Novel using substituted aminomethylchromans in treatment of motion disorder or undesirable effect caused by agents that are administrated in treatment of extrapyramid motion disorder

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to drugs and concerns using (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and its pharmaceutically acceptable salts. This substance is used for preparing a drug used in treatment of undesirable effects of anti-parkinsonic drugs in idiopathic Parkinson's disease, in treatment of undesirable effects of anti-parkinsonic drugs in parkinsonic syndromes, and in treatment of extrapyramid symptoms caused by neuroleptics.

EFFECT: valuable medicinal properties of substance and drug.

12 cl, 10 ex

 

The present invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts, in particular (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salts for the preparation of drugs for the treatment of unwanted actions antiparkinsonian medications for extrapyramidal movement disorders and/or for the preparation of drugs for the treatment of extrapyramidal symptoms (EPS)induced by neuroleptics.

In applications EP-A-0352613, EP-A-0540914 and EP-A-0749970 described derivatives aminomethylpropanol suitable for prevention, protection of the Central nervous system for the treatment of education brain infarction (bleeding in the brain), such as stroke and cerebral ischemia.

therapeutic efficacy of the compounds described in this document, is unknown. The basis of aminomethylpropanol, which are used according to the invention described in application EP-A-0352613, EP-A-0540914 and EP-A-0749970.

Preferred compounds according to the present invention are compounds of General formula I

where

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is an on-benzosulfimide,

n=3 or 4;

and aminomethylpropanol General formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3or-och(CH3)2or

R1and R2together form a radical of the formula

n=1 and

R3represents a cyclohexyl or cycloheptyl.

More preferable compound (-)-(R)-2-(4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-diox the d is known from the application EP-A-0352613, example 92. This connection, to which we refer, is described in the patent as a receptor antagonist 5-HT1A. Therefore, describes the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salts for the preparation of medicines for the prevention and control of effects of a heart attack of the brain (cerebral haemorrhage), such as stroke and cerebral ischemia, for the prevention and regulation of cerebral disorders, such as migraine, for the treatment of anxiety, intense and depression, sexual disorders caused by Central nervous system, disorders of sleep or eating.

In the present invention compounds aminomethylpropanol formula I can be represented in a variety of stereoisomeric forms, for example in the form of their (+) or (-) enantiomers or as mixtures of these enantiomers (racemate). To separate the racemate into the enantiomers can be applied in various ways known in the art.

According to the present invention can also be applied physiologically acceptable salt. Physiologically acceptable salts of substituted 2-aminomethylpropanol formula I can be a salt of the compounds in accordance with the invention suitably is mi organic or inorganic acids, in particular mineral acids, carboxylic acids or sulphonic acids. More preferred salts are, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, econsultancy acid, toluensulfonate, benzosulfimide acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

The object of the invention is the provision of new applications substituted aminomethylpropanol formula I, in particular (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and its physiologically acceptable salts.

It was found that substituted aminomethane formula I, in particular (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or a physiologically acceptable salt, also have therapeutic activity against extrapyramidal movement disorders, such as dyskinetic, horiatiki or dystonic syndromes, tremor syndrome Gilles de La Tourette, krupnorazmernyj hyperkinesis limb myoclonus syndrome tired legs or Reye dystrophy, as well as extrapo the amide musculoskeletal disorders [synonym are extrapyramidal symptoms (EPS)], caused by neuroleptics.

Additionally, it was found that substituted aminomethane formula I, in particular (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or a physiologically acceptable salt, also have therapeutic activity against unwanted actions antiparkinsonian medications for extrapyramidal movement disorders, in particular in respect of dopaminemediated unwanted actions ANTIPARKINSONISM drugs in idiopathic Parkinson's disease or parkinsonism syndromes.

It was found that (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or physiologically acceptable salts possess extraordinary abilities in the reverse development of catalepsy. Extrapyramidal motor side effects, such as rodents, are caused by the ability of drugs to induce catalepsy. The catalepsy is the condition in which the animal for a long time is in an abnormal (non-physiological 'uncomfortable') position of the body (for example: ..Stanley and S.D.Glick, Neuropharmacology, 1996; 15: 393-394; C.J.E.Niemegeers and .Janssen, Life Sci., 1979, 201-2216). For example, if the hind paw of rats placed on a high level, for example on the platform, raised on cm above ground level, the normal rat immediately draws back his hind leg from the platform to ground level. Cataleptic rat remains in such an unnatural pose for several minutes.

Previously described beneficial effects on the extrapyramidal motor system for other drugs with agonist 5-HT1Aaction. For example, buspirone, which by nature is a sedative means detects moderate protivodiabeticheskie properties in patients with progressively Parkinson's disease (.Kleedorfer etc., J Neural Neurosurg Psychiatry, 1991, 54: 376-377; V.Bonifati and others, Clin Neuropharmacol, 1994, 17: 73-82). The primary mechanism of this action is obviously stimulation by receptor 5-HT1Areflex signal transduction pathways through the black body and striped body.

