Novel using 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman and its physiologically acceptable salts

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

 

The present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders and/or for the manufacture of a medicine for treatment of adverse effects of antiparkinsonian drugs for extrapyramidal motor disorders and/or for the manufacture medicines for the treatment of extrapyramidal symptoms (EPS)induced by neuroleptics.

2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman, (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or their physiologically acceptable salts (US 5767132, column 9, line 6-32) and method (US 5767132, Examples 1, 5 and 19), which he/they may be obtained, is known from U.S. Patent US 5767132. Connections that are here referred to, is described in this patent as a combined selective antagonist of the dopamine D2 receptor and the agonist 5-HT1Athe receptor. Thus, it is disclosed the use of 2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane and its physiologically acceptable salts accession acid and the application of its enantiomer (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane and his fiziologicheskii salts accession acid for the manufacture of a medicine for the prevention and control of the consequences of ischemic stroke (apoplexia cerebri), such as apoplectically shock and cerebral ischemia, for the prevention and control of cerebral disorders, such as migraine, especially in geriatrics, in a sense, like certain ergot alkaloids, treatment of anxiety, tension and depression, sexual disorders caused by Central nervous system for the treatment of sleep disorders or eating or for the treatment of psychosis (schizophrenia).

In addition, they are suitable to address cognitive nedostatochnosty to improve learning ability and memory and for the treatment of Alzheimer's disease. Moreover, they can be used for the treatment of side effects in the treatment of hypertension, endocrinology and gynecology, for example, for the treatment of acromegaly, gipogenitalizma, secondary amenorrhoea, premenstrual syndrome or undesired puerperal lactation.

The purpose of this invention is the provision of new applications for (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane, (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane and their physiologically acceptable salts.

It was found that (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and also out therapeutic activity against extrapyramidal movement disorders, such as idiopathic Parkinson's disease, syndromes, Parkinson's disease, dyskinetic, horiatiki, or dystonic syndromes, tremor syndrome Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" or Wilson's disease, as well as extrapyramidal motor disorders [synonym extrapyramidal symptoms (EPS)]caused by neuroleptics.

In addition, it was found that (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts have therapeutic activity against adverse effects of antiparkinsonian drugs for extrapyramidal motor disorders, in particular against dopaminemediated adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease or Parkinson syndromes.

Moreover, it was found that (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts show an extremely low ability to cause extrapyramidal side effects. Extrapyramidal motor side effects, for example, in rodents measure the ability of drugs in order to predict catalepsy. Catalepsy is defined as a condition in which the animal remains in an abnormal (non-physiological awkward position for a long time (for example: ON Stanley and Click S.D., Neuropharmacology, 1996; 15: 393-394; C.J.E. Niemegeers and R. Janssen, Life Sci., 1979, 201-2216). For example, if the rear paw of the rat is at the high level, for example, the platform is raised to 3 cm above the base level, a normal rat will immediately pull away the back foot from the platform at a basic level. Cataleptic rat remains in this unnatural position, even for a few minutes.

Although (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or a physiologically acceptable salt or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts have dopamine antagonist mechanism of action, which is known to cause extrapyramidal motor side effects (C.J.E. Niemegeers and R. Janssen, Life Sci., 1979, 201-2216), suddenly (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts do not cause any catalepsy in rats at doses higher than 500 times in comparison with the doses effective in animal models showing above therapeutic indication.

Even more not idunno, (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts, however, are able to prevent the catalepsy caused by normal antidopaminergics drugs, and even annul the existing catalepsy caused by normal antidopaminergic drugs such as haloperidol; doses for this anticatholicism effect are in the same range of doses, which is shown effective in animal models showing above therapeutic indication.

Positive effects on the extrapyramidal motor system previously described for other drugs with 5-HT1Aagonistic action. Buspirone, for example, which is an anxiolytic drug, by nature, shows the average antidyskinetics properties in patients with advanced Parkinson's disease (Century Kleedorfer, etc., J Neurol Neurosurg Psychiatry, 1991, 54: 376-377; V. Bonifati, etc., Clin Newopharmacol, 1994, 17: 73-82). The main mechanism of action, obviously, goes through stimulation of 5-HT1Areceptors seam negralejo (raphe nigral) and seam veins (raphe striatal) ways. Unlike buspirone (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridyl thelaminated]-chroman or their physiologically acceptable salts are stronger agonists at 5-HT 1Areceptor (IC50buspirone: 30 nmol/l).

In addition, (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or their physiologically acceptable salts show D2antagonism at higher doses, which is an additional advantage in comparison with the conventional 5-HT1Aagonists such as buspirone. On the one hand, D2antagonism reduces the risk of psychotic reactions caused by stimulation of the serotonin receptors, and on the other hand, indirectly underlines D1property-applied selective D1/D2agonist 1-EXT. More selective stimulation of D1receptor is known to be useful for the treatment of dyskinesia in Parkinson's disease (P.J. Blanchet and others, J Neural Transm, 1995, 45 (Dupl.): 103-112). Therefore, as a 5-HT1Aagonistic and D2antagonistic properties of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or their physiologically acceptable salts contribute to the positive effects on the extrapyramidal motor system.

Pharmacological profile of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or physiologically acceptable with what she and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or physiologically acceptable salts, in addition, is characterized by high affinity for dopamine D3the receptor. Receptor D3evidently involved in the pathogenesis of dyskinesias. Thus, the correlation between genetic polymorphism of the dopamine D3receptor and a tendency to develop late dyskinesias was recently presented (Segmann and others 1999, Mol Psychiatry 4:247). Additionally, obviously, there is an increased density of dopamine D3receptors in patients with Parkinson's disease, with 1-DOPA-induced dyskinesia. Therefore, the interaction of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or physiologically acceptable salts with dopamine D3the receptor is an additional important mechanism leading to positive effects on the extrapyramidal system, in particular in the treatment of psoriasis.

