars. The left and right panels show control and recovery responses respectively. The middle three panels show equilibrium responses in the continuous presence of (−) nicotine 1, 3 and 10 μM respectively.
B: Peak ACh current responses were normalized to control levels and plotted as means (±SEM) against (−) nicotine concentration (n=12 per concentration). Estimation of IC50s and curve fitting were made according to the 4 parameter logistic equation (GraFit, Erithacus Software).
A: Original data for a single hippocampal neurone—Ach was applied as indicated by the bars. The left and right panels show control and recovery responses respectively. The middle three panels show equilibrium responses in the continuous presence of MRZ 2/616 10, 30 and 100 μM respectively
B: Peak ACh current responses were normalized to control levels and plotted as means (±SEM) against MRZ 2/616 concentration (n=11 per concentration). Estimation of IC50s and curve fitting were made according to the 4 parameter logistic equation (GraFit, Erithacus Software).
A: Original data for a single hippocampal neurone—Ach was applied as indicated by the bars. The left and right panels show control and recovery responses respectively. The middle three panels show equilibrium responses in the continuous presence of MRZ 2/705 0.3, 1.0 and 3.0 μM respectively
B: Peak ACh current responses were normalized to control levels and plotted as means (±SEM) against MRZ 2/705 concentration (n=9 per concentration). Estimation of IC50s and curve fitting were made according to the 4 parameter logistic equation (GraFit, Erithacus Software).
Effects of Amino-Alkylcyclohexanes on 5-HT3 Receptors
All ten amino-alkylcyclohexanes tested antagonized serotonin-induced inward currents in N1E-115 cells with similar potencies to those previously reported for NMDA-induced inward currents (
Summary of the potencies of amino-alkylcyclohexanes on NMDA and 5-HT3 receptors. Data for displacement of [3H]MK-801 binding in rat cortical membranes and antagonism of NMDA-induced inward currents (at −70 mV) in cultured rat hippocampal neurones are taken from Parsons et al., 1999. Potencies against 5-HT3 receptors were assessed as IC50s (μM) against “steady-state” responses of N1E-115 cells to serotonin (10 μM) applied for 2 secs.
Effects of Amino-Alkylcyclohexanes on Neuronal Nicotinic Receptors
Concentration-clamp application of Ach (1 mM) to cultured hippocampal neurones elicited rapid, pronounced inward currents which rapidly desensitized to a much lower plateau level. Nicotine caused a concentration dependent block of neuronal responses to Ach and concentrations achieved in the CNS of smokers caused a substantial antagonism (
We next accessed the potencies of a variety of amino-alkylcyclohexanes as α7 neuronal nicotinic antagonists. Simple amino-alkylcyclohexanes with low alkyl substitutions at positions R1 through R4 (see Table 1) were potent α7 neuronal nicotinic antagonists and some, as exemplified by MRZ 2/616 were actually much more potent in this regard than previously reported for NMDA receptors (see
Summary of the potencies of amino-alkylcyclohexanes on NMDA and α7 neuronal nicotinic receptors. Data for displacement of [3H]MK-801 binding in rat cortical membranes and antagonism of NMDA-induced inward currents (at −70 mV, PC NMDA) in cultured rat hippocampal neurones are taken from Parsons et al., 1999. Potencies against α7 neuronal nicotinic receptors (PC ACh) were assessed as IC50s (μM) against peak responses of cultured hippocampal neurones to Ach (1 mM) applied for 2 secs.
Conclusions
The present data show that amino-alkylcyclohexanes are antagonists of 5-HT3 receptors. These effects were seen at concentrations similar to, or even lower than, those required for uncompetitive antagonistic effects at NMDA receptors as reported by Parsons et al. 1999. Combined antagonistic effects of such compounds at NMDA and 5-HT3 receptors will therefore lead to positive synergistic effects contributing to their therapeutic safety and efficacy in Alzheimer's disease by increasing desired effects—cognitive enhancement and antidepressant effects—whilst further reducing possible negative effects of NMDA receptor antagonism by, e.g., reducing mesolimbic dopamine hyperactivity. Furthermore, 5-HT3antagonistic effects per se are useful in the treatment of cognitive deficits, depression, alcohol abuse, anxiety, migraine, irritable bowel syndrome, and emesis.
The present data show also that some amino-alkylcyclohexanes are in fact more potent as α7 neuronal nicotinic receptor antagonists than for actions at NMDA and/or 5-HT3 receptors. It is likely that many of these agents are also antagonists of α4β2 receptors, as already reported for agents like memantine and amantadine by Buisson et al. (1998). We propose that the positive effects reported by others for neuronal nicotinic agonists in animal models of various diseases are actually due to desensitization of α7 receptors and inactivation/down regulation of α4/β2 receptors or other forms of functional antagonism by, e.g., partial agonistic effects. Moderate concentrations of neuronal nicotinic receptor antagonists are therefore useful for neuroprotection against, or for the treatment of, disorders related to the malfunction of nicotinic transmission such as, e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, Tourette's syndrome, drug abuse, and pain.
The active ingredients of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing twenty (20) to one hundred (100) milligrams of active ingredient or, more broadly, ten (10) to two hundred fifty (250) milligrams per tablet, are accordingly representative unit dosage forms.
Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Dosage ranges may be 1-1000 milligrams daily, preferably 10-500 milligrams daily, and especially 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow.
(a) Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
The following examples are given by way of illustration only and are not to be construed as limiting.
A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
Another suitable formulation for a tablet containing 100 mg is as follows:
A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
filled in a gelatin capsule.
A suitable formulation for an injectable solution containing one percent of active ingredient is as follows:
A suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
180 g aerosol solution contain:
15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.
100 g solution contain:
1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use.
10 g of polybutylcyanoacrylate nanoparticles contain:
Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCl/ethanol mixture as polymerization medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
The compounds of the invention thus find application in the treatment of disorders of a living animal body, especially a human, in both 5HT3 and nicotinic receptor indications for both symptomatic and neuroprotective purposes
The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of the selected ailment or condition, particularly ailments or conditions susceptible to treatment with a 5HT3 or nicotinic receptor antagonist, is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament are all in accord with the foregoing and with the disclosure of our prior U.S. Pat No. 6,034,134 for the same 1-amino compounds, and representative acid addition salts, enantiomers, isomers, and hydrates, and their method of preparation is likewise disclosed in our prior USP and published WO application for the 1-amino-alkylcyclohexane compounds.
Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing and also in accord with examples of pharmaceutical compositions given in our U.S. Pat. No. 6,034,134 for these 1-amino-alkylcyclohexanes.
It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compositions, methods, procedures, or embodiments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope which can be legally accorded to the appended claims.
Buisson, B., Bertrand, D., 1998, Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53, 555-563.
Fan, P., 1994, Effects of antidepressants on the inward current mediated by 5-HT3 receptors in rat nodose ganglion neurones. Br J Pharmacol 112, 741-744.
Greenshaw, A. J., Silverstone, P. H., 1997, The non-antiemetic uses of serotonin 5-HT3 receptor antagonists. Clinical pharmacology and therapeutic applications. Drugs 53, 20-39.
Parsons, C. G., Danysz, W., Bartmann, A., Spielmanns, P., Frankiewicz, T., Hesselink, M., Eilbacher, B., Quack, G., 1999, Amino-alkylcyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics: in vitro and in vivo characterization. Neuropharmacology 38, 85-108.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09597102 | Jun 2000 | US |
| Child | 11643129 | Dec 2006 | US |
