HK1068793B - Novel use of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl] and its physiologically acceptable salts - Google Patents

Description

New use of 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman and physiologically acceptable salts thereof

The present invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of extrapyramidal movement disorders and/or for the manufacture of a medicament for the treatment of adverse consequences of anti-Parkinsonian drugs in extrapyramidal movement disorders and/or for the manufacture of a medicament for the treatment of extrapyramidal symptoms (EPS) induced by neuroleptics.

From the US patent US 5,767,132, 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl group]Chroman, (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl group]Chromans or physiologically acceptable salts thereof (US 5,767,132 column 9 lines 6 to 32) and processes capable of preparing same/them (US 5,767,132 examples 1, 5 and 19). The compounds mentioned herein are described in this patent as mixed selective dopamine D₂Receptor antagonists and 5-HT_1AA receptor agonist. Thus, 2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl group is disclosed]Chroman, the physiologically acceptable acid addition salts thereof and the enantiomer thereof (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl)]Chromans and their physiological rolesThe use of a received acid addition salt for the preparation of a medicament for the prevention and control of the sequelae of cerebral infarction (stroke), such as stroke and cerebral ischemia, for the prevention and control of cerebral disorders, such as migraine, in particular as seen in geriatrics, in a manner similar to certain ergot alkaloids, for the treatment of anxiety, stress and depression states, sexual dysfunction caused by the central nervous system, disorders of sleep or food absorption, or psychosis (schizophrenia).

In addition, they are suitable for the elimination of cognitive deficits, for the improvement of learning and memory, for the treatment of Alzheimer's disease. They can furthermore be used for the treatment of side effects in the treatment of hypertension, endocrinology and gynecology, for example for the treatment of acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome or unwanted postpartum lactation.

The object of the present invention is to provide novel uses of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans, (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromans and their physiologically acceptable salts.

It has been found that (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt is also therapeutically active against extrapyramidal movement disorders, such as idiopathic Parkinson's disease, dyskinesias, chorea or dystonia syndrome, tremor, Tourette's syndrome, ballism, myoclonus, restless legs syndrome or Wilson's syndrome, and extrapyramidal movement disorders (synonymously referred to as extrapyramidal symptoms (EPS)) induced by neuroleptics.

In addition, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt have been found to be therapeutically active against the adverse consequences of anti-Parkinsonian drugs in extrapyramidal movement disorders, in particular the dopamine-mimetic adverse consequences of anti-Parkinsonian drugs in idiopathic Parkinson 'S disease or Parkinson' S syndrome.

Furthermore, it has been found that (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts show a very low tendency to induce extrapyramidal side effects. In rodents, for example, extrapyramidal motor side effects are measured by the ability of drugs to induce catalepsy. Catalepsy is defined as a condition in which animals maintain an abnormal (non-physiological "uncomfortable") posture for extended periods of time (m.e.stanley and s.d.glick, Neuropharmacology, 1996, 15: 393 394; c.j.e.nieregees and p.janssen, Life sci, 1979, 201-. For example, if a rat's hind paw is placed on an elevated level, such as a platform 3cm above ground level, a normal rat immediately withdraws the hind paw from the platform to ground level. Catalepsy rats maintained this unnatural posture for even minutes.

Although (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof have a dopamine antagonistic action mechanism, it is known that this induces extrapyramidal motor side effects (C.J.E.Niemereers and P.Janssen, Life Sci., 1979, 201-one 2216), surprisingly, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-one) Fluorophenyl) -3-pyridylmethylaminomethyl ] chromans or physiologically acceptable salts do not induce any catalepsy in rats, even at doses up to 500-fold higher than those effective in animal models to predict the aforementioned therapeutic indications.

Even more surprisingly, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt and is capable of preventing catalepsy induced by conventional anti-dopaminergic agents and even reversing already existing catalepsy induced by conventional anti-dopaminergic agents, such as haloperidol; the dose for this anti-catalepsy effect is in the same range as the dose shown in animal models to be effective in predicting the aforementioned therapeutic indication.