In rats, the value of the ED50when administered orally (that is, the calculated dose, which causes reverse the development of catalepsy by 50%) for monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is a 0.6 mg/kg, which unexpectedly is 30-100 times more effective compared with other agonists of 5-HT1Asuch as ipsapirone (ED5023 mg/kg), buspirone (ED5030 mg/kg), gepirone (ED5016 mg/kg) or tandospirone (ED5060 mg/kg).

Thus, the present image is the buy refers to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl,

or R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of extrapyramidal movement disorders.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Thus, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of extrapyramidal movement disorders.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide I have is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-he-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of extrapyramidal movement disorders, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl }-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of extrapyramidal movement disorders.

(-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or a physiologically acceptable salt is suitable for the treatment of ekstrapiramidnykh of movement disorders, in particular for the treatment of dyskinetic, heretically or dystonic syndromes, extrapyramidal motor side effects of neuroleptics, tremor syndrome Gilles de La Tourette, kupersmith hyperkinesias limb myoclonus, tired leg syndrome or Reye dystrophy and/or suitable for the treatment of unwanted actions in idiopathic Parkinson's disease or parkinsonism syndromes, including the following composition of medicines, and before occhialino injected in doses of 0.01 to 100 mg, preferably in the range of about 0.1 and 10 mg of the Composition can be administered in daily doses. Individual dose for each patient depends on many factors, such as the specific activity of the applied compound, the age, body weight, General health, sex, diet, time and route of administration, rate of excretion, combination of drugs, and the severity of the particular disease, which is treatable. Oral administration is preferred, but can also be used parenteral routes of administration (e.g. intravenous or intradermal).

ANTIPARKINSONISM drugs are standard drugs, such as 1-DOPA (levodopa and levodopa combined with benserazide or carbidopa, dopamine agonists, such as bromocriptine, aponogeton, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or lisuride, and all drugs that act by stimulating 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.

Undesirable actions specified ANTIPARKINSONISM karstenii funds include all types of dyskinesias, such as hareesa, dystonic, ballistic and myoclonic dyskinesia, motor (response) oscillations or psychotic state.

Therefore, the present invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs in idiopathic Parkinson's disease.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Consequently, the invention relates to the use of (-)-(R)2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs in idiopathic Parkinson's disease.

The treatment of unwanted actions standard antiparkinsonian drugs, as described above, was investigated in a modified animal model of parkinsonism in monkeys kind of Cynomolgus in accordance with P.J.Blanchet etc., Exp. Neurology 1998; 153: 214-222. In monkeys caused parkinsonism by repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR). Monkeys with Parkinson's disease were subjected to prolonged treatment with standard therapy with levodopa in accordance with P.J.Blanchet and others, Mov. Disord., 1998; 13: 798-802. Long-term treatment with levodopa caused ekstrapiramidnye musculoskeletal side effects and psychotic state that both qualitatively and quantitatively determined by using the scale abnormal involuntary movements (P.J. Blanchet and others, Mov. Disord. 1998; 13: 798-802) on different parts of the body (face, neck, torso, each limb) and by assessing psychotic States using observations of care, reactivity and mobility of the apes. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide was completely reduced the manifestation of honeycake forms of dyskinesia and dystonic dyskinesias, and psychotic States.

A typical survey to study the efficiency of the compounds according to the invention is relatively undesirable action in the treatment of Parkinson's disease is described next. 40 patients each floor with idiopathic progressive Parkinson's complicated "maximum" dyskinesia, participated in a double blind study. The main criterion is included phase Hoehn &Yahr > 2,5 (literature: Hoehn H.M. and al, Neurology 1967; 17: 427-442), the age of patients 40-75 years, the symptoms are observed in at least 5 years and the treatment of levodopa continues for at least 3 years. Monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or placebo was administered as a "Supplement" to the usual treatment of parkinsonism, which remained unchanged throughout the study. The blind dose medications were picked up within 3 weeks in the range from 2.5 to 10 mg by injection twice a day. Then for 3 weeks treatment remained constant. Before determining the dose and at the end of the treatment period the patients were recorded observations in map-diary with a thirty-minute intervals within 48 hours. In map-diary distinguish between 5 different stages: (1) to "on" without dyskinesia, (2) "on" with dyskinesia, harassing, (3) "on" with dyskinesia that does not cause anxiety, (4) "off" time, and (5) sleep (Nauser RA and others, Clin. Neuropharmacol., 2000, 23, 75-81). Primary outcome variable of the Protocol was a modification of "on" time of dyskinesia, when inauma anxiety. Statistical analysis of daily data indicates a significant reduction of "on" time with dyskinesia, harassing, in the treatment with the use of monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide, while the "on" time without dyskinesia increases significantly. Other parameters were not changed.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs in idiopathic Parkinson's disease, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of unwanted actions protivoparkinsonichesky what their drugs in idiopathic Parkinson's disease.

