Novel use of substituted aminomethylchromans

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to drugs and concerns using (2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salts or solvates used for production of a drug for treatment of catalepsy. Also, invention proposes a pharmaceutical composition for treatment of catalepsy that comprises (2R,4R)-2-({[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-amino}-methyl)-chroman-4-ol as an active component taken in the pharmaceutically effective amount in combination with one or some pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

3 cl, 15 ex

 

The present invention relates to a new use of substituted aminomethylpropanol for the treatment of musculoskeletal disorders and adverse effects induced by administration of medicines intended for the treatment of extrapyramidal movement disorders.

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

where

R represents hydrogen or a protective group of hydroxyl, their optical isomers and pharmaceutically acceptable salts or solvate, in particular 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methylpropan-4-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)chroman-7-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol or their optical isomers, or a physiologically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders and/or for the manufacture of a medicinal product for the treatment of adverse effects of antiparkinsonian drugs used in extrapyramidal motor disorders and/or for the manufacture of a medicinal product for the treatment of extrapyramidal symptoms (EPS)induced by neuroleptics. The compounds of formula I are particularly useful when Leche is Sri dyskinesia.

The US patent No. 5,767,132 describes a simple derivative aminomethylpropanol that are acceptable for the prevention and control of complications of a heart attack brain (applicationscope cob), such as stroke, cerebral ischemia, for the prevention and control of cerebral disorders, such as migraine, especially in the elderly, by type, similar to certain ergot alkaloids for the treatment of anxiety, tension and depression, sexual dysfunctions caused by the Central nervous system, disorders of sleep or digestion or for the treatment of psychosis (schizophrenia).

In addition, they are acceptable to resolve cognitive failure, to improve the ability to memorize and improve memory, for the treatment of Alzheimer's disease. They can also be used to treat side effects of treatment of hypertension, endocrinology and gynecology, for example for the treatment of acromegaly, hypogonadism, secondary of amenorrhea, premenstrual syndrome or unwanted maternity lactation.

Such compounds are described in "the Metabolism of drugs and their properties", vol. 29, No. 7, 1042-1050, 2001.

In contrast to the compounds disclosed in US patent No. 5,767,132, the compounds in accordance with formula I are simple agonists Rotz the Torah, the 5-HT 1Aand antagonists of the dopamine receptor D4. They do not reveal inhibitory effect on dopamine receptors D2 or D3.

An unexpected advantage of the compounds of formula I and, in particular, those in which R=H and F is 4-position of the phenyl ring, is that they really have no antagonistic effect on the dopamine receptor D2 (and D3). Unlike receptor D4 of their antagonistic properties against the dopamine D2 receptor and the same, though less clearly, in relation to the D3 receptor, are associated with the induction of various extrapyramidal motor disorders that can be treated using compounds of formula I.

Used the principle of obtaining aminomethylpropanol formula I in accordance with the invention disclosed in US patent No. 5,767,132. The US patent No. 5,767,132 entered in this application as a reference.

Similar to the method described in US Patent no US 5,767,132, the compounds of formula I in accordance with paragraph 1 and their optical isomers and/or their pharmaceutically acceptable salt and solvate can be obtained in such a way that

(a) compound of formula II

where G represents Cl, Br, l, alkylsulfonate containing from 1 to 6 carbon atoms or arylsulfonyl containing from 6 to 10 carbon atoms, and R represents seminogram hydroxyl,

subjected to reaction with the amine of formula III

and, optionally, otscheplaut protective hydroxyl group to obtain the compounds of formula I where R=H; or

(b) a compound of formula IV obtained as described in US patent No. 5,767,132

where alkyl represents an alkyl group containing from 1 to 4 carbon atoms, are subjected to dezalkilirovania when using dealkiliruetsa agent to produce compounds of formula I, where R=N.

Particularly preferred is the method (s) to obtain compounds of the formula IA

having a clear stereochemistry, in which chromanin formula V

subjected to reaction with an aldehyde of the formula VI

and is treated with a hydride donor, preferably a complex hydride, such as borohydride sodium.

A new compound of formula IA is also the subject of this invention.

The original connection of the formula V for the method (C) is preferably obtained using the compounds of formula VII (obtained by enantioselective catalytic hydrogenation and crystallization in accordance with WO 02/20507),

which is subjected to hydrogenation to obtain after it is selected crystallization enantiomeric and diastereomeric pure compounds of formula VIII.