Other compounds having 5-HT have been described previously_1ADrugs with agonistic effects have beneficial effects on the extrapyramidal motor system. For example, bupropion, which is an anxiolytic drug, also exhibits modest anti-dyskinesia properties in advanced Parkinson patients (B.Kleedorfer et al, JNeurol Neurosurg Psychiatry, 1991, 54: 376-377; V.Bonifatti et al, Clin Neuropharmacol, 1994, 17: 73-82). The main mechanism of action is apparently via the nigrostriatal and striatal cleft pathway 5-HT_1AStimulation of the receptor. In contrast to buspirone, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]Chroman or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]The chromans or physiologically acceptable salts thereof are more potent 5-HT_1AReceptor agonists (IC of buspirone)₅₀：30nmol/l)。

Furthermore, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl group]Chroman or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]Chromans or physiologically acceptable salts thereof exhibit D at increased doses₂Antagonism, which represents a general 5-HT_1AAgonists (such as buspirone) have additional advantages. D₂Antagonism on the one hand reduces the risk of psychotic reactions caused by stimulation of serotonin receptors and on the other hand indirectly potentiates the co-administration of non-selective D₁/D₂D of agonist l-dopa₁And (4) properties. D₁More selective stimulation of receptors is known to be beneficialDyskinesia in Parkinson's disease (P.J. blanchet et al, J Neural Transm, 1995, 45 (Suppl.): 103-112). Thus, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]Chroman or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]5-HT of chromans or physiologically acceptable salts thereof_1AAgonistic properties and D₂Antagonistic properties contribute to the beneficial effects on the extrapyramidal motor system.

(R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl group]Chroman or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]The pharmacology of chromans or physiologically acceptable salts is furthermore that of para-dopamine D₃High affinity of the receptor is characteristic. D₃The receptor apparently participates in the pathogenesis of dyskinesia. Thus, dopamine D has recently been reported₃The association between the genetic diversity of the receptors and the predisposition to develop tardive dyskinesia (Segmann et al, 1999, Mol-Psychiatry 4: 247). In addition, increased density of dopamine D is evident in Parkinson patients with l-dopa induced dyskinesia₃A receptor. Thus, (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]Chroman or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]Chromans or physiologically acceptable salts with dopamine D₃Receptor interaction is another important mechanism for the beneficial effects on the extrapyramidal system, particularly in the treatment of dyskinesias.

The atypical antipsychotic clozapine is compatible with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or physiologically acceptable salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or physiologically acceptable salts, with respect to extrapyramidal effects, but not structural or side effects, especially in the range of anti-catalepsy properties. Recent studies have shown that clozapine ameliorates dyskinesias in Parkinson's disease (F. Perelli et al, Acta Neurol Scan, 1998, 97: 295-. In addition, clozapine is known to have a number of other beneficial effects on extrapyramidal movement disorders, such as tardive dyskinesia, tremor, Huntington's disease, Tourette's syndrome, akathisia and dopaminergic psychosis (C.Pfeiffer and M.L.Wagner, Am J Hosp Pharm, 1994, 51: 3047-. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof improves these kinds of dyskinesias without the fatal side effects of clozapine, such as agranulocytosis and acute nephritis (J.Alvir et al, N Engl J Med, 1993, 329: 162-cost 167; T.J.Elias et al, Lancet, 1999, 354: 1180-cost 1181).

The invention therefore relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment of extrapyramidal movement disorders.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride. A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (-) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

Accordingly, the present invention relates to the use of the preparation of a medicament for the treatment of extrapyramidal movement disorders, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

Accordingly, the present invention relates to the use of a pharmacologically acceptable salt for the manufacture of a medicament for the treatment of extrapyramidal movement disorders, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition comprising at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of their biocompatible salts and at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of extrapyramidal movement disorders.

(R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or their physiologically acceptable salts are useful for the treatment of extrapyramidal movement disorders, in particular for the treatment of idiopathic Parkinson 'S disease, Parkinson' S syndrome, movement disorders, chorea or dystonia syndrome, extrapyramidal movement adverse consequences of neuroleptic drugs, Tourette 'S syndrome, twitching, myoclonus, restless legs syndrome or Wilson' S syndrome, and/or for the treatment of adverse consequences in idiopathic Parkinson 'S disease or Parkinson' S syndrome, including the pharmaceutical compositions as defined below, preferably administered in a dose of 0.1 to 100mg, preferably between about 1 and 20 mg. The composition may be administered one or more times per day, for example 2, 3 or 4 times per day. The specific dosage for each patient will depend upon a variety of factors such as the activity of the specific compound employed, the age, body weight, general health, sex, diet, time and route of administration, rate of excretion, drug substance combination and the severity of the particular disorder involved in the therapy. Oral administration is preferred, but parenteral routes of administration (e.g., intravenous or transdermal) may also be employed.