Restrictive factor in the treatment of parkinsonism with levodopa and/or dopamine agonists is often the emergence of psychosis or dyskinesia and other motor fluctuations.

It was found that (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt amplify the antiparkinsonian effect of antiparkinsonian drugs, as described above, without causing extrapyramidal side effects.

Therefore, additional therapy with the help of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salts, in particular monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide, now opens up the possibility of increasing doses of levodopa and/or dopamine agonists, and/or other antiparkinsonian drugs, as mentioned above, in order to neutralize periods of poor mobility ("off" phase) without provoking the above-mentioned side effects. This represents a completely new approach in the treatment of Parkinson's disease, providing a significant advantage for patients.

Thus, the invention relates to farmace the political composition, containing as active ingredients (i) (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt, and (ii) at least one anti-Parkinsonian drug, in combination with one or more pharmaceutically acceptable excipients.

More preferably, the invention relates to pharmaceutical compositions containing as active ingredients (i) monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and (ii) l-DOPA or levodopa in combination with benserazide or carbidopa in combination with one or more pharmaceutically acceptable excipients.

The ratio of the respective amounts of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its physiologically acceptable salts and normal antiparkinsonian drugs may be different. Preferably, the mass ratio (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its physiologically acceptable salts by conventional anti-Parkinsonian medicinal product is in the range from 1:1 to 1:100, preferably from 1:10 to 1:90, and most preferably from 1:40 to 160.

Another object of the present invention is, in addition, the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its physiologically acceptable salts in combination with at least one anti-Parkinsonian drug for the preparation of the combined drugs intended to enhance the antiparkinsonian action of these anti-Parkinsonian drugs.

According to the invention, the term "combination drug" refers to any pharmaceutical composition as described above, in which two active components or connections are components of a single composition, or kit, containing two separate compositions, the first of which contains (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its physiologically acceptable salts as the only active component, and the second contains at least one anti-Parkinsonian drug as the active connection.

If combined drug presented as a set, the introduction of two songs that make up this set, despite some implementation, is simultaneously the La combined therapy. Preferred is the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide in the form of monohydrochloride.

Undesirable actions ANTIPARKINSONISM drugs, as mentioned above, also known as parkinsonism syndromes.

Parkinsonism syndromes represent, for example, multiple system atrophy (MSA), the syndrome Steele-Richardson-Olzewski (= progressive supranuclear palsy), kortiko-basal degeneration, oligometastases atrophy or syndrome Shay-Drager.

Consequently, the invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of Les is artenova a treatment for unwanted actions ANTIPARKINSONISM drugs when parkinsonism syndromes.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Thus, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs when parkinsonism syndromes.

Conventional animal model are rezervirovannye 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; N.R.Hughes and others, Mov. Disord., 1998; 13: 228-233). Reserpine significantly depletes the amount of monoamines and especially formed when complete akinesia both species. It is known that 24 hours after the introduction of distance traveled and time of activity is approximately equal to zero, while under normal activity is meters. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt, depending on dose reduction akineziyu, i.e. restore the distance and time of the activity to the values observed in normal animals.

The other is more modern model animal is the approach involving the degeneration of the black and striped nuclei in rats in accordance with G.K.Wenning and others, J.Neural Transm. Suppl, 1999; 55: 103-113. Rats were subjected to unilateral conduct 6-hydroxydopamine in the left medial perednebokova beam with subsequent introduction of quinolinic acid in the striatum that are on the same side of the body, causing degeneration and black striped kernels. This degeneration is manifested in the spinning behavior, which is caused by the introduction of diaminopimelic, such as apomorphine or amphetamine. Spinning behavior is measured in an automated recording device. This turning behavior induced by apomorphine or amphetamine, counteracts depending on the dose of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt.

Multiple system atrophy (MSA) develops due to the extensive degeneration of neurons in the extrapyramidal system and the autonomic nervous system that leads to Parkinson's disease, accompanied by akinesia and autonomic disorders. In contrast to idiopathic disease of Parkinson density Central dopamine receptors significantly reduced, and therefore, MSA patients difficult to treat using dopaminergic drugs. Although (-)-(R-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt are mainly through serotonin receptors in the extrapyramidal system, they are able to improve motor activity in these patients, which in most cases are not amenable to other treatment.

