WO2005115373A1 - Use of neboglamine (cr 2249) as an antipsychotic and neuroprotective - Google Patents

Use of neboglamine (cr 2249) as an antipsychotic and neuroprotective Download PDF

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WO2005115373A1
WO2005115373A1 PCT/EP2005/052340 EP2005052340W WO2005115373A1 WO 2005115373 A1 WO2005115373 A1 WO 2005115373A1 EP 2005052340 W EP2005052340 W EP 2005052340W WO 2005115373 A1 WO2005115373 A1 WO 2005115373A1
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pharmaceutical preparation
treatment
pharmaceutically acceptable
neboglamine
schizophrenia
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Francesco Makovec
Lucio Claudio Rovati
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Rottapharm SpA
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Priority to JP2007513918A priority Critical patent/JP4898666B2/en
Priority to EP05747915A priority patent/EP1755583B1/en
Priority to DK05747915.6T priority patent/DK1755583T3/en
Priority to DE602005020618T priority patent/DE602005020618D1/en
Priority to US11/569,545 priority patent/US7737180B2/en
Priority to PL05747915T priority patent/PL1755583T3/en
Priority to CA2567397A priority patent/CA2567397C/en
Priority to AU2005247114A priority patent/AU2005247114B2/en
Priority to AT05747915T priority patent/ATE464042T1/en
Publication of WO2005115373A1 publication Critical patent/WO2005115373A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • neboglamine (CR 2249) as an antlpsychotlc and neuroprotective
  • the present invention relates to a novel therapeutic use for (S) -4-amino-N- (4, -dimethylcyclohexyl) glutamic acid (CR 2249- neboglamine) (CAS Registry Number 163000-63-3), of the pharmaceutically acceptable salts thereof and of the main metabolite thereof, 4,4-dimethylcyclohexylamine (CR 2863), in the treatment of schizophrenia with predominant negative symptomatology, of type II bipolar disorders (h pomania with major depression) and in cyclothymic disorders (numerous episodes of hypomania and minor depression) .
  • Schizophrenia is a psychiatric condition characterised by positive symptoms, for example hallucinations, delusions, disturbances of thought, paranoia [Andreson, Mod. Probl . Pharmacopsychiatry 24, 73-88 (1990); Peralta et al . , Br. J. Psychiatry 161, 335-343 (1992)], negative symptoms, for example apathy which primarily manifests as emotional and motivational deficits and deficits in social interactions, cognitive deficit together with depression.
  • the facilitatory activity exerted by neboglamine at the level of the NMDA receptor complex should be of therapeutic utility under conditions involving glutamatergic hypofunctionality, which, as explained above, may contribute to the negative symptomatological picture of schizophrenia.
  • PCP Phenylcyclidine
  • neboglamine and the main metabolite thereof CR 2863 have been evaluated in experimental animal models in which PCP was used and which are recognised as being predictive for the evaluation of antipsychotic drugs.
  • Such models in fact reproduce both glutamatergic hypofunctionality and hyperactivity of the dopaminergic system (hyperactivity and stereotype behaviour) with a psychotomimetic state which greatly resembles schizophrenia, unlike amphetamine-induced models which only bring about positive type psychoses .
  • the first model used was the study of PCP-induced inhibition of the acoustic prestimulus (PPI) in the rat. Principle of the method
  • PPI pre-pulse inhibition
  • the method is based on that reported by Swerdlow et al. [J. Pharmacol. Exp. Ther. 256 530-536 (1991)] with slight modifications .
  • An acrylic cylinder is used which is equipped with a piezoelectric sensor mounted under the cylinder which detects and transduces movements of the cylinder.
  • a background noise of 60 dB is provided and subsequently two acoustic stimuli separated by 500 ms, the first of which is 20 dB above the background noise, while the second (startle stimulus) is 120 dB for a duration of 40 ms.