Atypical neuroleptic clozapine (clozapine) with respect to extrapyramidal effects - but not on the structure or side effects is comparable with (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or physiologically acceptable salts, especially within anticataplectic properties. Recent studies certificate is revealed, that clozapine improves dyskinesias in Parkinson's disease (F. Perelli and others, Acta Neurol Scan, 1998, 97: 295-299; P. Pollak, etc., Lancet, 1999, 353: 2041-2041). In addition, clozapine, as you know, has many other positive effects on extrapyramidal movement disorders such as tardive dyskinesia, tremor, disease, Huntington's disease, Tourette syndrome, akathisia and dopaminemediated psychosis (.Pfeiffer and M. L. Wagner, Am J Hosp Pharm, 1994, 51: 3047-3053). (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salts improve these types of musculoskeletal disorders even without the risk of harmful side effects of clozapine, such as agranulocytosis, and acute nephritis (J. Alvir, etc., N Engi J Med, 1993, 329: 162-167; T. J. Elias and others, Lancet, 1999, 354: 1180-1181).

Therefore, the present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride. Site is titelnoj salt (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (S)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the present invention relates to the use for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders, in which the pharmacologically acceptable salt is

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the present invention relates to the use for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders, in which the pharmacologically acceptable salt is

(S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Additionally, the present invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its biocompatible salts together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for the treatment of extrapyramidal movement disorders.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-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, syndromes PA is kinson, dyskinetic, heretically or dystonic syndromes, extrapyramidal motor adverse effects of neuroleptics, tremor syndrome Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" or Wilson disease and/or useful for treatment of adverse effects in patients with idiopathic Parkinson's disease or syndrome, Parkinson's, including pharmaceutical compositions, as described below, is preferably used in doses of from 0.1 to 100 mg, preferably between about 1 and 20 mg of the Composition may be applied one or more times a day, for example 2, 3 or 4 times daily. Certain dose for each patient depends on all kinds of factors, such as the effectiveness of certain connections in use, the age, body weight, General health, sex, diet, time and route of administration, rate of excretion, the pharmaceutical combinations of substances and the severity of the specific disorder, belongs to therapy. Oral administration is preferable, but can also be used parenteral use (e.g., intravenous or percutaneous).

Antiparkinsonian drugs are common medications, such as 1-DOPA (levodopa) and 1-DOPA in combination with benserazida (benserazide) or carbidopa, dopamine agonists such as parlodel, apamo the fin, cabergoline (cabergoline), pramipexol (pramipexol), ropinirole (ropinirol), pergolid (pergolide), dihydro-α-ergocryptine or Liguria (liswide) plus all drugs acting via stimulation of dopamine receptors, inhibitors of catechol-O-methyl transferase (COMT), such as entacapone (entacapone) or tolkapon (tolcapone), inhibitors monoamine oxidase (MAO)such as selegiline (selegiline) and receptor antagonists N-methyl-D-aspartate (NMDA), such as amantadine or BODIPY (budipine).

Adverse effects of these antiparkinsonian drugs are all kinds of dyskinesias, such as hareesa, dystonic, ballistic and myoclonic dyskinesia, as well as motor (response) oscillations or psychotic state.

Therefore, the present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicine for treatment of adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease.

Treatment of adverse effects of conventional anti-Parkinson drugs, as described above, determine on the variety of animal model parkinsonism cynomolgus monkeys in accordance with P.J. Blanchet and others, E is R. Neurology 1998; 153: 214-222. Monkeys do patients with Parkinson's disease through repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR). Monkeys, parkinsonism patients, constantly treat standard 1-DOPA therapy in accordance with P.J. Blanchet and others, Mov. Disord., 1998; 13: 798-802. Long-term treatment with the drug 1-DOPA causes extrapyramidal motor side effects and psychotic conditions that are determined both qualitatively and quantitatively, using a scale of Abnormal Involuntary Movements (P.J. Blanchet and others, Mov. Disord. 1998; 13: 798-802) for various parts of the body (face, neck, torso, each limb) and assessing psychotic state, watching the attention of the monkeys, reactivity and mobility of the apes. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman fully reduced choreiform dyskinesia and dystonic dyskinesias, as well as a psychotic state.

A typical study to investigate the effectiveness of the compounds in accordance with the invention for adverse effects in Parkinson's disease is described as follows. 40 patients of either sex with advanced idiopathic Parkinson's disease complicated by dyskinesia "peak dose", take part in a double-blind crossover trial. The main criterion in the your is-Hyun and Yar stage ≥ 2,5 (lit.: Hoehn H.M. and other Neurology 1967; 17: 427-442), aged 40-75 years, symptom duration of at least 5 years and the duration of drug treatment, 1-DOPA for at least 3 years.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, or placebo accept as "adding" to the usual treatment of Parkinson's disease, which support unchanged during the whole study. Dose-blind treatment titrated over a 3-week period in the range from 2.5 to 10 mg twice a day. Then the treatment is kept constant within 1 week. Before titration and at the end of the treatment period provocative dose of 1-DOPA perform in accordance with R. Damier and others (Movement Disord, 1999, 14 (top), 54-59), using a video. The main resultant unit Protocol is an average assessment of dyskinesia during the first hour in the "on" state after the provocative dose of 1-DOPA. Therefore, the researcher every minute assesses the severity of dyskinesia (0=absent, 4=strong blocking involuntary movements) from 0 to 4 in seven parts of the body (upper and lower extremities, face, trunk, neck). After a two-week washout period of two branches of study cross and the Protocol repeated. Statistical analysis the average assessment of dyskinesia demonstrates the value is positive clinical improvement in the treatment of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride. The preferred salt of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the present invention relates to the use for the manufacture of a medicine for treatment of adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the present invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its biocompatible salts or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its biocompatible salts together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for the treatment of adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease.