The compound of formula VIII hydrolyzing to the compounds of formula V by conventional methods, preferably by treatment with a solution of alkali metal hydroxide such as sodium hydroxide.

In the preferred method of obtaining the compounds of formula VIII compound of formula VII

is diastereoselective hydrogenated by means of a complex hydride, preferably the alkali metal borohydride, such as borohydride sodium in alcohol, such as methanol or ethanol, leading to the after optional crystallization enantiomeric and diastereomeric pure compounds of formula VIII.

This method of hydrogenation of the compounds of formula VII has the advantage of allowing for compound VIII, not containing or containing only minor amounts of undesired diastereoisomer Vllla:

Thus, the present invention also relates to a method for producing compounds of the formula IA

having a clear stereochemistry where chromanin formula V

subjected to reaction with an aldehyde of the formula VI

and process donore the hydride.

The invention also relates to a method for producing compounds of formula IB, which includes the following steps:

a) hydrogenation of compounds of formula VII

to connect VIII

which is not necessarily crystallized for cleaning,

b) hydrolysis of compound VIII obtained in step a), to the compounds of formula V

(C) reaction of the compound of formula V obtained in step b), with the compound of the formula VI and processing of donor hydride

Preferred is the above method of obtaining the compounds of formula IA, where the hydrogenation of the compounds of formula VII to the compound VIII in step a) is conducted diastereoselective using a complex hydride, preferably the alkali metal borohydride, such as borohydride sodium in alcohol, such as methanol or ethanol.

Especially preferred is the above-described procedure to obtain (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol using the compounds of formula VIA, instead of VI

The alkyl group in the formula IV is preferably unbranched and has 1, 2, 3, or 4 carbon atoms, preferably is stands, ethyl, propylene, isopropyl, bootrom, from what bootrom, Deut. bootrom or tert. bootrom. Particularly preferred is methyl.

In alkylsulfonyl group containing from 1 to 6 carbon atoms, the alkyl residue may be the stands, ethyl, propylene, isopropyl, bootrom, Pentium or hexyl. A particularly preferred group for alkylsulfonate is methansulfonate.

In arylsulfonyl group containing from 6 to 10 carbon atoms, an aryl residue may be a phenyl, o-, m - or p-tolila, o-, m-, p-ethylphenyl, o-, m - or p-propylphenyl or naphthyl. Especially preferred for arylsulfonate are benzosulfimide, p-toluensulfonate, naphthalene-1 - or naphthalene-2-sulfonyloxy.

The expression "protective hydroxyl group" is generally known and relates to groups suitable for protecting a hydroxyl group against chemical reactions, but these groups can be easily removed after completion of the desired chemical reactions at other positions in the molecule.

Traditional groups of this type are unsubstituted or substituted aryl, aralkyl, aroyl or acyl, and alkyl groups, alkyl-, aryl - or aralkylamines group or O - or O, S-acetals. The nature and size of the protective groups of hydroxyl are not critical, because they are removed after completion of the desired chemical reaction or sequence of reactions is; in this case a group containing 1-20, in particular 1-10, carbon atoms, are preferred. Examples of protective groups are hydroxyl, among others, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl or aroline groups, such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluensulfonyl, alkyl groups such as methyl or tert. butyl, and allyl, alkylsilane groups, such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert. butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylmethyl, arylalkylamine group, such as tert. butyldiphenylsilyl (TBDPS), cyclic acetals, such as isopropylidene, cyclopentolate, cyclohexylidene, benzylidene-, p-methoxy - benzilidene-or o-, p-dimethoxybenzaldehyde, acyclic acetals, such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzoyloxymethyl (CMV) or methylthiomethyl (MTM). Acyl group containing from 2 to 5 carbon atoms, such as acetyl, propionyl, butyryl and pivaloyl, are most preferred as the protective group hydrocycle in the compounds of formula I in accordance with the invention.

The compounds of formula I can be otherwise obtained by methods known in themselves, such as those described in the literature (for example, in the well-known servant of the tah, such as Huben-Weyl, "Methods of organic chemistry", Georges-Tim-Verlag, Stuttgart), specifically under such reaction conditions that are not mentioned in detail in this application.

Compounds of formulas II and III are known; the compounds of formula II or III can be easily obtained analogously to known compounds, for example similar to those described in US patent No. 5,767,132.