  • PPI was calculated as a percentage reduction in the level of startle in the presence of the prestimulus compared to that without the acoustic prestimulus. Rats weighing approx. 250 g were used, which were treated intraperitoneally (i.p.) with the products under investigation 15 minutes prior to subcutaneous (s.c.) administration of 3 mg/kg of PCP and 30 minutes before the beginning of the experiment. The results obtained are shown in Table 1 below.
  • Table 1 Reversion of PCP-induced Inhibition of the acoustic prestimulus (PPI) in the rat PPI (% inhibition) 1 % inhibition by PCP 2 Control 55% PCP 20% PCP+NU) 3 27% 20.0 PCP+N(3) 3 40 * 57.1 PCP+N(10) 3 48 * 80.0 PCP+CR2863(10) 3 38 * 51.4
  • the test involves inducing a state of depression in the animal, which is forced to swim in a glass cylinder from which it cannot escape.
  • the state of depression was accentuated by 14 days ' pre-treatment with a daily 10 mg/kg (s.c.) injection of PCP.
  • the animals were additionally pretreated (i.p.) with physiological solution or neboglamine 30 minutes before the beginning of the test.
  • the duration of immobility (sign of depression) in seconds was evaluated during the experiment of an overall duration of 360 seconds.
  • the results obtained in this manner calculated between the 3rd and 6th minute of the experiment, i.e. for a period of 240 seconds, are shown in Table 2.
  • Neboglamine ' s ability to reverse the effect of PCP at a neuronal level was also evaluated in an in vitro test carried out on slices of rat frontal cortex.
  • the method involved preparing 0.4 mm thick cortical slices, incubating them for 20 minutes with 3 H-dopamine in physiological solution in the presence of 0.1 ⁇ M 6- nitroquipazine and 0.1 uM nisoxetine (selective serotonin and noradrenaline reuptake inhibitors) , aerated with 95%Oa + 5%C0 2 at 37°C, which, after appropriate washing with artificial cerebrospinal fluid (aCSF) , were superperfused for 30 minutes with aCFS at a rate of 1 ml/minute to equilibrate the system.
  • aCSF cerebrospinal fluid
  • PCP and neboglamine were added at the stated concentrations to the perfusion liquid for the entire duration of the experiment, while, after 45 minutes, NMDA (100 uM) stimulation was provided for 5 minutes. Another four 5 minute fractions of eluate were then collected and their radioactivity determined.
  • Table 3 Effect of neboglamine in inhibiting PCP-induced blocking on the release of tritiated dopamine brought about by NMDA in slices of rat prefrontal cortex
  • neboglamine and the main metabolite thereof could additionally exhibit neuroprotective activity: such properties could in fact prove to be extremely useful because a considerable sub-population of schizophrenic patients suffers from progressive structural degeneration of the brain (neurodegeneration) , the prevention of which is essential if cognitive function is to be maintained or restored.
  • halothane-anaesthetised animals are subjected to bilateral occlusion of the carotid arteries for 5 minutes . After 7 days, the animals are sacrificed, the brain is removed, deep frozen and 10 ⁇ m sections from the hippocampal area are prepared which are stained with cresyl violet . A quantitative determination (in mm 2 ) of the area occupied by CHI pyramidal neurons is then performed by means of an image analyser. The type of hippocampal neurodegeneration arising from this model of ischaemia involves a significant reduction in the area of the neuronal nuclei . The drugs were administered intraperitoneally (i.p.) lh before the ischaemia. The results obtained in this manner are shown in Tables 4 and 5 below.
  • the data are means + SD. * P ⁇ 0.05 vs sham animals. + P ⁇ 0,05 vs ischaemic animals
  • compositions for the use of the compounds according to the invention may be prepared using conventional methods.
  • the formulations include those suitable for oral use such as capsules, tablets, suspensions, emulsions, solutions; sterile solutions for parenteral use (including subcutaneous, intramuscular, intravenous) , or preparations for topical or rectal use or other forms suitable for achieving the desired therapeutic effect, for example solid formulations for oral use with delayed action which allows slow release of the active ingredient over time.