Moreover, the present invention relates to the use of the mode (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its biocompatible salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its biocompatible salts for the manufacture of medicinal tools for the treatment of idiopathic Parkinson's disease.

Typical animal model for idiopathic Parkinson's disease is Parkinsonia cynomolgus monkey in accordance with P.J. Blanchet and others, Exp.Neurology 1998; 153: 214-222. Monkeys do patients with Parkinson's disease through repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR). Parkinsonism symptoms qualitatively evaluated by applying the Scale of Disability from the University of Laval (B. Gomez-Mancilla and others, 1993; Mov. Disord. 8: 144-150), measuring the following symptoms: posture, mobility, Slobodyan, gait, holding food, pronunciation of words, bringing the proper form, social interaction. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman reduced all symptoms of Parkinson's disease and increased General activity,

A typical study to investigate the effectiveness of the compounds in accordance with the invention in the treatment of a foolish Parkinson's disease is described as follows. 180 patients of either sex with idiopathic Parkinson's disease participated in a double blind study. The main criterion for inclusion is stage-Hyun and Yar ≥2,0 (Hoehn H.M. and other Neurology 1967; 17: 427-442) aged 50-80 years, symptom duration of at least 5 years.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine the]-chroman hydrochloride, or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman, or placebo accept as "adding" to the usual treatment of Parkinson's disease, which support unchanged during the whole study. Dose-blind treatment titrated over a 4-week period in the range from 2.5 to 10 mg twice a day. Then the treatment is kept constant within 1 week. Before starting the titration, at the end of the treatment period and 2 weeks after the end of the titration perform the evaluation of each patient using a Standardized ratings Scale for Parkinson's Disease (UPDRS part I to V according to S. Fahn and others, in: Recent developments in PA's disease, volume 2, MacMillan health information 1987, 153-163). This allows you to define a positive effect (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its biocompatible salts or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its biocompatible salts, in particular (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, gross motor function, dystonia, motor fluctuations and psychosis. Moreover, the effectiveness of the treatment of tremor shown by UPDRS. Statistical analysis of UPDRS assessment demonstrates significant clinical improvement when Leche is NII (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethyl-aminomethyl]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the present invention relates to the use for the manufacture of a medicine for the treatment of idiopathic Parkinson's disease, in which the physiologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the present invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its biocompatible salts or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its biocompatible salts together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for the treatment of idiopathic Parkinson's disease.

The limiting factor in the treatment of Parkinson's disease with 1-DOPA and/or dopamine agonists is the frequent occurrence of psychosis or dyskinesia and other motor fluctuations.

It was found that (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt amplify the antiparkinsonian effect of antiparkinsonian drugs, as described above, does not cause the extrapyramidal side effects.

So dobavitelj therapy (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt and/or treatment (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt, in particular their hydrochloride, now opened up the possibility to increase the dose of 1-DOPA and/or dopamine agonists and/or all other antiparkinsonian drugs, as described above, in order to neutralize the periods of lack of mobility ("off" phase), without causing the above side effects. This represents a completely new approach in the treatment of Parkinson's disease, which leads to a significant improvement of patients.

Thus, the invention relates to pharmaceutical compositions comprising as active substance: (i) (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt, and (ii) at least one anti-Parkinson medication in combination with one or more pharmaceutically acceptable fillers.

Especially the invention concerns pharmaceutical compositions comprising as active substance (i) (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-f is arvanil)-3-pyridylmethylamine]-chroman hydrochloride, and (ii) 1-stage or 1-DOPA together with benserazida or carbidopa in combination with one or more pharmaceutically acceptable excipients.

Thus, the ratio of the respective amounts of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its physiologically acceptable salts and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its physiologically acceptable salts and conventional anti-Parkinson drug change in values. Preferably the weight ratio (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its biocompatible salts or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its physiologically acceptable salts by conventional anti-Parkinson drug varies from 1:1 to 1:100, preferably from 1:10 to 1:90, and more preferably from 1:40 to 1:60.

Another objective of the present invention is, in addition, the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its physiologically acceptable salts, or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or one of its physiologically acceptable salts in combination with at least one anti-Parkinson drug to obtain combinations of drugs designed to increase the antiparkinsonian effect of the decree is different antiparkinsonian drugs.

In accordance with the invention, the term "pharmaceutical combination", as implied, is or pharmaceutical compositions, as defined above, in which the two active substances or compounds are the main components of the same composition, or kit, comprising two separate compositions, the first of which includes the (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its physiologically acceptable salts as the only active substance, and the second of which includes, at least one antiparkinsonian drug as the active connection.

In accordance with the invention, the term "pharmaceutical combination", as implied, is or pharmaceutical compositions, as defined above, in which the two active substances or compounds are the main components of the same composition, or kit, comprising two separate compositions, the first of which includes (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or one of its physiologically acceptable salts as the only active substance, and the second of which includes at least one antiparkinsonian drug as the active connection.

When drug combination is represented as a set, the reception of two compositions, costal is operating this set, although they performed separately, occurs simultaneously for combination therapy. Preferred is the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane as hydrochloride.

In addition, adverse effects of antiparkinsonian drugs, as described above, known especially for the syndromes of Parkinson's disease.