Anti-parkinson agents are conventional agents, such as l-dopa (levodopa) and l-dopa in combination with benserazide or carbidopa; dopamine agonists such as bromocriptine, apomorphine, cabergoline, pramipexole, ropinirole, pergolide, dihydro-alpha-ergocriptine or lisuride plus various drugs which act by stimulating dopamine receptors; catechol-O-methyltransferase (COMT) inhibitors, such as entacapone or tolcapone; monoamine oxidase (MAO) inhibitors, such as selegiline; and N-methyl-D-aspartate (NMDA) receptor antagonists, such as amantadine or budesonide.

Adverse consequences of the anti-parkinsonian drugs are various types of dyskinesias, such as chorea, dystonia, ballism and myoclonic dyskinesia, as well as motor (response) fluctuations or psychotic states.

The invention therefore relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of the adverse consequences of anti-Parkinsonism in idiopathic Parkinson' S disease.

Treatment of adverse consequences of conventional anti-parkinson drugs as defined above may be utilized according to p.j.blanchet et al, exp.neurology 1998; 153: 214-222 was determined in an animal model of cynomolgus monkey with Parkinson's disease. Monkeys were repeatedly injected with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to develop parkinson's disease. According to p.j.blanchet et al, mov.dis, 1998; 13: 798-802, Parkinson's disease monkeys are treated with standard l-dopa therapy. Different body parts (face, neck, trunk, limbs) were evaluated by means of the Absolute Involution modification Scale (P.J. blanchet et al, Mov.Disord.1998; 13: 798-802) and psychotic status was assessed by observing attention, responsiveness and motility of monkeys, long-term l-dopa treatment qualitatively and quantitatively inducing extrapyramidal motor side effects and psychotic status. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman reduce overall chorea and dystonic dyskinesia as well as psychotic states.

A typical study for investigating the efficacy of the compounds according to the invention on adverse consequences in parkinson's disease is described below. 40 men and women with advanced idiopathic Parkinson's disease with "peak dose" dyskinesia were enrolled in a double-blind crossover study. The main admission criteria are Hoehn & Yahr stage ≧ 2.5(Hoehn H.M. et al, Neurology 1967; 17: 427-. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or placebo was administered "added" to conventional Parkinson' S treatment, which remained unchanged throughout the study. The dose of double-blind drug treatment was titrated over a 3-week period in the range of 2.5 to 10mg b.i.d. Drug treatment was then kept constant for 1 week. Before titration began and at the end of the treatment period, a l-dopa challenge was performed using video recordings, as per p.damier et al (Movement disorder, 1999, 14 (supply.1), 54-59). The primary measure for this protocol is the mean dyskinesia score during the first hour in the "on" state after l-dopa challenge. Therefore, researchers evaluate the severity of dyskinesia in seven parts of the body (upper and lower limbs, face, trunk, neck) every minute, from 0 to 4(0 being absent, 4 being severe and ineffective involuntary movements). After a 2-week washout period, the two sets of research equipment were crossed and the protocol repeated. Statistical analysis of the mean dyskinesia scores demonstrated significant clinical improvement under treatment with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride. A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of the adverse consequences of an anti-parkinson' S disease, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition containing at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts and at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of the adverse consequences of an anti-Parkinson' S disease.

Furthermore, the invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts for the preparation of a medicament for the treatment of idiopathic Parkinson' S disease.

A typical animal model of idiopathic parkinson's disease is according to p.j. blanchet et al, exp.neurology 1998; 153: 214-222 Parkinson's disease cynomolgus monkeys. Monkeys were repeatedly injected with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to develop parkinson's disease. Parkinson's disease symptoms were assessed qualitatively using a Laval University diagnosis Scale (B.Gomez-Mancilla et al, 1993; Mov.Disord.8: 144-150) and the following symptoms were measured: posture, motility, climbing, gait, taking food, sounding, cleaning, social interaction. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane reduces all Parkinson' S disease symptoms and increases overall activity.