Regular study to examine the effectiveness of the compounds according to the invention on patients with MSA was performed on 30 patients of each gender, in which the symptom lasted for at least 5 years and a significant decrease in Central dopamine receptor was confirmed using positron emission tomography (PET). The study was performed similar to the above for Parkinson's disease. Picked up a dose of monohydrochloride (-)-(R)-2-(4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or a placebo as add ons to conventional treatment (at doses of 1-20 mg three times a day). After a period of double-blind dose-dependent studies for 3 weeks, during which determined the individual dose for each patient based on tolerability and efficacy, the dose remained constant for 3 additional weeks. Before determining the dose and at the end of the treatment period for each patient performed a full assessment of the UPDRS (primary measured outcome). Statistical analysis of UPDRS showed significant clinical improvement for the symptoms of Parkinson's disease after treatment with monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2 is-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs when parkinsonism syndromes, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Additionally, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of unwanted actions ANTIPARKINSONISM drugs when parkinsonism syndromes.

The present invention also relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -OCH2CH3, -Och(CH3)2or With the 2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of dyskinetic and/or hereticism syndromes.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Consequently, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of dyskinetic and/or hereticism syndromes.

Dyskinetic and/or horiatiki syndromes represent, for example, Huntington's disease, small horey or horey pregnant. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt is in particular suitable for the treatment of diseases Hanti is gton.

Conventional animal model is a model of systemic injections of 3-nitropropionic acid (3-NP) rats in accordance with C.V.Borlongan and others, Brain Res., 1995; 697: 254-257. Rats were injected selective neurotoxin striatum of 3-NP intraperitoneally every third day (C.V.Borlongan and others, Brain Res. Protocols, 1997; 1: 253-257). After two injections of 3-NP in rats was observed night reflex symptoms of increased activity early Huntington's disease, whereas after four injections of 3-NP in rats was observed night reflex symptoms akinesia (low activity) late Huntington's disease. Nocturnal activity was automatically measured in normal cells for activity measurement using infrared rays. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt reduces as the night increased activity and akineziyu.

A common experience to study the action of the compounds according to the invention with trochaic to random motor activity and functional disability in patients with Huntington's disease was conducted on 32 patients with genetically confirmed diagnosis. Monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or placebo was administered as a "Supplement" to the usual treatment, which establishmentarianism throughout the study. Dose-blind drug was determined for 3 weeks in the range from 2.5 to 20 mg, with the introduction of twice a day. Then the drug was administered at a constant dose for 1 week. The evaluation was performed one week before and on the last day of testing. Assessment horey was performed using the scale, abnormal involuntary movements (AIMS, W.Guy, in: ECDEU manual implementation. Rockville, MD: Department of health, education and welfare, USA, 1976: 534-537), the uniform grading scale Huntington's disease (UHDRS, research group Huntington, 1996, Movement Disord, 11: 136-42), and evaluation of observations. Random motor activity was measured using the motor scale UHDRS. Patients and their assistants completed the questionnaire on functional disability. Statistical analysis of data showed significant improvement in voluntary and involuntary motor activity in patients with Huntington's disease after treatment with (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-on the oxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of dyskinetic and/or hereticism syndromes, in particular for the treatment of Huntington's disease, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Additionally, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of dyskinetic and/or hereticism syndromes.

The present invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -OCH2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of dystonic syndromes.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Consequently, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of dystonic syndromes.

Dystonic syndromes represent, for example, spasmodic Krivoshey, writing spasm, blepharospasm, syndrome Maga or Papaconstantinou dystonia. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salts are particularly suitable for the treatment of spasmodic Krivoshei and/or tonic blepharospasm.

Conventional animal model are mutant dystonic hamsters in accordance with A.Richter and W.Löscher, Prog. Neurobiol. 1998; 54: 633-677. These genetically dystonic hamsters dystonic attacks provoked when buying animals from cells and place them on the scale. Dystonic syndrome includes the sequence of abnormal movements and severity of individual symptoms assessed using metrics. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt, depending on the dose reduced the severity of dystonic symptoms.

To prove the effectiveness of the compounds according to the invention with dystonic syndromes conducted a double blind study with placebo control in patients with cervical dystonia (spasmodic torticollis), which do not tolerate the introduction of botulinum toxin. Picked up a dose of monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide as described above, using doses ranging from 2.5 to 20 mg twice a day. As the primary measured outcome used the scale spasmodic Krivoshei Toronto Western (TWSTRS, C.L. Cornelia and others, 1997, Movement Disord, 12: 570-575). Patients treated (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its pharmaceutically acceptable salts noted a significant improvement in the values of the scale TWSTRS.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran the-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-he-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of dystonic syndromes, in particular spasmodic Krivoshei and/or tonic blepharospasm, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Additionally, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of dystonic syndromes.

The present invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1 to 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of extrapyramidal symptoms induced by neuroleptics.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Consequently, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of extrapyramidal symptoms induced by neuroleptics.

Extrapyramidal disorders of movements caused by neuroleptics, are, for example, early dyskinesia, dystonia, akathisia, Parkinsonian state, in particular bradykinesia, or late dyskinesia.