  • Substances commonly used in the pharmaceutical sector such as excipients, binders, disintegrants, substances capable of promoting transdermal absorption may be used together with the active ingredient in the pharmaceutical formulation.
  • Neboglamine compounds and the compound thereof, CR 2863 may accordingly be used as such or as pharmaceutically acceptable salts.
  • the sodium or potassium salt or the hydrochloride is preferred, while the hydrochloride is preferred in the case of CR 2863.
  • Example 1 Composition of neboglamine capsules
  • Example 2 Composition of an oral solution (syrup) of neboglamine (per 100 ml of syrup)
  • Example 3 Composition of a sterile vial of neboglamine for parenteral use

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Abstract

Use of neboglamine, (S)-4-amino-N-(4,4- dimethylcyclohexyl) glutamic acid (CR 2249) (CAS Registry Number 163000-63-3), of the racemate thereof or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of schizophrenia.

Description

Use of neboglamine (CR 2249) as an antlpsychotlc and neuroprotective
The present invention relates to a novel therapeutic use for (S) -4-amino-N- (4, -dimethylcyclohexyl) glutamic acid (CR 2249- neboglamine) (CAS Registry Number 163000-63-3), of the pharmaceutically acceptable salts thereof and of the main metabolite thereof, 4,4-dimethylcyclohexylamine (CR 2863), in the treatment of schizophrenia with predominant negative symptomatology, of type II bipolar disorders (h pomania with major depression) and in cyclothymic disorders (numerous episodes of hypomania and minor depression) .
Schizophrenia is a psychiatric condition characterised by positive symptoms, for example hallucinations, delusions, disturbances of thought, paranoia [Andreson, Mod. Probl . Pharmacopsychiatry 24, 73-88 (1990); Peralta et al . , Br. J. Psychiatry 161, 335-343 (1992)], negative symptoms, for example apathy which primarily manifests as emotional and motivational deficits and deficits in social interactions, cognitive deficit together with depression.
This complex scheme of symptoms which is observed in schizophrenic patients suggests the existence of dysfunctions at various levels in the brain of these individuals and it is ' thus difficult to hypothesise that malfunctioning of a single neurotransmitter system could explain the complex pathological picture of the disease.
The until recently accepted hypothesis suggested hyperactivity of the dopaminergic system as the primary cause of the clinical manifestations of schizophrenia. This hypothesis was largely derived from the observation that amphetamine brings about positive symptoms which resemble those present in paranoid patients; this symptomatology is brought about by increased dopaminergic neurotransmission in the central nervous system (CNS) (Sayed et al., Psychopharmacol . Bull. §_, 283-288 (1983)].
However, many schizophrenic patients and in particular those exhibiting predominantly negative symptoms do not respond adequately to treatment with dopamine antagonist drugs, so demonstrating that the dopaminergic model can only provide a partial explanation of the complexity of the disease.
Functional anatomical studies have revealed morphometric changes in the cerebral cortex of schizophrenic individuals, these changes probably arising from modified cortical development. Glutamate is the primary neurotransmitter at this level and it is thus probable that dysfunction of the glutamatergic pathways may well play an important part in schizophrenia as it does in bipolar disorders. The dopaminergic and glutamatergic hypotheses are not mutually exclusive because there are maj or unctional interactions between these two neurotransmitter systems .
One limitation of preclinical studies into novel molecules with potential antipsychotic activity is the limited availability of animal models capable of meaningfully reproducing a complex pathological picture such as that presented by schizophrenia. Despite this, there are models which can sufficiently effectively reproduce the symptoms of such disease with the aim of assessing the pharmacological activity of the potential candidate drug in specific functional changes .
On the basis of published preclinical data, the compound neboglamine (CR 2249) has shown that it possesses considerable modulating properties for the (strychnine- insensitive) glycine site coupled to the NMDA receptor complex [Lanza et al., Neuropharmacology 3_6, 1057-64 (1997)] together with interesting properties promoting memory and learning in various animal models [Garofalo et al. J. Pharm. Pharmacol. 48, 1290-97 (1996)].