The syndromes of Parkinson represent, for example, multiplane system atrophy (MSA), the syndrome Steele-Richardson-Alapaevskogo (=a syndrome of progressive supranuclear paralysis), cortical-basal degeneration, olivopontocerebellar atrophy or chronic idiopathic hypotension (Shy Drager syndrome).

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or a physiologically acceptable salt and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt is useful for the treatment of syndromes of Parkinson's, especially multiplane system atrophy.

Therefore, the present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of blagopriyatnyh effects syndromes Parkinson's.

In addition, the present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of syndromes of Parkinson's disease.

Typical animal model is reserpinized rat or mouse (for example, M.S. Starr and B.S. Starr, J. Neural Transm. - Park. Dis. Dement. Sect., 1994; 7: 133-142; M. Gossel, etc., J. Neural Transm. - Park. Dis. Dement. Sect., 1995; 10: 27-39; NR Hughes and others, Mov. Disord., 1998; 13: 228-233). Reserpine is a strong absorber of monoamines and leads to almost complete akinesia in both species. Within 24 hours after applying the distance and activity time are almost zero when measured at normal meter activity.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt dose-dependently reduced akinesia, has regained the distance and activity time approximately to the level of a normal animal.

Another more modern animal model is the approach striatonigral degeneration in rats in accordance with G.K. Wenning, etc., J. Neural Transm. Suppl., 1999; 55: 103-113. Rats get od is storonniy injection 6-hydroxydopamine in the left medial beam forebrain, which is accompanied by the injection of quinolinic acid in the ipsilateral striatum, causing striatonigral degeneration. Degeneration leads to directed behavior to the provocative dose dopaminemediated means, such as apomorphine or amphetamine. Facing the behavior is measured using an automated recording device. Facing the behavior induced by apomorphine or amphetamine, dozozawisimo protivodejstvuet (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt.

Multiplane system atrophy (MSA) is due to extensive neurodegeneration in the extrapyramidal and autonomic nervous system, which leads to akineticalkie parkinsonism syndrome with autonomic disorders. In contrast to idiopathic Parkinson's disease the density of Central dopamine receptors is markedly reduced, and therefore, MSA patients react poorly to dopaminergic drugs. Since (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt act mainly through the receptors of serotonin n the extrapyramidal system they are able to improve motor characteristic in contrast to the majority of untreated patients.

A typical study to investigate the effectiveness of the compounds in accordance with the invention, in MSA patients includes 30 patients of either sex with symptom duration of at least 5 years and a significant reduction of Central dopamine receptors on the scan positron emission tomography (PET). The model study is similar to that described above for Parkinson's disease.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, or placebo titrated as "adding" to the usual treatment (doses ranging from 2.5 to 20 mg twice a day). Before titration and at the end of the treatment period full UPDRS assessment carried out in each patient (the primary measure of outcome). After a 2-week washout period of two branches of study cross and the Protocol repeated. Statistical analysis of UPDRS demonstrates significant clinical improvement in the treatment of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicine for treatment of adverse effects is antiparkinsonicheskih drugs in the syndromes of Parkinson's disease, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicine for treatment of adverse effects of antiparkinsonian drugs in the syndromes of Parkinson's disease, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for treatment of adverse effects of antiparkinsonian drugs in the syndromes of Parkinson's disease.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of syndromes of Parkinson's disease, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride. Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of syndromes Parkin is she, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for treatment of syndromes of Parkinson's disease.

The present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and/or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of dyskinetic and/or horiatiki syndromes.

Dyskinetic and/or horiatiki syndromes represent, for example, Huntington's disease, rheumatic horey or horey pregnancy.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt is particularly useful for cured is I the case of Huntington's disease.

Typical animal model is a system model 3-nitropropionic acid (3-NP) rats in accordance with C.V. Borlongan, etc., Brain Res., 1995; 697: 254-257. Rats inject selective veins of the neurotoxin 3-NP intraperitoneally every third day (C.V. Borlongan et al. Brain Res. Protocols, 1997; 1: 253-257). After two injections of 3-NP rats show night hyperactivity, showing the early symptoms of Huntington disease, whereas rats treated with four injections of 3-NP, show night akineziyu (underactive), showing symptoms of late disease Huntington. Nocturnal activity is automatically measured in normal cell activity using infrared rays. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt reduce night as hyperactivity and night akineziyu.

A typical study to investigate the effectiveness of the compounds in accordance with the invention, for horei, voluntary motor action, and functional disability in patients with Huntington disease includes 32 genetically diagnosed patient. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydro is lurid, or placebo taken as "adding" to the usual treatment, which supports unchanged during the whole study. Dose-blind treatment titrated over a 3-week period in the range from 2.5 to 20 mg twice a day. Then the treatment is kept constant within 1 week. Evaluation do the week before and on the last day of the study. Horey assessed using the Scale Abnormal Involuntary Movements (AIMS, Guy W., in: ECDEU assessment manual. Rockville MD: US dept. of health, education and welfare, 1976: 534-537), Standardized Assessment Scale Disease Huntington's disease (UHDRS, Huntington study group, 1996, Movement Disord, 11:136-42) and assessment videos. Arbitrary locomotor activity assessed using the UHDRS motor scale. Patients and their partners completed the questionnaire on functional disability. Statistical analysis demonstrates a significant improvement in voluntary and involuntary motor action in patients suffering from Huntington disease, in the treatment of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine] -chroman hydrochloride.

So the WMD invention relates to the use for the manufacture of a medicinal product for the treatment of dyskinetic and/or horiatiki syndromes in particular for the treatment of Huntington's disease, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

The preferred salt of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of dyskinetic and/or horiatiki syndromes, in particular for the treatment of Huntington's disease, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for treatment of dyskinetic and/or horiatiki syndromes.

The present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethyl aminomethyl]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of dystonic syndromes.