(-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt is suitable in particular for the treatment of akathisia, and/or tardive dyskinesia, and/or Parkinsonian state.

Conventional animal model is muscle rigidity in rats induced by neuroleptics, in accordance with S.Wolfarth etc., Arch. Pharmacol. 1992; 345: 209-212. Rats were injected conventional neuroleptic is the drug haloperidol, what caused the increased muscle tone. Muscle tone was measured electromehanichesky as resistance to passive flexion and extension of the hind legs. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt reduced increased muscle tone caused by haloperidol.

Another common animal model are monkeys sensitized neuroleptics in accordance with D.E.Casey, Psychopharmacology, 1996; 124: 134-140. Monkeys subjected to repeated treatment with conventional neuroleptics, are very sensitive to subsequent provocative introduction of neuroleptic drugs. When provocation in monkeys immediately apparent extrapyramidal motor side effects such as dystonia, dyskinesia, akathisia and bradykinesia, which are measured using metrics. Conventional neuroleptic drug haloperidol is entered as a provocateur. If you observe the above extrapyramidal motor side effects, enter (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt; (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide dependent decreases in the minute dose extrapyramidal motor side effects.

Late dyskinesia is a common side effect with long-term treatment with neuroleptics. Regular study to examine the effectiveness of the compounds according to the invention when tardive dyskinesia is described below. The study was conducted on 32 patients with schizophrenia (DSM-III-R)who were hospitalized, age 25-60 years who were receiving long-term continuous antipsychotic treatment (which lasted at least 5 years). Introduced monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or a placebo as "additions" to antipsychotic treatment, which remained constant throughout the study. The blind dose medications were picked up for 3 weeks in the range from 1 to 20 mg three times a day. Then the introduction of drugs was carried out in conditions of double-blind study within 2 weeks. After two weeks of hatching were passed on to the introduction of the tested drugs. Assessment of tardive dyskinesia by using the scale abnormal involuntary movements (AIMS, see above) and parkinsonism extrapyramidal side effects (UPDRS, see above) was performed before and after treatment. The scale AIMS during treatment with monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran--yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide were significantly lower than the period of the introduction of a placebo.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H˜benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of extrapyramidal symptoms induced by neuroleptics, particularly akathisia and/or tardive dyskinesia, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Additionally, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of ekstrapiramidnykh symptoms induced by neuroleptics.

The present invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3 )2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of tremor.

More preferred compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Consequently, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of tremor.

Tremor includes all types of tremors, such as essential (familial) tremor, activated physiological tremor, cerebellar tremor, orthostatic tremor or tremor caused by drugs.

(-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salts are particularly suitable for the treatment of essential the first tremor and/or tremor, caused by drugs.

Conventional animal models are models that use either genetic mutant animals, or models in which the tremor is caused by pharmacological means (for review see: .Wilms and others, Mov. Disord., 1999; 14: 557-571).

Standard genetic models in mutant animals are syndrome Campus on the Pietrain pigs in accordance with A.Richter, and other (Exp. Neurology 1995; 134: 205-213) or mutant mouse Weaver in accordance with J.R.Simon and .Ghetti (Mol. Neurobiol, 1994; 9: 183-189). On the model of the syndrome Campus, these mutant pigs were observed intensity tremor when standing and moving, but not when lying down at rest. Tremor was assessed using accelerometric registration. In mice with a mutation Weaver degenerative cerebellar atrophy was detected in combination with tremor, unsteady gait, and tilting to the side a few steps. Unstable gait and tilting resulted in a significant decrease in locomotor activity, which was measured distance and the time required for taking up, in normal cells to measure activity.

(-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its pharmaceutically acceptable salts improve the course of the syndrome Campus in Pietrain pigs, i.e. reduce disability is serouse tremor when standing and moving, and increase the locomotor activity of the mutant mouse Weaver.

Conventional animal model for tremor caused by drugs is terror caused by oxotremorine (for example, .Hallberg and .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 is measured by using the scale of assessments. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino] butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its pharmaceutically acceptable salts inhibits the tremor caused by oxotremorine.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of tremors, in particular essential tremors and/or tremors caused by drugs, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Additionally, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-METI is]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of tremor.

The present invention relates to the use of substituted aminomethylpropanol formula I

in which

R1represents hydrogen,

R2represents hydrogen, hydroxyl or a radical of the formula-och3, -Och2CH3, -Och(CH3)2or-CH2C(CH3)2-Cl, or

R1and R2together form a radical of the formula

R3is cyclopentyl, cyclohexyl, cycloheptyl or following radical designated as on-benzosulfimide:

and

n represents 1, 2, 3, 4 or 5,

and their optical isomers and pharmaceutically acceptable salts for the preparation of drugs for the treatment of extrapyramidal movement disorders selected from the group comprising the syndrome of Gilles de La Tourette, krupnorazmernyj hyperkinesis limbs, myoclonus, tired leg syndrome or Reye dystrophy.