The facilitatory activity exerted by neboglamine at the level of the NMDA receptor complex should be of therapeutic utility under conditions involving glutamatergic hypofunctionality, which, as explained above, may contribute to the negative symptomatological picture of schizophrenia.
Phenylcyclidine (PCP) induced psychosis is one model which better reflects the pathophysiology of the disease. In fact, both in experimental animals and in humans, PCP induces behavioural effects which exhibit considerable similarities with the symptoms of schizophrenia [Jentsch et al., Neuropsychopharmacology 20_, 201-225 (1999) ] . Accordingly, in humans, chronic administration of PCP (as may occur, for example, in drug addicts) brings about persistent neurobiological changes which are manifested with both positive and negative typologies, and mimic those present in schizophrenic patients .
Thus, neboglamine and the main metabolite thereof CR 2863 have been evaluated in experimental animal models in which PCP was used and which are recognised as being predictive for the evaluation of antipsychotic drugs. Such models in fact reproduce both glutamatergic hypofunctionality and hyperactivity of the dopaminergic system (hyperactivity and stereotype behaviour) with a psychotomimetic state which greatly resembles schizophrenia, unlike amphetamine-induced models which only bring about positive type psychoses .
The first model used was the study of PCP-induced inhibition of the acoustic prestimulus (PPI) in the rat. Principle of the method
The extent of the startle reflex response to an acoustic stimulus is reduced if it is preceded by a weak stimulus which, by itself, does not bring about a significant startle response. This phenomenon is known as "pre-pulse inhibition" (PPI) . This PPI response is present both in many animal species and in humans, while it has on the contrary been reported that schizophrenic patients generally exhibit a PPI deficit. Such a deficit may be reproduced experimentally with drugs which induce psychotic phenomena, such dopamine agonists and NMDA antagonists.
The method is based on that reported by Swerdlow et al. [J. Pharmacol. Exp. Ther. 256 530-536 (1991)] with slight modifications . An acrylic cylinder is used which is equipped with a piezoelectric sensor mounted under the cylinder which detects and transduces movements of the cylinder. A background noise of 60 dB is provided and subsequently two acoustic stimuli separated by 500 ms, the first of which is 20 dB above the background noise, while the second (startle stimulus) is 120 dB for a duration of 40 ms. The session of 30 trials at 30 second intervals with an overall duration of approx. 15 minutes involved subjecting the animal randomly to a startle stimulus either isolated or preceded by the low intensity stimulus. PPI was calculated as a percentage reduction in the level of startle in the presence of the prestimulus compared to that without the acoustic prestimulus. Rats weighing approx. 250 g were used, which were treated intraperitoneally (i.p.) with the products under investigation 15 minutes prior to subcutaneous (s.c.) administration of 3 mg/kg of PCP and 30 minutes before the beginning of the experiment. The results obtained are shown in Table 1 below. Table 1: Reversion of PCP-induced Inhibition of the acoustic prestimulus (PPI) in the rat PPI (% inhibition)1 % inhibition by PCP2 Control 55% PCP 20% PCP+NU)3 27% 20.0 PCP+N(3)3 40* 57.1 PCP+N(10)3 48* 80.0 PCP+CR2863(10)3 38* 51.4
Note N = neboglamine
(1) : The results relate to 10 animals per group; *P<0.05 (ANOVA vs PCP only group) (2) : Percentage inhibition is calculated with the formula : [ (N+PCP)-PCP] x 100 CONTRO -PCP (3) : The numbers in brackets are the doses of drug in mg/kg i.p.
Analysis of the PPI data of the animals pretreated with the drugs under investigation shows how neboglamine dose- dependently inhibits the blocking of PPI by PCP. This inhibition is already significant at a dose of 3 mg/kg (i.p.) . The metabolite CR 2863 proves to be approx. 3 times less active than the "parent" in this experimental model.