A typical study for investigating the efficacy of the compounds according to the invention in the treatment of idiopathic parkinson's disease is described below. Both men and women 180 patients with idiopathic parkinson's disease were enrolled in a double-blind study. The main admission criteria are that the Hoehn & Yahr stage ≧ 2.0(Hoehn H.M. et al, Neurology 1967; 17: 427-. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or placebo was administered "added" to conventional Parkinson' S treatment, which remained unchanged throughout the study. The dose of double-blind drug treatment was titrated over a 4-week period in the range of 2.5 to 10mg b.i.d. Drug treatment was then kept constant for 1 week. Each patient was evaluated prior to the start of titration, at the end of the treatment phase and 2 weeks after the end of the titration phase using the unified Parkinson's disease assessment criteria (UPDRS sections I to V, according to S.Fahn et al, Recent definitions in Parkinson's disease, vol.2, MacMillan health information 1987, 153-. This allows simultaneous detection of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or one of its biocompatible salts or of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or one of its biocompatible salts, in particular of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride on the overall motor function, Dystonia, motor fluctuations and psychosis. In addition, efficacy in treating tremor was demonstrated with the aid of UPDRS. Statistical analysis of the UPDRS score demonstrated significant clinical improvement under treatment with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of idiopathic Parkinson' S disease, wherein the physiologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition comprising at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts and at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of idiopathic Parkinson' S disease.

The limiting factor in the treatment of Parkinson's disease with l-dopa and/or dopamine agonists is often the occurrence of psychosis or dyskinesias and other motor fluctuations.

It has been found that (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof enhances the anti-Parkinson 'S effect of the anti-Parkinson' S drug as defined above without inducing extrapyramidal side effects.

Thus, the addition of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt therapy thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt therapy thereof, in particular their hydrochloride salts, has now opened up the possibility of increasing the dose of l-dopa and/or dopamine agonists and/or other anti-Parkinsonian drugs as defined above, with the aim of counteracting the insufficient motility phase ("off phase"), without causing the above-mentioned side effects. This represents a completely new treatment for parkinson's disease, bringing significant benefits to the patient.

Thus, the present invention relates to a pharmaceutical composition comprising as active ingredients (i) (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof, and (ii) at least one anti-Parkinson' S drug, in combination with one or more pharmaceutically acceptable excipients.

Specifically, the present invention relates to pharmaceutical compositions comprising as active ingredients (i) (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or hydrochloride, and (ii) l-dopa or l-dopa in combination with benserazide or carbidopa, in combination with one or more pharmaceutically acceptable excipients.

The ratio of the amounts of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its physiologically acceptable salts and/or of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its physiologically acceptable salts to the conventional antiparkinsonian drugs varies depending on the result. Preferably, the weight ratio of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its biocompatible salts or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its physiologically acceptable salts to the conventional antiparkinsonian drug is 1: 1 to 1: 100, preferably 1: 10 to 1: 90, more preferably 1: 40 to 1: 60.

Another object of the present invention is additionally the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or one of its physiologically acceptable salts or a combination of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or one of its physiologically acceptable salts and at least one anti-Parkinson agent for the preparation of a pharmaceutical combination for potentiating the anti-Parkinson' S effect of said anti-Parkinson agent.

According to the present invention, the term "pharmaceutical combination" is intended to indicate a pharmaceutical composition as defined above, wherein both active ingredients or compounds are essential components of the same composition, or a kit comprising two separate compositions, a first composition comprising (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its physiologically acceptable salts as single active ingredient, and a second composition comprising at least one anti-parkinson agent as active compound.

According to the present invention, the term "pharmaceutical combination" is intended to indicate a pharmaceutical composition as defined above, wherein both active ingredients or compounds are essential components of the same composition, or a kit comprising two separate compositions, a first composition comprising (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of its physiologically acceptable salts as the single active ingredient, and a second composition comprising at least one anti-parkinson agent as the active compound.

When the pharmaceutical combination is in the form of a kit, administration of the two compositions making up the kit, although separately, is simultaneous with respect to the combination therapy. Preference is given to using (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane in the form of the hydrochloride.

The adverse consequences of anti-parkinsonian drugs as defined above are additionally known, in particular parkinsonism.

Parkinsonism is, for example, Multiple System Atrophy (MSA), Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy), corticobasal degeneration, olivopontocerebellar atrophy or Shy Drager syndrome.

(R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof are useful for the treatment of Parkinson' S syndrome, in particular multiple system atrophy.

The invention therefore relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of adverse consequences in Parkinson' S syndrome.

The invention further relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof for the production of a medicament for the treatment of Parkinson' S syndrome.