The reaction of compounds of formulas II and III is carried out in accordance with methods known in the literature for the alkylation of amines. Components can be melted together in the absence of a solvent in a closed vessel or autoclave, if necessary. It is also possible, however, to conduct the reaction compounds in the presence of inert solvent. Examples of acceptable solvents are hydrocarbons, such as benzene, toluene or Xilin; ketones, such as acetone or butanone; ethers, such as tetrahydrofuran or dioxane; amides, such as dimethylformamide or n-organic; or NITRILES, such as acetonitrile, or, if it is desired, mixtures of these solvents or their mixtures with water. It is desirable to add an agent to bind the acid, for example a hydroxide of an alkali metal or a hydroxide of alkaline-earth metal carbonate or bicarbonate or another salt of alkaline metal or alkaline-earth metal with the prevalence of the second acid, preferably the salt of potassium, sodium or calcium, or to add an organic base such as triethylamine, dimethylamine, pyridine or quinoline, or an excess of amine compounds. The reaction time is from several minutes to 14 days, depending on conditions, and the reaction temperature is from about 0 to 150°C, normally from 20 to 130°C.

Preferred compounds in the context of this invention are those which are characterized by the General formula I

where

OR is 4-, 7 - or 8-position in the system chromane, and F is 4-position of the phenyl ring.

Thus, the preferred compounds are 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol, or their optical isomers or their physiologically acceptable salt or a solvate, such as

a) (2R/S,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

b) (2S,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

c) (2S,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

d) (2S,4S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

e) (2R,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

f) (2,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

g) (2R,4S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

h) (2R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol,

i) (2S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman 7-ol,

j) (2S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol,

k) (2R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol,

I) (2R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol,

m) (2S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol,

or their physiologically acceptable salt, or MES.

Particularly preferred compounds of formula I are compounds selected from the group consisting of

a) (2R/S,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

b) (2S,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

c) (2S,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)chroman-4-ol,

d) (2S,4S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

e) (2R,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

f) (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

g) (2R,4S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol,

or their physiologically acceptable salt or solvate.

The most preferred compound of formula I is (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-mate is)-chroman-4-ol, or its physiologically acceptable salt, or MES.

In the context of this invention, the connection aminomethylpropanol formula I can be represented in different stereoisomeric forms, i.e. in the form or (+) or (-) enantiomers or as a mixture of these enantiomers (racemate). Regarding the separation of racemates on enantiomeric forms should make reference to relevant, well-known specialist sources of information.

In the context of the present invention can also be used physiologically acceptable salt. Physiologically acceptable salts of substituted 2-aminomethylpropanol formula I can be salts in accordance with the invention with acceptable organic or inorganic acids, in particular mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, econsultancy acid, toluensulfonate acid, benzosulfimide acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid, benzoic acid.

The preferred salt of 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-meth is l)-chroman-4-ol or its optical isomers is monohydrochloride or the hemihydrate of monohydrochloride.

The preferred salt of 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol or its optical isomers is a hydrobromide or maleate.

The preferred salt of 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol or its optical isomers is a hydrobromide or maleate.

The object of the invention is a new application of substituted aminomethylpropanol formula I, their optical isomers and/or their physiologically acceptable salts and solvate.

It was found that substituted aminomethane formula I

where

R represents hydrogen or a protective group of hydroxyl,

and their optical isomers and pharmaceutically acceptable salt and solvate, in particular 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methylpropan-4-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methylpropan-7-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol or an optical isomer, or a physiologically acceptable salt, or their MES have therapeutic activity against estrapiramidnyh movement disorders, such as idiopathic Parkinson's disease, syndromes, Parkinson's disease, dyskinetic, horiatiki or dystonic syndromes, tremor syndrome of Gilles de La Tourrettes, ballism, myoclonus syndrome restless legs Il the disease Wilson, as well as extrapyramidal motor disorders [synonym extrapyramidal symptoms (EPS)]induced by neuroleptics.

In addition, it was found that substituted aminomethane formula I

where

R represents hydrogen or a protective group of hydroxyl,

and their optical isomers and their pharmaceutically acceptable salt and solvate, in particular 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino)-methyl)-chroman-4-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol, 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol, or optical isomer, or a physiologically acceptable salt, or their MES have therapeutic activity against adverse effects of antiparkinsonian medications for extrapyramidal motor disorders, in particular in relation to dopaminemediated adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease or syndromes Parkinson's.