An animal model of depression (which may be considered as a negative symptom of schizophrenia) was then used to study the activity of neboglamine on the PCP-induced depressive effects in the mouse using the swimming test according to Porsolt et al. [Arch. Int. Pharmadyn . 229, 327-336 (1977)].
Method
The test involves inducing a state of depression in the animal, which is forced to swim in a glass cylinder from which it cannot escape. The state of depression was accentuated by 14 days ' pre-treatment with a daily 10 mg/kg (s.c.) injection of PCP. On the 15th day, the animals were additionally pretreated (i.p.) with physiological solution or neboglamine 30 minutes before the beginning of the test. The duration of immobility (sign of depression) in seconds was evaluated during the experiment of an overall duration of 360 seconds. The results obtained in this manner, calculated between the 3rd and 6th minute of the experiment, i.e. for a period of 240 seconds, are shown in Table 2.
Table 2 : Reversion of PCP-induced depression in the mouse swimming test
Figure imgf000007_0001
(1) : P<0.01 vs PCP only group (n=10 animals/group) (2) : Percentage inhibition is calculated with the formula: [PCP- (N+PCP) ] x 100 (PCP-CONTROL)
It may be inferred from the data shown in Table 2 how 2 weeks ' chronic treatment with PCP at a dose of 3 mg/kg brings about a behavioural change in the animals in an experiment which is considered as a possible model of the negative symptomatology of schizophrenia. The duration of immobility of the PCP-treated group in fact increased by approx. 3 times relative to the untreated control group In the dose range from 3-10 mg/kg, neboglamine successfully inhibits this effect, which becomes statistically significant at a dose of 10 mg/kg, with virtually complete inhibition (87.8%) of the depressive effect.
Neboglamine ' s ability to reverse the effect of PCP at a neuronal level was also evaluated in an in vitro test carried out on slices of rat frontal cortex.
The method involved preparing 0.4 mm thick cortical slices, incubating them for 20 minutes with 3H-dopamine in physiological solution in the presence of 0.1 μM 6- nitroquipazine and 0.1 uM nisoxetine (selective serotonin and noradrenaline reuptake inhibitors) , aerated with 95%Oa + 5%C02 at 37°C, which, after appropriate washing with artificial cerebrospinal fluid (aCSF) , were superperfused for 30 minutes with aCFS at a rate of 1 ml/minute to equilibrate the system. Then, PCP and neboglamine were added at the stated concentrations to the perfusion liquid for the entire duration of the experiment, while, after 45 minutes, NMDA (100 uM) stimulation was provided for 5 minutes. Another four 5 minute fractions of eluate were then collected and their radioactivity determined.
The effect of the drugs was evaluated by calculating the ratio between the percentage radioactivity present in the effluent fraction corresponding to the maximum effect and that in the first effluent fraction collected. The results obtained are shown in Table 3 below.
Table 3: Effect of neboglamine in inhibiting PCP-induced blocking on the release of tritiated dopamine brought about by NMDA in slices of rat prefrontal cortex
Figure imgf000009_0001
(1) : All concentrations are μM; (2): P<0.05 (ANOVA) (n=9 x group) (3) : Percentage inhibition was calculated with the formula: [III (IV) -II] x 100 {I-ID
It may be inferred from the data shown in Table 3 how neboglamine powerfully and dose-dependently prevents PCP- induced blocking of NMDA-evoked dopamine release. This inhibition was deemed significant from a dose of as low as 10 μM. It should furthermore be noted that, at both the concentrations tested, neboglamine has no effect on basal dopamine release.
Neuroprotection experiments
It was decided to investigate whether neboglamine and the main metabolite thereof (CR 2863) could additionally exhibit neuroprotective activity: such properties could in fact prove to be extremely useful because a considerable sub-population of schizophrenic patients suffers from progressive structural degeneration of the brain (neurodegeneration) , the prevention of which is essential if cognitive function is to be maintained or restored.