More predpochtitelnei compound of formula I is (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

Consequently, the invention relates to the use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2 is)-one-1,1-dioxide or pharmacologically acceptable salts for the preparation of drugs for the treatment of extrapyramidal movement disorders, selected from the group comprising the syndrome of Gilles de La Tourette, krupnorazmernyj hyperkinesis limbs, myoclonus, tired leg syndrome and Reye dystrophy.

Conventional animal model for myoclonus myoclonus is induced by acute hypoxia in accordance with D.D.Truong and others, Mov. Dsiord., 1994; 9: 201-206. In this model of posthypoxic myoclonus in rats is cardiac arrest within 8 minutes, and then reanimate them. Myoclonic seizures occur spontaneously, but can cause an audible stimulus, besides worsen after a few days after the heart stops. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its pharmacologically acceptable salts, depending on the dose reduced the number of spontaneous and induced sound myoclonic convulsions.

The preferred salt of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Consequently, the invention relates to the use for the preparation of drugs for the treatment of extrapyramidal movement disorders selected from the group comprising the syndrome of Gilles de La Tourette's, largest is sweeping hyperkinesis extremities, myoclonus, tired leg syndrome and Reye dystrophy, where the pharmacologically acceptable salt is monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide.

Additionally, the invention relates to use of pharmaceutical compositions containing at least one compound (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or one of its biocompatible salts for the treatment of extrapyramidal movement disorders selected from the group comprising the syndrome of Gilles de La Tourette, krupnorazmernyj hyperkinesis limbs, myoclonus, tired leg syndrome and Reye dystrophy.

Extrapyramidal movement disorders such as syndrome Steele-Richardson-Olzewski (= progressive supranuclear palsy), kortiko-basal degeneration, levomethamphetamine atrophy syndrome Shay-Drager, small chorea, chorea pregnant, writing spasm, blepharospasm, syndrome Maga, dopustila dystonia syndrome Gilles de La Tourette, krupnorazmernyj hyperkinesis limbs, myoclonus, tired leg syndrome and Reye dystrophy, not so often, in order to produce efficient, double-blind study. However, there is an urgent medical pot is ebest in this area, as there is currently no satisfactory treatment methods.

So open kategorirovanie observations of some selected patients are an adequate way to confirm the effectiveness of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt.

All the pharmaceutical compositions used for the treatment of extrapyramidal movement disorders and/or for the treatment of unwanted actions antiparkinsonian medications for extrapyramidal movement disorders, including combined drug can be used as pharmaceuticals in the treatment of human and in veterinary medicine.

The composition of the invention preferably injected parenterally or 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)cases, while parenteral transmission or topical application and do not react with (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and/or one of its biocompatible salts, for example water, vegetable oils, benzyl sleep is you, alkalophile, glycols, glyceroltrinitrate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc, vaseline. Forms, which are used for oral administration are, in particular, tablets, pills, tablets, sugar coating, capsules, powders, granules, syrups, solutions or drops; forms for rectal injection are suppositories; forms for parenteral administration are solutions, preferably oil-based or aqueous solutions, and also suspensions, emulsions or implants, and forms for local injection are transdermal patches, ointments, creams or powders. (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl] amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and/or one of its pharmaceutically acceptable salts can also be lyophilized and the resulting lyophilizate can be used, for example, for the preparation of injection preparations. The above-mentioned preparations can be sterilized and/or may include excipients, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsification, salts for modifying the osmotic pressure, buffer substances, colorants, flavorings and/or other active ingredients, for example one or more vitamins. The compositions can, if necessary, will dedicate the camping for slow release of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its biocompatible salts.

The following examples relate to pharmaceutical preparations

Example: Vials for injection

the pH of a solution of 100 g of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt and 5 g of Na2HPO4in 3 l of bidistilled water was set at 6.5 using 2 N. hydrochloric acid, sterilized by filtration, transferred into vials for injection, liofilizirovanny under sterile conditions and sealed under sterile conditions. Each vial for injection contains 5 mg of the active component.

Example: Suppositories

A mixture of 20 g of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt is melted with 100 g of soya lecithin and 1400 g of cocoa butter, the mixture was poured into molds and cooled. Each suppository contains 20 mg of the active component.

Example: Solution

The solution is prepared from 1 g of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt, 9,38 g NaH2PO4·2H2Oh, 28,48 g Na2HPO4·12 H2O and 0.1 g of benzylaniline in 940 ml of bidistilled water. the pH of the solution was set to 6.8, and the solution volume was brought to 1 l and sterilized by irradiation. the same solution can be used in the form of eye drops.