It was found that substituted aminomethane formula I

where

R represents hydrogen or a protective group of hydroxyl,

and their optical isomers, pharmaceutically acceptable salts, in particular 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino)-methyl)-XP is man-4-ol, or its optical isomer, or its physiologically acceptable salt or MES, have exceptional effectiveness in removing catalepsy.

Extrapyramidal motor side effects, for example, in rodents are determined by the ability of drugs to induce catalepsy. Catalepsy is defined as a condition in which the animal remains in an abnormal (non-physiological "uncomfortable") pose for a long period of time (for example, ..Stanley and S.D.Glick, Neuropharmacology, 1996; 15: 393-394; .J.E.Niemegeers and .Janssen, Life Sci., 1979, 201-2216). For example, if the rear paw of the rat is in a raised state, in particular at the site, placed 3 cm above the surface of the earth, with normal rat immediately puts a paw up to ground level. Cataleptic rat remains in such an unnatural pose for several minutes.

Beneficial effects on the extrapyramidal motor system has previously been described for other drugs with 5-HT1Aagonistic activity. Buspirone, for example, which is an anxiolytic drug, demonstrates moderate antidyskinetics properties in patients with advanced Parkinson's disease (.Kleedorfer and others, J.Neurol Neurosurg. Psychiatry, 1991, 54: 376-377; V.Bonifati and others, Clin. Neuropharmacol., 1994, 17: 73-82). The main mechanism of action is s becomes apparent during stimulation of the receptors 5-HT 1Ablack and striped pathways.

In addition, antipsychotic drug clozapine, which has an extremely high affinity for the dopamine receptor D4, as well as a variety of other receptors demonstrates beneficial antidyskinetics effect in patients with Parkinson's disease (for example, F. Durif, etc., Neurology 1997; 48: 658-662). Recent experimental compounds 8-methyl-6-(4-methyl-1-piperazinyl)-11N-pyrido-[2,3-b][1,4]-benzodiazepine, a structural analog of clozapine significantly increased as compared to clozapine selectivity for the dopamine receptor D4 (Liegeois JF and others, Eur. J. Pharmacol. 1995; 273: R1-R3), was shown a beneficial effect on monkeys with symptoms of Parkinson's disease (Tahar Academy of Sciences and others, Eur. J. Pharmacol. 2000; 399: 183-186).

In rats after subcutaneous administration is ED50(i.e. calculated dose to eliminate catalepsy 50%) for (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is approximately 2 mg/kg, which is comparable or even more effective in comparison with other agonists of 5-HT1Asuch as ipsapirone (ED5010 mg/kg) or buspirone (ED506 mg/kg) and D4 antagonist 8-methyl-6(4-methyl-1-piperazinyl)-11N-pyrido[2,3-b] [1,4,] benzodiazepine (ED503 mg/kg).

Thus, the present invention relates to the use of substituted amine is methylchromone formula I and their optical isomers and pharmaceutically acceptable salts and solvate for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders.

Thus, the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol his or pharmacologically acceptable salt or MES for production of medicines for the treatment of extrapyramidal movement disorders.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate of monochloride (2R,4R)-2-({5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

Thus, the invention in particular relates to the use for the manufacture of a medicinal product for the treatment of extrapyramidal movement disorders, with pharmacologically acceptable salt is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for the treatment of extrapyramidal movement disorders.

The compound of formula I in accordance with paragraph 1, or a physiologically acceptable salt, or MES, useful for extrapyramidal movement disorders, in particular the treatment of idiopathic Parkinson's disease, Sindh who Ohm Parkinson, dyskinetic, heretically or dystonic syndromes, extrapyramidal adverse effects on the motility caused by neuroleptics, tremor, syndrome of Gilles de La Tourrettes, ballism, myoclonus syndrome restless legs or illness Wilson, and/or useful for treatment of adverse effects in patients with idiopathic Parkinson's disease or syndromes Parkinson's disease, while pharmaceutical compositions, as defined above, preferably injected in doses of from 0.1 to 100 mg, preferably approximately from 1 to 20 mg of the Composition can be entered one or more times a day, for example 2, 3 or 4 times a day. The specific dose for each patient depends on various factors, such as activity-specific connections in use, the age, body weight, General health, sex, time and route of administration, rate of excretion, from a combination of pharmaceutical substances and the severity of the private disorder, to which is applied the specified therapy. Oral route of administration is preferred, but can also be used parenteral routes of administration (e.g. intravenous or percutaneous).