Dystonic syndromes are, for example, spastic torticollis, writing cramp, blepharospasm, Meigs syndrome or dopustila dystonia. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt is particularly useful for the treatment of spastic Krivoshei and/or blepharospasm.

Typical animal model is a mutant dystonic hamsters in accordance with A. Richter and W. Loscher, Prog. Neurobiol. 1998; 54: 633-677. These genetically dystonic hamsters dystonic seizures are caused when you take an animal from a permanent cell and put it on the balancer. Dystonic syndrome consists of a sequence of abnormal movements, and severity of individual symptoms assessed through a system of quantitative indicators.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt dose-dependently reduces the severity of dystonic symptoms.

To demonstrate the effectiveness of compounds in accordance with the invention dystonic syndromes, double-blind, placebo-controlled study performed on patients who have cervical dystonia (spasmodic torticollis), who do not tolerate the injection of botulinum toxin. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride titrated as described above, in the interval from 2.5 to 20 mg twice a day. Western Assessment Scale Spastic Krivoshei Toronto (TWSTRS, C.L Cornelia and others, 1997, Movement Disord, 12: 570-575) is used as the primary measure of outcome. Significant improvement in TWSTRS estimates observed for patients who were treated with (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of dystonic syndromes, particularly spastic Krivoshei and/or blepharospasm, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

The preferred salt of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine] -chroman hydrochloride.

p> Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of dystonic syndromes, particularly spastic Krivoshei and/or blepharospasm, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for treatment of dystonic syndromes.

The present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of extrapyramidal symptoms induced by neuroleptics.

Extrapyramidal movement disorders caused by neuroleptics, are, for example, early dyskinesia, dystonia, akathisia, parkinsonia (parkinsonoid), especially bradykinesia, or the late is I dyskinesia.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt is useful especially for the treatment of akathisia and/or tardive dyskinesia and/or parkinsonia.

Typical animal model is caused by neuroleptics muscle rigidity in rats in accordance with Wolfarth S., and others, Arch. Pharmacol. 1992; 345: 209-212. Rats inject provocative doses of conventional neuroleptics haloperidol, which increases muscle tone. Muscle tone electromehanichesky measured as resistance to passive flexion and extension of the hind limbs. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt reduce muscle tone, increased by haloperidol.

Another common animal model is sensitized brain monkey in accordance with D.E. Casey, Psychopharmacology, 1996; 124: 134-140. Monkeys repeatedly received injections of conventional neuroleptics, are highly sensitive to subsequent provocative dose neuroleptika drugs. After the introduction of the provocative dose monkeys immediately show extraer Minnie musculoskeletal side effects such as dystonia, dyskinesia, akathisia, and bradykinesia, which is assessed through a system of quantitative indicators. Conventional neuroleptique drug haloperidol give as a provocative test. When there are mentioned above extrapyramidal motor side effects, use (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt; (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman dose-dependently reduce extrapyramidal motor side effects.

Late dyskinesia is a common adverse effect of long-term treatment with neuroleptics. A typical study to investigate the effectiveness of the compounds in accordance with the invention when tardive dyskinesia is described as follows. The study involved 32 schizophrenic (DSM-III-R) of patients undergoing hospital, aged 25-60 years, for long continuous antipsychotic treatment (duration of at least 5 years). (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, or (8)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, or placebo taken as "to the t" to antipsychotic treatment, which support unchanged during the whole study. Dose-blind treatment titrated over a 3-week period in the range from 2.5 to 20 mg twice a day. Then the treatment is maintained under conditions of double-blind study within 2 weeks. After a 2-week washout test drugs cross. Assessment of tardive dyskinesia using a scale of abnormal involuntary movements (AIMS, see above) and parkinsonism extrapyramidal side effects (UPDRS, see above) are pre-and after treatment. AIMS of the evaluation during treatment (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride are significantly lower than during the placebo period.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of extrapyramidal symptoms induced by neuroleptics, particularly akathisia and/or tardive dyskinesia, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

The preferred salt of (S)-(+)-2-[5-(4-forfinal)-3-PIR is dimethylaminomethyl]-chromane is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of extrapyramidal symptoms induced by neuroleptics, particularly akathisia and/or tardive dyskinesia, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for treatment of extrapyramidal symptoms induced by neuroleptics.

The present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of tremor.

Tremor includes all types of tremors, such as essential tremor, activated physiological tremor, cerebellar tremor, orthostatic tremor or tremor, caused by medication is I.

(R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt is particularly useful for the treatment of essential tremor and/or tremors caused by medicine.

Typical animal models used or genetically mutated animals or are models where the tremor causes a pharmacological agent (for review: N. Wilms and other Mov. Disord., 1999; 14: 557-571).

Typical genetic models in mutant animals are syndrome Campus in Pietrain pigs in accordance with A. Richter and others (Exp.Neurology, 1995; 134: 205-213) or Weaver mutant mouse in accordance with J.R. Simon and B. Ghetti (Mol. NeurobioL, 1994; 9: 183-189). In the model syndrome Campus these mutant pigs show a high frequency tremor when standing and during locomotion, but not while lying at rest. Assessment of tremor performed using accelerometric account. The Weaver mutant mouse degenerative cerebellar atrophy was found in conjunction with tremor, gait instability and loss of balance after a few steps. The instability of gait and loss of balance leads to dramatically reduced motor activity, measured distance and the time spent walking in normal cell activity.

(/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt improves syndrome Campus in Pietrain pigs, i.e. it reduces the disabling tremor when standing and during locomotion, and increases locomotor activity in Weaver mutant mouse.