Example D: Ointment

500 mg of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl] amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt was mixed with 99.5 g of vaseline under aseptic conditions.

Example E-1: Tablets

A mixture of 1 kg of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide 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 alloy preformed in the usual way so that each tablet contained 10 mg of the active component.

Example E-2: Tablets

A mixture of 100 g of monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide, 1 kg of levodopa, 250 g benserazide, 4 kg of lactose, 1.6 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate alloy preformed in the usual way so that each tablet contained 5 mg of monohydrochloride (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide, 50 mg of levodopa and 12.5 mg benserazide.

Example F: Tablets with sugar coating

The alloy preformed mixture analogously to Example E and then the tablets were coated in the usual way by a coating of sucrose, potato starch, talc, tragakant and dye.

Example G: Capsules

2 kg (-)-(R)-2-{4-[[3,4-dihydro-2H-benzo is Piran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt was placed in hard gelatin capsules in a conventional way so each capsule contained 20 mg of the active component.

Example N: Ampoules

A solution of 1 kg of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt in 60 l of bidistilled water were sterilized filtered, transferred into ampoules, liofilizirovanny under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of the active component.

Example I: Aerosol for inhalation

14 g of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its physiologically acceptable salt was dissolved in 10 l of isotonic NaCl solution and the resulting solution was placed in a commercially available containers for aerosol with a pumping device. 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)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]-butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and its pharmaceutically acceptable salts for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs in idiopathic Parkinson's disease.

2. The use according to claim 1, characterized by the fact that undesirable actions ANTIPARKINSONISM drugs is ri idiopathic Parkinson's disease are motor fluctuations.

3. The use according to claim 1, characterized by the fact that undesirable actions ANTIPARKINSONISM drugs in idiopathic Parkinson's disease represent dyskinesia.

4. The use according to claim 3, characterized in that the specified dyskinesia is a dyskinesia associated with treatment in Parkinson's disease.

5. The use according to claim 3, characterized in that the specified dyskinesia is a dyskinesia induced by levodopa in Parkinson's disease.

6. The use according to claims 1 to 5, characterized in that the antiparkinsonian drug is an L-DOPA (levodopa).

7. The use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and its pharmaceutically acceptable salts for the preparation of drugs for the treatment of unwanted actions ANTIPARKINSONISM drugs when parkinsonism syndromes.

8. The use according to claim 7, characterized in that the antiparkinsonian drug is an L-DOPA.

9. The use of (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide and its pharmaceutically acceptable salts for the preparation of drugs for the treatment of extrapyramidal when Nemov, caused by neuroleptics.

10. The use according to claim 9, where the extrapyramidal symptom caused by neuroleptics, represents a late dyskinesia.

11. Pharmaceutical composition for the treatment of movement disorders or unwanted actions, callable for the treatment of extrapyramidal movement disorders, comprising as active components

(i) (-)-(R)-2-{4-[[3,4-dihydro-2H-benzopyran-2-yl)-methyl]amino]butyl}-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide or its pharmaceutically acceptable salt in an effective amount,

and (ii) L-DOPA,

in combination with one or more pharmaceutically acceptable excipients.

12. The composition according to claim 11, where (i) an active component is used in the form of his monohydrochloride.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry, steroids.

SUBSTANCE: invention discloses derivatives of steroid sapogenins of the general formula (I): wherein R means alkylcarbonyl, alkoxycarbonyl substituted possibly with amino-group and others under condition that R is not acetyl and R is not ethoxycarbonyl if C3 is in S and C25 in R-configurations simultaneously; R is nor succinyl if C3 and C25 are in S-configuration simultaneously, or C3 R(α) or S(β), and C25 in R-configuration. Also, invention discloses using these compounds in treatment of cognitive dysfunction, noncognitive neurodegeneration, noncognitive neuromuscular degeneration and loss of receptors in absence of cognitive, nervous and neuromuscular insufficiency. Also, invention discloses methods for synthesis of these compounds, treatment and pharmaceutical composition containing thereof.

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

30 cl, 2 tbl, 5 dwg, 16 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to amine derivatives of general formula I , wherein R1 is hydrogen or hydroxyl; R2 is hydrogen, -COOH, -COOR4 (R4 is C1-C6-alkyl); R3 is hydrogen or hydroxyl; or pharmaceutically acceptable salts thereof. Also disclosed is method for production of said compounds (wherein n = 1 or 2) including activation of carboxyl group of p-hydroxyphenylacetic acid or phenylacetic acid by interaction of with diphenylphosphorylazide and triethylamine in organic solvent under cooling followed by interaction with amine compound. Method for production of said compounds (wherein n = 1) includes converting of p-hydroxyphenylacetic acid or phenylacetic acid to activated N-oxysuccinimide ester by N'dicyclohexylcarbodiimide method followed by interaction of N-succinimide ester with amine derivative. Disclosed are pharmaceutical composition and agent having cyclooxygenase inhibitor activity, containing effective amount of claimed compound (wherein n = 1 or 2) as active ingredient. Also disclosed is method for cyclooxygenase inhibition by administering to mammalian of effective amount of claimed compound (wherein n = 1 or 2) or pharmaceutically acceptable salt thereof.