Antiparkinsonian drugs are traditional medicines, such as 1-DOPA (levodopa) or 1-DOPA in combination is a decarboxylase inhibitor, such as benserazide or carbidopa, dopamine agonists such as parlodel, apomorphine, cabergoline, pramipexol, ropinirole, pergolid, dihydro-α-ergocryptine or lisuride plus all medicines acting through 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 antagonists of N-methyl-D-aspartate (NMDA) receptors, such as amantadine or BODIPY.

Adverse effects of antiparkinsonian drugs are all types of psoriasis, such as horiatiki, dystonic, ballistic and millonaria dyskinesia and motor (response) oscillations or psychotic conditions, such as optical or acoustic hallucinations.

Thus, the present invention relates to the use of substituted aminomethylpropanol formula I and their optical isomers, pharmaceutically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease.

Thus, the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its Farmak is logically acceptable salt or MES for production of a medicine for treatment of adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease.

Treatment of adverse effects of traditional anti-Parkinson medicines, as indicated above, is determined by using the modification of animal models monkeys, cynomolgus with the shaking palsy in accordance with .J.Blanchet etc., Exp. Neurology 1998; 153: 214-222. Monkeys led to a state of shaking palsy by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR). Monkeys with the shaking palsy was constantly subjected to treatment with traditional 1-DOPA therapy in accordance with .J.Blanchet and others, Mov. Disord., 1998; 13: 798-802. Long-term treatment with 1-DOPA induces extrapyramidal motor side effects and psychotic state that both qualitatively and quantitatively evaluated using an evaluation scale for abnormal involuntary movements (.J.Blanchet and others, Mov. Disord. 1998; 13: 798-802) for various parts of the body (face, neck, torso, each limb) and by assessing psychotic conditions when monitoring attention monkeys, their reactivity and mobility. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol decreases as the total choreiform dyskinesia and dystonic dyskinesia and psychotic state.

A typical study the efficacy of compounds in accordance with the invention in relation to the adverse effects of Parkinson's disease are described below 40 patients of both sexes with advanced idiopathic Parkinson's disease, complicated dyskinesia "peak dose", participated in a double blind study. The main inclusion criterion was the degree Hoehn and Yahr >2.5 (literary source: Hoehn N.M. and others, Neurology 1967; 17: 427-442), age 40-75 years, duration of symptoms at least 5 years and the treatment of 1-DOPA during a period of at least 3 years. The hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or placebo was administered by addition to the traditional treatment of Parkinson's disease, which is kept unchanged during the whole study period. The dose of the drug in a blind study was determined during a period of 3 weeks in the interval from 2.5 to 10 mg twice a day. Then the treatment was maintained without change for 3 weeks. Before defining and at the end of the treatment period, the patients filled out the registration card within 30-minute intervals within 48 hours. Registration card distinguish between 5 different States: (1) phase mobility without dyskinesia, (2) phase mobility with dyskinesia, harassing, (3) phase mobility dyskinesia that does not cause anxiety, (4) phase, when there is no mobility, and (5) sleep time (Hauser RA, etc., Clin. Neuropharmacol., 2000, 23, 75-81). Primary changing the Protocol was to determine changes in dyskinesia, precieuse the anxiety, in the phase mobility. Statistical analysis data cards account showed a significant reduction in dyskinesia during phase mobility, causing concern in the treatment of hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, while significantly increased the rate of absence of dyskinesia during the study period. Other parameters were not changed.

The preferred salt of (2R,4R)-2-(([5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol represented the hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

Thus, the invention in particular relates to the use for the manufacture of a medicinal product for the treatment of adverse effects of antiparkinsonian drugs in idiopathic Parkinson's disease, while the pharmacologically acceptable salt is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for treatment of adverse effects of antiparkinsonian medication the funds in idiopathic Parkinson's disease.

In addition, the present invention relates to the use of substituted aminomethylpropanol formula I, their optical isomers and pharmaceutically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of idiopathic Parkinson's disease.

Thus the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a pharmacologically acceptable salt or MES for production of medicines for the treatment of idiopathic Parkinson's disease.