Typical animal model for tremors caused by medicine, is oxotremorine-induced tremor (e.g., N. Hallberg and O. Almgren, Acta Physiol. Scand., 1987; 129: 407-13; J.G. Clement and W.R. Dyck, J. Pharmacol. Meth., 1989; 22: 25-36). Oxotremorine causes tremor, which measured by rating scales. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt inhibit oxotremorine-induced tremors.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of tremors, especially of essential tremors and/or tremors caused by medicine, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

The preferred salt of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention cases the use for the manufacture of a medicinal product for the treatment of tremors, in particular, essential tremors and/or tremors caused by medicine, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for treatment of tremor.

The present invention concerns the use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders selected from the group consisting of a syndrome of Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" and Wilson disease.

Typical animal model for myoclonus myoclonus is caused by acute hypoxic attack in accordance with D.D. Truong and others, Mov. Dsiord., 1994; 9: 201-206. In this model posthypoxic is of myoclonus rats subjected to cardiac arrest within 8 minutes and then revive. Myoclonic seizure movements occur spontaneously, but can be caused by auditory stimulation, as well whodas in the following days after the heart stops. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt dose-dependent decrease the number of spontaneous and caused by auditory stimulation myoclonic seizure movements.

The preferred salt of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders selected from the group consisting of a syndrome of Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" and Wilson disease, in which the pharmacologically acceptable salt is (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

The preferred salt of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

Therefore, the invention concerns the use for the manufacture of a medicinal product for the treatment of ekstrapiramidna the movement disorders, selected from the group consisting of a syndrome of Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" and Wilson disease, in which the pharmacologically acceptable salt is (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride.

In addition, the invention relates to the use of pharmaceutical compositions containing at least one connection (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt together with at least one solid, liquid or semi-liquid excipient or auxiliary substance for the treatment of extrapyramidal movement disorders selected from the group consisting of a syndrome of Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" and Wilson disease.

Extrapyramidal movement disorders such as syndrome Steele-Richardson-Olszewski (=a syndrome of progressive supranuclear paralysis), cortical-basal degeneration, olivopontocerebellar atrophy, chronic idiopathic hypotension, rheumatic chorea, chorea of pregnancy, writing cramp, blepharospasm, Meigs syndrome, DOPA-responsive dystonia. The syndrome of Gilles de La Tourette, shaking palsy, m is oconus, syndrome "tired legs" and Wilson's disease, occur often enough to conduct regular double-blind studies. However, the health needs in this area require immediate action, so far not available no adequate therapy.

So open study of a few selected patients is an adequate method to demonstrate the effectiveness of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt.

All the pharmaceutical compositions used for the treatment of extrapyramidal movement disorders and/or for treatment of adverse effects of antiparkinsonian drugs for extrapyramidal motor disorders, including drug combination, can be used as drugs in the treatment of human or in veterinary medicine.

Compositions of the invention are preferably used parenteral or more preferably orally, although other routes of application, such as rectal use, are excluded.

Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral),parenteral or topical application and which do not react with (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromanol or its physiologically acceptable salt, for example, water, vegetable oils, benzyl alcohols, alkalophile, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or vaseline. The forms that are used for oral administration are, in particular, tablets, pills, tablets, coated with a sugar shell, capsules, powders, granules, syrups, liquids or drops, forms for rectal injection are, in particular, suppositories, forms for parenteral administration are, in particular solutions, preferably solutions of oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and forms for local use are transdermal patches, ointments, creams or powders. (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or its physiologically acceptable salts can also be lyophilized and the resulting lyophilizate used, for example, to get injectables. These preparations can be sterilized and/or may include excipients, such as sliding substances, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying OSMO is practical pressure, buffer substances, colorants, flavorings and/or other active ingredients, for example one or more vitamins.

Drugs if necessary, can be designed for slow release (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt.

The following examples relate to pharmaceutical products:

Example: Vials

the pH of a solution prepared from 100 g of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt and 5 g of sodium hydrogen phosphate in 3 l of bidistilled water, adjusted to 6.5 using 2N hydrochloric acid, the resulting solution is filtered under sterile conditions, distributed into vials lyophilizer under sterile conditions and sealed under sterile form. Each vial contains 5 mg of active substance.

Example: Suppositories

A mixture of 20 g (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and cooled. Each suppository contains 20 mg of active substance.

Example: Solution

A solution is prepared from 1 g of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or it is physiologically acceptable salts, 9,38 g NaH2PO4·2H2O, 28,48 g Na2HPO4·N2O and 0.1 g benzalkonium chloride in 940 ml of bidistilled water. the pH of the mixture was adjusted to 6.8, and the solution volume was adjusted to 1 l and sterilized by irradiation. This solution can be used as eye drops.

Example D: Ointment

500 mg of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt is mixed with 99.5 g of vaseline under sterile conditions.

Example E-1: Tablets

A mixture of 1 kg of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed accepted way to obtain tablets each containing 10 mg of active substance.

Example E-2: Tablets

A mixture of 20 g (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, 1 kg, 1-stage, 250 g benserazida, 4 kg of lactose, 1.6 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed accepted way of obtaining tablets, each containing 0.2 mg of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman hydrochloride, 10 mg of 1-DOPA and 2.5 mg benserazida.

Example F: Tablets with sugar coating

Analogously to Example E tablets pressed, and then they accepted way put a coating of sucrose, SD card is compulsory starch, talc, tragakant and dye.

Example G: Capsules

2 kg (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts distribute the conventional way in hard gelatin capsules so that each capsule contains 20 mg of active substance.

Example N: Ampoules

A solution of 1 kg of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt in 60 l of bidistilled water is sterile filtered, distributed in ampoules, lyophilizer under sterile conditions and sealed under sterile form. Each ampoule contains 10 mg of active substance.