A typical animal model is a reserpized rat or mouse (M.S.Starr and B.S.Starr, J.neural.Transm. -park.Dis.Dement.Sect., 1994; 7: 133-. Reserpine is an effective monoamine depleting agent, producing almost complete akinesia in both animals. It is evident that after 24 hours of administration, the distance spanned and the time of activity are almost zero, as measured by a conventional activity meter. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof dose-dependently reduces akinesia, i.e., restores the spanned distance and the time of activity to about the level of normal animals.

Another more recent animal model is that according to g.k.wenning et al, j.neural.trans.suppl.1999; 55: 103-113 by degeneration of striatum substantia nigra in rats. The degeneration of the nigrostriatal body is induced by injecting 6-hydroxydopamine unilaterally into the left anterior middle cerebral tract of a rat, and then injecting quinolinic acid into the ipsilateral striatum. Degeneration results in a swivel behaviour in response to dopamine-mimetic attacks, such as apomorphine or amphetamine. Swivel behaviour was measured using an automatic recorder. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof dose-dependently antagonize apomorphine-or amphetamine-induced swivel behaviour.

Multiple System Atrophy (MSA) is due to extensive neurodegeneration outside the pyramidal tract and in the autonomic nervous system, which causes akinesia parkinsonism with vegetative disturbances. In contrast to idiopathic parkinson's disease, the density of central dopamine receptors is significantly reduced, and therefore MSA patients respond poorly to dopaminergic drugs. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof acts on the extrapyramidal system mainly via serotonin receptors, which are capable of improving the motor performance of these most treatable patients.

A typical study to investigate the efficacy of the compounds according to the invention on MSA patients covers 30 patients, both male and female, with symptoms lasting at least 5 years, with a significant reduction of central dopamine receptors in Positron Emission Tomography (PET). The study design was similar to that described above for parkinson's disease. Titration was performed "on addition" to (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or placebo (dose range 2.5 to 20mg b.i.d.). A complete UPDRS assessment (primary measurement) was performed for each patient before titration began and at the end of the treatment period. After a 2-week washout period, the two sets of research equipment were crossed and the protocol repeated. Statistical analysis of UPDRS demonstrated significant clinical improvement under treatment with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of the adverse consequences of an anti-parkinson' S drug in parkinsonism, in which the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride. The invention therefore relates to the use of the preparation of a medicament for the treatment of the adverse consequences of an anti-parkinson' S drug in parkinsonism, in which the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition containing at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or one of their biocompatible salts and at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of the adverse consequences of an anti-Parkinson 'S disease in Parkinson' S syndrome.

The invention therefore relates to the use of the preparation of a medicament for the treatment of Parkinson' S syndrome, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride. The invention therefore relates to the use of a pharmacologically acceptable salt for the manufacture of a medicament for the treatment of parkinson' S syndrome, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition comprising at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of Parkinson' S syndrome.

The invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and/or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof for the production of a medicament for the treatment of dyskinesia and/or chorea syndrome.

Dyskinesia and/or chorea syndromes are, for example, Huntington's disease, mild chorea or chorea in pregnancy. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts thereof are particularly useful for the treatment of Huntington' S disease.

A typical animal model is based on c.v. borlongan et al Brain res, 1995; 697: a systemic 3-nitropropionic acid (3-NP) model in rats 254-257. Rats were injected i.p. with the selective striatal neurotoxin 3-NP every four days (C.V.Borlongan et al Brain Res. protocols, 1997; 1: 253-containing 257). After two injections of 3-NP, rats showed nocturnal hyperactivity, which reflects symptoms of early Huntington's disease, while rats injected with four 3-NP showed nocturnal akinesia (hypomotility), which reflects symptoms of late Huntington's disease. Night activity is automatically measured in a conventional activity cage by means of infrared light beams. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof reduces nocturnal hyperactivity and akinesia.

A typical test to establish the effect of the compounds according to the invention on chorea, voluntary motor performance and functional disability in huntington's patients covers 32 genetically diagnosed patients. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or placebo are "added" to the conventional therapeutic administration, which remains unchanged throughout the study period. The dose of double-blind drug treatment was titrated over a 3-week period in the range of 2.5 to 20mg b.i.d. Drug treatment was then kept constant for 1 week. The evaluation was performed one week and the last day before the experiment. Chorea scores were determined using the Absolute Involution move Scale (AIMS, W.Guy, ECDEEU assessment manual, Rockville MD: US depth. of health, assessment and welfare, 1976: 534-537), the unified Huntington's disease assessment criteria (UHDRS, Huntington study group, 1996, motion disorder, 11: 136-42) and video recordings. Arbitrary motor performance was assessed using UHDRS motor criteria. The patient and their accompanying person complete a questionnaire about the functional disability. Statistical analysis demonstrated significant improvement in performance of huntington' S voluntary and involuntary locomotor activity in the treatment of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of dyskinesia and/or chorea syndromes, in particular huntington' S disease, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of dyskinesia and/or chorea syndromes, in particular huntington' S disease, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition for the treatment of dyskinesia and/or chorea syndrome, which composition comprises at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and at least one solid, liquid or semi-liquid excipient or auxiliary.

The invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of dystonic syndrome.

Examples of dystonic syndromes are spasmodic torticollis, writer's cramp, blepharospasm, meifever syndrome or dopa-sensitive dystonia. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof are particularly useful for the treatment of spastic torticollis and/or blepharospasm.

Typical animal models are according to a.richter and w.loscher, prog.neurobiol., 1998; 54: 633-677 mutant dystonic hamsters. In this genetically dystonic hamster, the animal is removed from the cage and placed on a balance, provoking the onset of dystonia. Dystonic syndrome consists of a series of abnormal movements, with the severity of a single symptom being assessed by means of a scoring system. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof dose-dependently reduces the severity of symptoms of the disorder.

To demonstrate the efficacy of the compounds according to the invention in the dystonic syndrome, a double-blind, placebo-controlled study was carried out in patients suffering from cervical dystonia (spastic torticollis) who were intolerant to injections of botulinum toxin. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride are titrated in the range of 2.5mg to 20mg b.i.d. as described above. The Toronto Western torticollis evaluation criteria (TWSTRS, C.L. Comella et al 1997, motion Disord, 12: 570-575) were used as the primary measurement. A significant improvement in TWSTRS scores was observed in patients treated with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of dystonic syndrome, in particular spastic torticollis and/or blepharospasm, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of dystonic syndrome, in particular spastic torticollis and/or blepharospasm, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the present invention relates to the use of a pharmaceutical composition comprising at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of dystonic syndrome.

The present invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of extrapyramidal symptoms induced by neuroleptics.

Examples of extrapyramidal movement disorders induced by antipsychotics are early dyskinesia, dystonia, akathisia, Parkinson's disease, in particular hyperkinesia, or tardive dyskinesia. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof are particularly useful for the treatment of akathisia and/or tardive dyskinesia and/or Parkinson-like disease.

Typical animal models are based on the results of s.wolffarth et al, arch.pharmacol, 1992; 345: 209-212 neuroleptic induced muscle stiffness in rats. Rats were challenged with haloperidol, a conventional antipsychotic drug that enhances muscle tone. Muscle tone is measured electromechanically and appears to be resistant to passive flexion and extension of the hind limbs. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof reduces the muscular tension enhanced by haloperidol.

Another typical animal model is according to d.e. casey, Psychopharmacology, 1996; 124: 134-140 monkey sensitized with antipsychotic. Monkeys treated repeatedly with conventional antipsychotics are highly sensitive to subsequent challenge doses of the antipsychotic. When challenged, monkeys immediately display extrapyramidal motor side effects such as dystonia, dyskinesia, akathisia, and bradykinesia, which are evaluated with the aid of a scoring system. Conventional antipsychotic drugs haloperidol were used as challenge. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof is administered when the aforementioned extrapyramidal motor side effects occur; (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane dose-dependently reduce extrapyramidal motor side effects.

Tardive dyskinesia is a common adverse consequence of long-term treatment with neuroleptic drugs. A typical study to investigate the efficacy of the compounds according to the invention on tardive dyskinesia is described below. There were 32 schizophrenia (DSM-III-R) hospitalized patients enrolled in the study, who were 25-60 years of age and had received chronic stable antipsychotic treatment (for at least 5 years). (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or placebo are "added" to the antipsychotic treatment administration, which remains constant throughout the study period. The dose of double-blind drug treatment was titrated over a 3-week period in the range of 2.5 to 20mg b.i.d. Drug treatment was then kept constant for 2 weeks under double-blind conditions. After a 2-week washout period, test drugs were crossed. Assessment of tardive dyskinesia was performed with the aid of the Abnormal invasion Movement Scale (AIMS, supra) and the extrapyramidal side effects of Parkinson's disease (UPDRS, supra) before and after treatment. The AIMS score during treatment with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride was significantly lower than that of placebo.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of extrapyramidal symptoms, in particular akathisia and/or tardive dyskinesia, induced by neuroleptics, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

The invention therefore relates to the use of the preparation of a medicament for the treatment of extrapyramidal symptoms, in particular akathisia and/or tardive dyskinesia, induced by neuroleptics, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the present invention relates to the use of a pharmaceutical composition comprising at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and at least one solid, liquid or semi-liquid excipient or auxiliary agent for the treatment of extrapyramidal symptoms induced by neuroleptics.

The invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof for the production of a medicament for the treatment of tremors.

Tremor includes various types of tremor, such as essential tremor, active physiological tremor, cerebellar tremor, orthostatic tremor, or drug-induced tremor. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof are particularly useful for the treatment of essential tremor and/or drug-induced tremor.

Typical animal models are genetically mutant animals or models in which tremor is induced by pharmacological components (H.Wilms et al, Mov.Disord, 1999; 14: 557-571).

Typical genetically mutant animal models are Pietrain porcine campus syndrome according to A.Richter et al (Exp. neurology, 1995; 134: 205-. In the campus syndrome model, these mutant pigs showed high frequency of tremor during standing and exercise, but not when lying still. The assessment of tremor was performed by means of an accelerometer recording. In Weaver mutant mice, degenerative cerebellar atrophy associated with tremor, gait instability and lateral collapse after several steps was seen. Gait instability and side fall dramatically lead to reduced locomotor activity, reflected in the distance spanned and the time taken to move within a conventional activity cage.

(R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof improves the campus syndrome in Pietrain pigs, i.e., reduces ineffective tremor when standing and moving, and enhances locomotor activity in Weaver mutant mice.

A typical animal model of drug-induced tremor is oxotremor-induced tremor (h.hallberg and o.almgaren, Acta physiol.scand., 1987; 129: 407-13; j.g.clement and w.r.dyck, j.pharmacol.meth., 1989; 22: 25-36). Oxotremorine induces tremors, which are measured by means of evaluation criteria. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof inhibits oxotremor induced by tremor.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

The present invention therefore relates to the use of the preparation of a medicament for the treatment of tremors, in particular essential tremors and/or drug-induced tremors, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

Accordingly, the present invention relates to the use of the preparation of a medicament for the treatment of tremors, in particular essential tremors and/or drug-induced tremors, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the invention relates to the use of a pharmaceutical composition for the treatment of tremors, which composition comprises at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and at least one solid, liquid or semi-liquid excipient or auxiliary.

The present invention relates to the use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of extrapyramidal movement disorders selected from the group consisting of Tourette 'S syndrome, twitch, myoclonus, restless legs syndrome and Wilson' S disease.

A typical animal model of myoclonus is myoclonus induced by an acute hypoxic episode according to D.D. Truong et al (Mov.Disord., 1994; 9: 201- & 206). In this model of posthypoxic myoclonus, rats experienced cardiac arrest for 8 minutes and were then resuscitated. The myoclonic reflex occurs spontaneously, but can also be provoked by auditory stimuli, worsening during the days following cardiac arrest. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or a physiologically acceptable salt thereof dose-dependently reduces the number of myoclonic reflexes of spontaneous and auditory arousal.

A preferred salt of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

Accordingly, the present invention relates to the use of the preparation of a medicament for the treatment of extrapyramidal movement disorders selected from the group consisting of Tourette 'S syndrome, twitching, myoclonus, restless legs syndrome and Wilson' S disease, wherein the pharmacologically acceptable salt is (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

A preferred salt of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride.

Accordingly, the present invention relates to the use of the preparation of a medicament for the treatment of extrapyramidal movement disorders selected from the group consisting of Tourette 'S syndrome, twitching, myoclonus, restless legs syndrome and Wilson' S disease, wherein the pharmacologically acceptable salt is (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman hydrochloride.

In addition, the present invention relates to the use of a pharmaceutical composition for the treatment of extrapyramidal movement disorders selected from the group consisting of Tourette 'S syndrome, twitching, myoclonus, restless legs syndrome and Wilson' S disease, which composition comprises at least one compound (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and at least one solid, liquid or semi-liquid excipient or auxiliary agent.