EFFECT: phenyl-containing N-acylamine derivatives having cyclooxygenase inhibitor activity and useful in treatment pain, inflammation and other disorders of joints and connective tissues.

19 cl, 9 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: the suggested transdermal therapeutic system (TTS) includes adhesive matrix that contains biologically active substance - rotigotin. The adhesive matrix contains thermofusible contact glue, the latter consists of contact glue, the mixture of different contact glues or contact glue with a plastifier and at 160°C is of dynamic viscosity being 100 Pa·sec, not more. TTS has been obtained due to hot fusion technique: before stratifying the adhesive matrix its components should be fused and homogenized without usage of solvents at 70-200°C. According to the present innovation TTS has got high degree of filling with rotigotin which is released out of thermofusible matrices constantly and at therapeutically desirable rate. Rotigotin in case of carrying out the technique of hot fusion keeps its stability at heating up to 160°C. There is no necessity in applying, removing, regenerating or burning up organic solvents and providing corresponding safety measures during TTS manufacturing.

EFFECT: higher efficiency.

24 cl, 10 dwg, 10 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: the present innovation deals with obtaining a biologically active peptide fraction out of poultry blood serum being useful at some human and animal diseases and disorders. It is necessary to carry out electrostimulation of a bird's head at the mode of about 70-80 V for about 2-3 sec to sample blood and incubate it at 4-8°C for about 18-24 h, then the serum sampled should be irradiated with C0 60 at the mode of 25±5.0 kGy and extracted after irradiation with 0.5 mM solution of phenylmethane sulfonyl fluoride in distilled water at the ratio of 1:10 to be mixed at 5°C for 1 h and centrifuged at 12000 rot./min for 30 min, then the residue should be repeatedly centrifuged under the same conditions, supernatant should be filtered successively through the membrane at pore's diameter being 0.45 mcm and 10 kDa, and a target product being a peptide fraction at molecular weight up to 10 kDa should be lyophilized and kept at about 4-8°C. The suggested pharmaceutical composition is characterized by the fact that as an active substance it contains efficient quantity of peptides of molecular weight up to 10 kDa obtained to a certain technique and a pharmaceutically acceptable carrier or filler. The innovation enables to obtain new biologically active peptide fraction up to 10 kDa and develop its medicinal form.

EFFECT: higher efficiency.

2 cl, 2 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

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

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, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated azepino[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers and their pharmaceutically acceptable salts and/or hydrates. In the general formula (1) a dotted line with accompanying unbroken line represents a simple or double bond; R1 and R2 represent independently of one another substitutes of amino-group chosen from hydrogen atom, possibly substituted (C1-C8)-alkyl possibly substituted with aryl, 5-6-membered azaheterocyclyl, (C1-C8)-alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino- or thiocarbonylamino-group, substituted acyl, (C1-C8)-alkylsulfonyl, possibly substituted arylsulfonyl and wherein substitutes in indicated R1 and R2 are chosen independently from (C1-C8)-alkyl, halogen atoms, nitro-, carboxy-, alkoxy-group, aryl; Rin represents one or some similar or different substitutes of cyclic system chosen from hydrogen atom, (C1-C8)-alkyl, (C6-C10)-aryl, halogen atom, 5-6-membered azaheterocyclyl. Also, invention relates to methods for synthesis of these compounds, their using and pharmaceutical composition and libraries of compounds. Synthesized compounds possess neuroprotective, cognitive-stimulating and anti-histaminic properties and can be used in treatment of different neurological disorders, allergic and autoimmune diseases, for example, for memory improvement.

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

25 cl, 2 tbl, 12 ex

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: method involves carrying out pharmacotherapeutic treatment for 20 days. Method involves treatment with mexidolum in the dose 150-200 mg per 24 h by intravenous drop route, diazepam in the dose 15-20 mg per 24 h by intramuscular route, immune correcting drug thymogenum in the dose 1 ml of 0.01% solution by intramuscular route, once per 24 h for the first 10 days and then five injections every other day by intramuscular route. Hyperbaric oxygenation under excessive pressure 0.8-1 atm at the rate compression and decompression 0.1 atm per a minute, isopression period for 40 min, 2 times per 24 h, is carried out with pharmacotherapy simultaneously. Invention provides rapid and stable reducing the main psychopathological symptoms: simple and complex motive tics and vocalism based on nonspecific complex normalizing effect on neurohomeostasis.

EFFECT: enhanced and valuable method of disease treatment.

1 ex

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

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: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

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