Example I: Aerosol for inhalation

14 g (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salt is dissolved in 10 l of isotonic NaCl solution and the resulting solution is filtered in a commercially available pump-drive capacity for aerosol. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg

1. The use of (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or their physiologically acceptable salts for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders.

2. The use according to claim 1, in cat the rum extrapyramidal motor disorders are the adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease.

3. The use according to claim 2, in which the adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease are motor fluctuations.

4. The use according to claim 2, in which the adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease represent dyskinesia.

5. The use according to claim 4, in which the specified dyskinesia is a dyskinesia associated with treatment of Parkinson's disease.

6. The use according to claim 4, in which the specified dyskinesia is a dyskinesia induced by levodopa in Parkinson's disease.

7. The use according to claim 2 to 6, in which the anti-Parkinson drug is selected from the group comprising L-Dopa (levodopa), L-Dopa in combination with benserazida or carbidopa, dopamine agonists, such as bromocriptine, apomorphine, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or Liguria plus all drugs acting via stimulation of dopamine receptors, inhibitors of catechol-O-methyl transferase (COMT), such as entacapone or tolkapon, monoamine oxidase inhibitors (MAOIS)such as selegiline and receptor antagonists N-methyl-D-aspartate (NMDA), such as amantadine or BODIPY.

8. The use according to claim 7, wherein said antiparkinsonian drug is a L-Dopa.

9. Use the .1, in which extrapyramidal motor disorders represent undesirable effects of antiparkinsonian drugs for Parkinson's disease.

10. The use according to claim 9, in which the anti-Parkinson drug is selected from the group comprising L-Dopa (levodopa), L-Dopa in combination with benserazida or carbidopa, dopamine agonists, such as bromocriptine, apomorphine, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or Liguria plus all drugs acting via stimulation of dopamine receptors, inhibitors of catechol-O-methyl transferase (COMT), such as entacapone or tolkapon, monoamine oxidase inhibitors (MAOIS)such as selegiline and receptor antagonists N-methyl-D-aspartate (NMDA), such as amantadine or BODIPY.

11. The use of claim 10, wherein said antiparkinsonian drug is a L-Dopa.

12. The use according to claim 1, in which extrapyramidal motor disorders represent dyskinesia and honeycake syndromes, such as Huntington's disease.

13. The use according to claim 1, in which extrapyramidal motor disorders are dystonic syndromes.

14. The use according to claim 1, in which extrapyramidal motor disorder represents a late dyskinesia.

15. The use according to claim 1, in which extrapyramidal motor is the second disorder is a tremor.

16. The use according to claim 1, in which extrapyramidal movement disorders selected from the group consisting of a syndrome of Gilles de La Tourette, shaking palsy, myoclonus syndrome "tired legs" and Wilson disease.

17. Pharmaceutical composition for the treatment of extrapyramidal movement disorders, including therapeutically effective amounts of the active substance (i) (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or their physiologically acceptable salt and (ii) at least one anti-Parkinson medication in combination with one or more pharmaceutically acceptable excipients.

18. The composition according 17 to enhance ANTIPARKINSONISM effect of antiparkinsonian drug.

19. The composition according to 17 or 18, in which at least one traditional antiparkinsonian drug is selected from the group comprising L-Dopa (levodopa), L-Dopa in combination with benserazida or carbidopa, dopamine agonists, such as bromocriptine, apomorphine, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or Liguria plus all drugs acting via stimulation of dopamine receptors, inhibitors of catechol-O-methyl transferase (COMT), such as entacapone or tolkapon, inhibitors of monoamine oxidase (MAO), is as selegiline and receptor antagonists N-methyl-D-aspartate (NMDA), such as amantadine or BODIPY.

20. The composition according to claim 19, in which at least one traditional antiparkinsonian drug is a L-Dopa.

21. Used in therapeutically effective amounts of (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane or its physiologically acceptable salts together with at least one anti-Parkinson drug to obtain the combined drugs.

22. Use item 21, in which at least one antiparkinsonian drug is selected from the group comprising L-Dopa (levodopa), L-Dopa in combination with benserazida or carbidopa, dopamine agonists such as bromocriptine, apomorphine, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or Liguria plus all drugs acting via stimulation of dopamine receptors, inhibitors of catechol-O-methyl transferase (COMT), such as entacapone or tolkapon, monoamine oxidase inhibitors (MAOIS)such as selegiline and receptor antagonists M-methyl-O-aspartate (NMDA), such as amantadine or BODIPY.

23. The application of article 22, in which at least one antiparkinsonian drug is a L-Dopa.

24. Set for the treatment of extrapyramidal movement disorders, comprising two separate compositions, in which the first contains therapeutically effectiveagainst (R/S)-(-/+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chroman or their physiologically acceptable salt as the sole constituent parts of active substance and the second contains a therapeutically effective amount of at least one antiparkinsonian drug as the active connection.

25. Set in paragraph 24, in which at least one antiparkinsonian drug is selected from the group comprising L-Dopa (levodopa), L-Dopa in combination with benserazida or carbidopa, dopamine agonists, such as bromocriptine, apomorphine, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or Liguria plus all drugs acting via stimulation of dopamine receptors, inhibitors of catechol-O-methyl transferase (COMT), such as entacapone or tolkapon, inhibitors of monoamine oxidase (MAO)such as selegiline and receptor antagonists N-methyl-D-aspartate (NMDA), such as amantadine or BODIPY.