It was accordingly decided to investigate the possible neuroprotective effects of neboglamine and CR 2863 on a model of hippocampal ischaemia brought about in the gerbil by bilateral occlusion of the carotid arteries.
In brief, halothane-anaesthetised animals are subjected to bilateral occlusion of the carotid arteries for 5 minutes . After 7 days, the animals are sacrificed, the brain is removed, deep frozen and 10 μm sections from the hippocampal area are prepared which are stained with cresyl violet . A quantitative determination (in mm2) of the area occupied by CHI pyramidal neurons is then performed by means of an image analyser. The type of hippocampal neurodegeneration arising from this model of ischaemia involves a significant reduction in the area of the neuronal nuclei . The drugs were administered intraperitoneally (i.p.) lh before the ischaemia. The results obtained in this manner are shown in Tables 4 and 5 below.
Table : Ischaemia induced in the gerbil by bilateral occlusion of the carotid arteries: protective effect of neboglamine
Substances Dose area (mm') 0. mg/kg protection mortality
Controls - 25.22 ± 2.13 - 0
(Sham)
Ischaemia - 9.05 ± 5.98* - 50
CR 2249 12.5 8.42 ± 4.46* 0 50
CR 2249 25 16.47 ± 5.54*+ 45.9 25
CR 2249 50 20.48 + 5.3+ 70.7 0
The data are means + SD. * P <0.05 vs sham animals. + P <0.05 vs ischaemic animals
Table 5: Ischaemia induced in the gerbil by bilateral occlusion of the carotid arteries : protective effect of CR 2863
Substances Dose area (mm2) % % mg/kg protection mortality
Controls - 22.39 ± 1.15 - 0
(Sham)
Ischaemia - 5.55 ± 3.1* - 28.57
CR 2863 4 9.74 + 0.9*+ 24.88 11.11
CR 2863 8 12.16 ± 5.49* 39.25 5.88
CR 2863 16 15.23 + 5.49*+ 57.82 0
The data are means + SD. * P <0.05 vs sham animals. + P <0,05 vs ischaemic animals
It can be seen from the data shown in Tables 4 and 5 how neboglamine provides dose-dependent protection from neuronal degeneration. Indeed, while ischaemia produces a mortality of 50% in the control animals, neboglamine at the higher dose completely eliminates any mortality. Furthermore, in this model, the metabolite CR 2863 proves to be still more active than the "parent", since complete protection against mortality is achieved at a dose of as low as 16 mg. These results would suggest that the neuroprotective effect exhibited by neboglamine is principally due to its main metabolite CR 2863.
Pharmaceutical formulations for the use of the compounds according to the invention may be prepared using conventional methods. The formulations include those suitable for oral use such as capsules, tablets, suspensions, emulsions, solutions; sterile solutions for parenteral use (including subcutaneous, intramuscular, intravenous) , or preparations for topical or rectal use or other forms suitable for achieving the desired therapeutic effect, for example solid formulations for oral use with delayed action which allows slow release of the active ingredient over time.
Substances commonly used in the pharmaceutical sector such as excipients, binders, disintegrants, substances capable of promoting transdermal absorption may be used together with the active ingredient in the pharmaceutical formulation.
Neboglamine compounds and the compound thereof, CR 2863, may accordingly be used as such or as pharmaceutically acceptable salts. In the case of neboglamine, the sodium or potassium salt or the hydrochloride is preferred, while the hydrochloride is preferred in the case of CR 2863.
The effective therapeutic quantity of neboglamine to be used for the treatment of schizophrenia should be between 10 and 600 mg of active ingredient per day, preferably from 30 to 300 mg, depending on the specific condition of the treated patient, on the individual response to treatment, the age and weight of the patient.
The following Examples are intended to illustrate better the present invention in a purely exemplary, non-limiting manner.