Some extrapyramidal motor disorders, such as Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy), cortico-basal degeneration, olivopontocerebellar atrophy, Shy Drager syndrome, mild chorea, chorea gravis, writer's cramps, blepharospasm syndrome, dopa-sensitive dystonia, tourette syndrome, twitching, myoclonus, restless legs syndrome and wilson's disease, are less common than formal double blind trials. However, the medical need in the art is still urgent, as no adequate therapy is available to date. Thus, the open-label observation in several selected patients is a suitable method for demonstrating the efficacy of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof.

All pharmaceutical preparations, including pharmaceutical combinations, for the treatment of extrapyramidal movement disorders and/or for the treatment of adverse consequences of anti-parkinson's drugs in extrapyramidal movement disorders can be used as medicaments in human or veterinary medicine.

The compositions of the invention are preferably administered parenterally, or better still orally, although other routes of administration, such as rectal administration, are not excluded.

Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and which do not react with (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc, petroleum gels. The dosage forms for oral administration are in particular tablets, pills, sugar-coated tablets, capsules, powders, granules, syrups, liquids or drops, for rectal administration are in particular suppositories, for parenteral administration are in particular solvents, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants, and for topical administration are transdermal plasters, ointments, creams or powders. (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts thereof may also be freeze-dried and the freeze-dried products obtained are used, for example, for the preparation of injectable products. The preparations mentioned can be in sterilized form and/or contain auxiliaries, such as glidants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, colorants, flavorings and/or other active ingredients, for example one or more vitamins.

If desired, the formulations may be designed to release slowly (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof.

The following examples relate to pharmaceutical products:

example A: vial formulation

A solution of 100g of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and 5g of disodium hydrogenphosphate in 3L of redistilled water is adjusted to pH 6.5 with 2N hydrochloric acid, filtered, sterilized, filled into vials, freeze-dried under aseptic conditions and sealed in an aseptic manner. Each bottle contained 5mg of active ingredient.

Example B: suppository

A mixture of 20g of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof and 100g of soybean lecithin and 1400g of cacao butter was melted, and the mixture was poured into a mold and allowed to cool. Each suppository contains 20mg of active ingredient.

Example C: solution preparation

Preparation of 1g of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl]Chroman or physiologically acceptable salt thereof, 9.38g NaH₂PO₄.2H₂O、28.48gNa₂HPO₄.12H₂A solution of O and 0.1g benzalkonium chloride in 940ml bidistilled water. The pH was adjusted to 6.8, the solution was added to 1L and sterilized by irradiation. The solution may be used in the form of eye drops.

Example D: ointment formulation

500mg of (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof are mixed with 99.5g of petroleum gel under aseptic conditions.

Example E-1: tablet formulation

A mixture of 1kg of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate are compressed in a conventional manner into tablets, each containing 10mg of active ingredient.

Example E-2: tablet formulation

A mixture of 20g of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride, 1kg of l-dopa, 250g of benserazide, 4kg of lactose, 1.6kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate are compressed in the usual manner to tablets, each tablet containing 0.2mg of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane hydrochloride, 10mg of l-dopa and 2.5mg of benserazide.

Example F: sugar-coated tablet

The mixture is compressed into tablets analogously to example E, and the tablets are subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and a coloring agent.

Example G: capsule preparation

2kg of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or its physiologically acceptable salts are filled in hard gelatin capsules in a conventional manner, each capsule containing 20mg of active ingredient.

Example H: ampoule agent

A solution of 1kg of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof in 60L of double distilled water is filter-sterilized, filled into ampoules, freeze-dried under aseptic conditions and sealed in an aseptic manner. Each ampoule contains 10mg of active ingredient.

Example I: inhalation spray

14g of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chroman or a physiologically acceptable salt thereof are dissolved in 10L of an isotonic NaCl solution, and the solution is filled into commercially available pump spray containers. The solution may be sprayed orally or intranasally. Each push (about 0.1ml) corresponds to a dose of about 0.14 mg.

Claims (4)

1. Use of (R/S) - (/ +) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or (S) - (+) -2- [5- (4-fluorophenyl) -3-pyridylmethylaminomethyl ] chromane or physiologically acceptable salts thereof for the manufacture of a medicament for the treatment of movement disorders, dyskinesia and chorea syndromes induced by anti-Parkinsonian drugs and extrapyramidal symptoms induced by neuroleptics.

2. The use according to claim 1, wherein the anti-parkinson's drug inducing dyskinesia is L-dopa.

3. Use according to claim 1, wherein the chorea syndrome is huntington's disease.

4. The use according to claim 1, wherein the extrapyramidal symptom induced by neuroleptic is tardive dyskinesia.