26. Set A.25, in which at least one antiparkinsonian drug is a L-Dopa.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzothiazole of the general formula (I): and their pharmaceutically acceptable acid-additive salts used as ligands of adenosine receptors and to a medicinal agent based on thereof. In compound of the general formula (I) R means phenyl, pyridine-2-yl, -C(O)-O-(lower)-alkyl, -C(O)-(lower)-alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2 or -(CH2)n-O-(lower)-alkyl; R' means hydrogen atom or (lower)-alkyl. Compounds can be used in treatment and prophylaxis of diseases mediated by adenosine receptors A2A and A1, for example, in Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 sch, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

Fumaric acid amides // 2290946

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) wherein radicals R1, R2 and alk have values given in claim 1 of the invention claim. Compounds prepared by a method by claim 6 are important antagonists of 5-HT2A-receptors and can be sued in treatment psychosis, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's chorea, nutritional disturbances, such as bulimia, nervous-psychic anorexia, premenstrual syndrome and/or for the positive effect on obsessive-compulsive disorder.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 12 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention proposes a medicinal preparation for treatment of extrapyramidal disorders (Parkinson's disease, dyskinetic and choreic syndromes, in particular, Huntington chorea, dystonic syndromes, later dyskinesia, tremor, Gilles de la Tourette's disease, ballism, fatigue legs syndrome and Wilson's disease), and a pharmaceutical composition and a set for the same designation also. As a medicinal preparation invention proposes (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or its physiologically acceptable salt known early as a combined selective antagonist of dopamine D2 receptors and antagonist of serotonin receptor of 1A subtype. These properties and high affinity to D3 receptor show favorable effect on extrapyramidal and motor systems. Pharmaceutical composition and set comprise (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or its salt and a medicinal preparation against Parkinson's disease as active compounds. The compound (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman decreased extrapyramidal moving disorders caused by neuroleptics and enhanced their anti-parkinsonic effect, i. e. it shows property to diminish symptoms of Parkinson's disease and to enhance the general activity.

EFFECT: improved and valuable medicinal properties of compound and pharmaceutical composition.

26 cl, 10 ex

FIELD: pharmacology, in particular agent for treatment and/or prophylaxis of Parkinson disease or Parkinson syndrome.

SUBSTANCE: claimed agent includes compound improving astrocyte function as active ingredient, namely (R)-2-propyloctanoic acid, non-toxic salt or hydrate thereof. Method for production of claimed agent by using (R)-2-propyloctanoic acid also is disclosed.

EFFECT: agent for high effective treatment.

3 cl, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new agent with expressed selective activity with respect to central muscarinic acetylcholine receptors belonging to subtype M1. Agent represents 1-phenyl-1-(1'-methylcyclopentyl)-4-piperidino-2-butyne-1-ol hydrochloride of the formula (1) known early as low toxic cholinolytic. Agent expands a set of ligands used in research of mechanisms of the central nervous system function. Agent shows high capacity for penetration through blood-brain barrier, low toxicity and high effectiveness.

EFFECT: valuable medicinal properties of agent.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves applying system based on silicon. The system has a mixture of at least one silicon glue of high adhesiveness showing its effectiveness under press action and at least one silicon glue of moderate adhesiveness showing its effectiveness under press action as basic gluing ingredients. The transcutaneous therapy system has surface of 10 to 40 cm2 and comprises 0.1-3.15 mg/cm2 of Rotigotine in free base form as active ingredient for preparing antiparkinsonian drug. The present invention improves patient health state evaluated as 2 units or higher according to UPDRS, part II and III, when compared to placebo, during at least 7 weeks after injection as a result of improved Rotigotine release parameters and provided Rotigotine dose-activity relation optimum.

EFFECT: enhanced effectiveness of treatment.

13 cl, 2 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: invention proposes a medicinal preparation for treatment of extrapyramidal disorders (Parkinson's disease, dyskinetic and choreic syndromes, in particular, Huntington chorea, dystonic syndromes, later dyskinesia, tremor, Gilles de la Tourette's disease, ballism, fatigue legs syndrome and Wilson's disease), and a pharmaceutical composition and a set for the same designation also. As a medicinal preparation invention proposes (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or its physiologically acceptable salt known early as a combined selective antagonist of dopamine D2 receptors and antagonist of serotonin receptor of 1A subtype. These properties and high affinity to D3 receptor show favorable effect on extrapyramidal and motor systems. Pharmaceutical composition and set comprise (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or its salt and a medicinal preparation against Parkinson's disease as active compounds. The compound (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman decreased extrapyramidal moving disorders caused by neuroleptics and enhanced their anti-parkinsonic effect, i. e. it shows property to diminish symptoms of Parkinson's disease and to enhance the general activity.

EFFECT: improved and valuable medicinal properties of compound and pharmaceutical composition.

26 cl, 10 ex

The invention relates to a new one with selective affinity to T6receptors, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]triazines General formula I, where X denotes a =C(R4)- or =N-, R1denotes phenyl, optionally substituted by one or more radicals of lower alkyl, halogen, lower alkoxygroup, tolyl, pyridyl, naphthyl or thiophenyl, R2denotes hydrogen, (ness.)alkyl, (ness.)thioalkyl or hydroxy(ness.) alkoxygroup, R3denotes amino(ness.)alkylamino, di(ness.)alkylamino, piperazinil, optionally substituted by one or more radicals, lower alkyl, benzyl, phenyl or hydroxy(NISS

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with surgical, antiseptic, antiphlogistic and wound-healing glue that contains collagen hydrolyzate, sodium salt of alginic acid, catapol, dioxidin, poviargol; additionally, it contains glycerol, nipagin, nipasol and aqueous solution of sodium hypochlorite. The innovation provides increased antimicrobial activity and regulation of biodegradation rate of covering depending upon the level of inflammatory process in the wound that leads to faster wound healing.

EFFECT: higher efficiency of application.

4 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

9 cl, 1 tbl, 41 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

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