Typical animal model for idiopathic Parkinson's disease is a monkey, cynomolgus in accordance with .J.Blanchel etc., Exp. Neurology 1998; 153: 214-222. Monkeys led to a state of shaking palsy by repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR). Parkinsonism symptoms qualitatively assessed using the scale capacity graduated from Laval University (.Gomez-Mancilla and others, 1993; Mov. Disord. 8: 144-150), defining the following symptoms: posture, mobility, climbing, gait, manner of holding food, the edition of the sounds, scratching, interaction with the herd. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol reduces all parkinsonism symptoms and improves the overall activity.

A typical study of the effectiveness soedinenii accordance with the invention in the treatment of idiopathic Parkinson's disease are described below. 180 patients of both sexes with idiopathic Parkinson's disease were subjected to a double blind study. The main inclusion criterion was a stage Hoehn and Yahr >2.0 (Hoehn N.M. and others, Neurology 1967; 17: 427-442), age 50-80 years, duration of symptoms at least 5 years. The hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or placebo was administered by adding to the traditional treatment of Parkinson's disease, which is kept unchanged during the whole study period. The dose of the drug was determined in a time period of 4 weeks in the interval from 2.5 to 10 mg twice a day. Then the treatment was maintained without change for 1 week. Before defining and at the end of the treatment period, the patients filled out the registration card within 30-minute intervals within 48 hours. Registration card distinguish between 5 different States: (1) phase mobility without dyskinesia, (2) phase mobility with dyskinesia, harassing, (3) phase mobility dyskinesia that does not cause anxiety, (4) phase, when there is no mobility, and (5) sleep time (Hauser RA, etc., Clin. NeuropharmacoL, 2000, 23, 75-81). This allowed us to determine simultaneously the beneficial effect of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES, in particular Geiger is and monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, on gross motor function, dystonia, motor fluctuations and psychosis. In addition, it has been shown effective for the treatment of tremor. The analysis showed a significant clinical improvement in the treatment using the hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol represented the hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

Thus, the invention applies in particular to the use for the manufacture of a medicinal product for the treatment of idiopathic Parkinson's disease, with physiologically acceptable salt is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate in combination with at least one solid, liquid or semi-liquid excipient or additive 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 the submitted is the occurrence of psychosis or dyskinesia or other movement fluctuations.

It was found that the compounds of formula I in accordance with paragraph 1, or a physiologically acceptable salt, or their solvate improve antiparkinsonian effect of antiparkinsonian drugs, as defined above, without the induction of extrapyramidal side effects.

Thus, additional therapy, in particular, using (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES, in particular of the hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, in the present time opens the possibility of increasing doses of 1-DOPA and/or dopamine agonists, and/or any other antiparkinsonian drugs, as defined above, in order to counteract periods of insufficient mobility ("off" phase) without provocation the above side effects. This represents a completely new approach to the treatment of Parkinson's disease that leads to significant benefits for patients

Thus, the invention relates to pharmaceutical compositions containing as active ingredients (i) compound in accordance with paragraph 11 or 12, and (ii) at least one anti-Parkinson medication in combination with one or more pharmaceutically acceptable fill the oil.

In particular, the invention relates to pharmaceutical compositions containing as active ingredients (i) (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES and (ii) 1-DOPA.

Thus, the invention relates to pharmaceutical compositions containing as active ingredients (i) compound in accordance with paragraph 11 or 12, (ii) at least one anti-Parkinson drug, and, at least, (iii) one decarboxylase inhibitor, in combination with one or more pharmaceutically acceptable excipients.

In particular, the invention relates to pharmaceutical compositions containing as active ingredients (i) (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES, (ii) 1-stage, and (iii) benserazide or carbidopa in combination with one or more pharmaceutically acceptable excipients.

The ratio of the respective quantities of the compounds in accordance with paragraph 11 or 12, and traditional antiparkinsonicheskogo medicines, optionally together with a decarboxylase inhibitor, thus, can be varied. Preferably, when the mass ratio of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one and which of its physiologically acceptable salt or solvate traditional antiparkinsonian drugs is in the range from 1:1 to 1:100, preferably from 1:10 to 1:90 and more preferably from 1:40 to 1:60.

Another object of the present invention is also the use of compounds of formula I in accordance with paragraph 1, in particular (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its physiologically acceptable salt or solvate in combination with at least one antiparkinsonian drug for the preparation of pharmaceutical compositions intended to enhance the antiparkinsonian effect of these antiparkinsonian drugs.