Example 1 : Composition of neboglamine capsules
Snap Fit hard gelatin capsules. Size 1 Neboglamine 100 mg
Pregelatinised maize starch 228 mg
USP talcum 2 mg
Example 2 : Composition of an oral solution (syrup) of neboglamine (per 100 ml of syrup)
Neboglamine 1 g
Sodium hydroxide pellets 0.15 g
Essential oil 0.05 g
Sorbitol, 70% 65 g
Ethyl alcohol, 95% 5 g
Distilled water to make up to 100 ml
Example 3 : Composition of a sterile vial of neboglamine for parenteral use
Neboglamine 50 mg
Sodium hydroxide pellets 7.5 mg
Pyrogen-free physiological solution to make up to 3 ml

Claims

1. use of neboglamine, (S) -4-amino-N- (4, 4- dimethylcyclohexyl) glutamic acid (CR 2249) (CAS Registry Number 163000-63-3) , of the racemate thereof or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of schizophrenia.
2. A pharmaceutical preparation comprising as active substance at least one of the compounds according to claim 1 for use in the therapeutic treatment of the negative symptoms of schizophrenia.
3. A pharmaceutical preparation according to claim 2 for use in the therapeutic treatment of type II bipolar (manic- depressive) disorders.
4. A pharmaceutical preparation according to claim 2 for use in the therapeutic treatment of cyclothymic disorders .
5. A pharmaceutical preparation according to claim 2 for use in the therapeutic neuroprotective treatment of pathological conditions characterised by progressive structural degeneration of the brain.
6. A pharmaceutical preparation according to claim 2 furthermore comprising pharmaceutically acceptable inactive ingredients selected from the group consisting of carriers, binders, flavourings, sweeteners, disintegrants, preservatives, humectants and mixtures thereof, or ingredients which promote parenteral, transdermal, transmucosal or rectal absorption and which enable controlled release over time of the active substance .
7. Use of 4, 4-dimethylcyclohexylamine (CR 2863) or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of depression.
8. Use of 4, 4-dimethylcyclohexylamine (CR 2863) or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of schizophrenia.
9. A pharmaceutical preparation comprising as active substance 4, 4-dimethylcyclohexylamine (CR 2863) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.
10. A pharmaceutical preparation according to claim 9 for use in the therapeutic treatment of the negative symptoms of schizophrenia .
11. A pharmaceutical preparation according to claim 9 for use in the therapeutic treatment of type II bipolar (manic- depressive) disorders.
12. A pharmaceutical preparation according to claim 9 for use in the therapeutic neuroprotective treatment of pathological conditions characterised by progressive structural degeneration of the brain.
PCT/EP2005/052340 2004-05-24 2005-05-23 Use of neboglamine (cr 2249) as an antipsychotic and neuroprotective Ceased WO2005115373A1 (en)

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JP2007513918A JP4898666B2 (en) 2004-05-24 2005-05-23 Use of nebogramine (CR2249) as an antipsychotic and neuroprotective agent
EP05747915A EP1755583B1 (en) 2004-05-24 2005-05-23 Use of neboglamine for the treatment of schizophrenia
DK05747915.6T DK1755583T3 (en) 2004-05-24 2005-05-23 Use of neboglamine for the treatment of schizophrenia
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US11/569,545 US7737180B2 (en) 2004-05-24 2005-05-23 Use of neboglamine (CR 2249) as an antipsychotic and neuroprotective
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CA2567397A CA2567397C (en) 2004-05-24 2005-05-23 Use of neboglamine (cr 2249) as an antipsychotic and neuroprotective
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WO2007039869A3 (en) * 2005-10-04 2007-07-05 Rottapharm Spa Use of neboglamine in the treatment of toxicodependency
AU2006298393B2 (en) * 2005-10-04 2011-04-14 Rottapharm Biotech S.R.L. Use of neboglamine in the treatment of toxicodependency
US8258185B2 (en) 2005-10-04 2012-09-04 Rottapharm S.P.A. Use of neboglamine in the treatment of toxicodependency

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EP1755583A1 (en) 2007-02-28
PT1755583E (en) 2010-05-07
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US20070249715A1 (en) 2007-10-25
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