In accordance with the invention, the term "pharmaceutical composition" is intended to denote or pharmaceutical compositions, as defined above, in which two active principle or compounds are essential components of a single composition, or kit, containing two separate compositions, the first of which contains, for example, (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its physiologically acceptable salt or solvate as the sole active agent, and the second one contains at least one antiparkinsonian drug as the active connection.

When the pharmaceutical composition is in the form of a kit, the introduction of two compositions, the constituents of this is abortion practices, although they performed separately, is simultaneous for combination therapy. It is preferable to use (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol in the form of a hemihydrate of monochloride.

Adverse effects of antiparkinsonian drugs, as defined above, are known, in particular, for the syndromes of Parkinson's disease.

The syndromes of Parkinson represent multiple system atrophy (MSA), the syndrome Steele-Richardson-Olzewski (=progressive supranuclear paralysis), kortiko-basal degeneration, Olivone-cerebral atrophy or syndrome Shi of Dragør.

Thus, the invention relates to the use of substituted aminomethylpropanol formula I and their optical isomers and pharmaceutically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of syndromes of Parkinson's disease and/or treatment of adverse effects of antiparkinsonian drugs in the syndromes of Parkinson's disease.

Thus, the invention, in particular, refers to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES for production of medicines for the treatment of syndromes of Parkinson's disease and/or treatment of adverse effects of antiparkinsonian Lech of the public funds, used to treat syndromes of Parkinson's disease.

Typical animal model is a rat or mouse, which is subjected to the action of reserpine (e.g., .S.Starr and .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 et al., Mov. Disord., 1998; 13: 228-233). Reserpine is a powerful agent for depletion of monoamines and causes almost complete akinesia both types.

In the first 24 hours after application of the distance and time the activity was approximately equal to zero, which was measured by means of the counter activity. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3--methyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES depending on the dose reduced akineziyu, that is, restored the distance and time of the activity to approximately the same level, which was normal animals.

Another more recent animal model is an approach of using the process of degeneration striped bodies in rats in accordance with G..Wenning etc., J. Neural Transm. Suppl., 1999; 55: 103-113. Rats received a unilateral injection of 6-hydroxydopamine in average left front cluster, followed by injection quinolinol acid in the striatum, which is the same side that induced degeneration phone striped Degeneration has led to a change in behavior is possible in response to the introduction dopamine mimetics, such as apomorphine or amphetamine. Behavior change was measured using an automatic recording device. The change in behavior induced by apomorphine or amphetamine, depending on the dose antagonizers (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-I or its pharmaceutically acceptable salt or MES.

Multiple system atrophy (MSA) is achieved thanks to the extensive neurodegeneration in the extrapyramidal and autonomic nervous system, which leads to akineticalkie the Parkinson's disease with autonomic disorders. In contrast to idiopathic Parkinson's disease the distribution of dopamine receptors in the Central nervous system is greatly reduced, and thus, patients with MSA weakly respond to dopaminergic drugs. Since (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES act primarily through serotonin receptors extrapyramidal system, they are able to improve motor behavior in patients who had undergone treatment by other means, mainly, in untreated patients.

A typical study the efficacy of compounds in accordance with the invention, in patients with MSA covers 30 patients of both sexes with what entomon, which has a duration of at least 5 years, and with a significant decrease in the number of dopamine receptors in the Central nervous system with positron emission tomography (PET) scanning. The research model is similar to that which was described for Parkinson's disease.

The hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or placebo was titrated in addition to the traditional treatment (interval doses ranging from 2.5 to 20 mg twice a day). After the double-blind phase determination doses duration of 3 weeks, during which the identified individual dose for each patient based on tolerability and efficacy, doses were maintained without change for 3 additional weeks. Before defining and at the end of the treatment period for each patient performed a full assessment of the UPDRS (primary measurement results). Statistical analysis of UPDRS showed a significant clinical improvement of the symptoms of Parkinson's disease during treatment with hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for the treatment of syndromes and/or treatment of adverse effects of antiparkinsonian drugs in the syndromes of Parkinson's disease.

The present invention relates also to the use of substituted aminomethylpropanol formula I, and their optical isomers and pharmaceutically acceptable salts and solvate for the manufacture of a medicinal product for the treatment of dyskinetic and/or horiatiki syndromes.

Thus, the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a pharmacologically acceptable salt or MES for production of medicines for the treatment of dyskinetic and/or hereticus the x syndromes.

Dyskinetic and/or horiatiki syndromes represent, for example, Huntington's disease, mild horey or horey pregnant. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES are in particular useful for the treatment of Huntington's disease.

Typical animal model is a system model 3-nitropropionic acid (3-NP) in rats in accordance with .V.Borlongan and others, Brain Res., 1995; 697: 254-257. Rats were subjected to treatment with injections of the selective neurotoxin for the striatum of 3-NP, which was administered administered intraperitoneally every third day (.V.Borlongan and other Brain Res. Protocols, 1997; 1: 253-257). After two injections of 3-NP rats demonstrated a night hyperactivity, reflecting the symptoms of early Huntington's disease, whereas rats that received four injections of 3-NP showed a night akineziyu (underactive), which reflects the late symptoms of Huntington's disease. Nocturnal activity is automatically measured in normal cells for research activity using an infrared beam. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES were reduced as a night hyperactivity and akineziyu.

Typical experience to establish the effect of compounds in accordance with what Britanie on horey, arbitrary motor behavior, functional disability in patients with Huntington's disease covered 32 genetically diagnosed patient. The hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or placebo was administered as a Supplement to traditional treatment, which was maintained unchanged during the whole period of study. The dose in a blind way of handling drug was determined during a period of 3 weeks in the range from 2.5 to 20 mg twice a day. Then the processing of the medicinal product is kept unchanged during the period of one week. The evaluation was performed during the week and on the last day of the survey. Horey was 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 rating scales for Huntington's disease (UHDRS, Huntington study group, 1996, Movement Disord, 11: 136-42) and conclusions based on the video.

Involuntary motor symptoms were assessed using the motor scale UHDRS. Patients and their partners completed a questionnaire related to functional disability. Statistical analysis showed a significant improvement of voluntary and involuntary motor symptoms in patients with heart disease Hanti is gton when treated with (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

Thus, the invention applies in particular 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, with pharmacologically acceptable salt is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for the treatment destinationsa and horiatiki syndromes.

The present invention relates to the use of substituted aminomethylpropanol formula I and their optical isomers and pharmaceutically acceptable salts and solvate for the manufacture of a medicinal product for the treatment of dystonic syndromes.

Thus, the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a pharmacologically acceptable salt or MES for production of the medicinal product for the treatment of dystonic syndromes.

Dystonic syndromes represent, for example, spasmodic Krivoshey, convulsions when writing, blepharospasm, the syndrome Mage or datasensitive dystonia. (2R,4R)-2-({[5-(4-forfinal)-pyridine-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES, in particular, are useful for the treatment of spasmodic 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 attacks of dystonia are provoked by removal of the animal from the cage for habitat and placing it on the balancing scales. Dystonic syndrome consists of a sequence of abnormal movements, with one symptom severity assessed using rating scales. (2R,4R)-2({[5(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES depending on the dose reduced the severity of dystonic symptoms.

To demonstrate the effectiveness of compounds in accordance with the invention in respect of dystonic syndromes conducted a double-blind, controlled with placebo, the study of patients with cervical dystonia (spasmodic torticollis), which had an aversion to injections of botulinum toxin. The hemihydrate manohla the IDA (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol was titrated so, as described above within the range of doses between 2.5 to 20 mg For the initial evaluation results used the scale to determine the value spasmodic Krivoshei Toronto western (TWSTRS, .L. Cornelia and others, 1997, Movement Disord, 12: 570-575). A significant improvement in the values TWSTRS were noted for patients who had undergone treatment with (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its pharmaceutically acceptable salts and solvate.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol. Thus, the invention applies in particular to the use for the manufacture of a medicinal product for the treatment of dystonic syndromes, in particular spasmodic Krivoshei and/or blepharospasm, with pharmacologically acceptable salt of the compounds is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for the treatment of dystonic syndromes.

The present image is the buy refers to the use of substituted aminomethylpropanol formula I and their optical isomers and pharmaceutically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of extrapyramidal symptoms, induced by neuroleptics.

Extrapyramidal motor disturbances, induced by neuroleptics, are, for example, early dyskinesia, dystonia, akathisia, parkinsonia, in particular bradykinesia or late dyskinesia.

(2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino)-methyl)-chroman-4-ol or a physiologically acceptable salt or MES are useful for the treatment of akathisia, and/or tardive dyskinesia, and/or parkinsonia.

Typical animal model is a muscle rigidity in rats induced by neuroleptics, in accordance with S.Wolfarth etc., Arch. Pharmacol. 1992; 345: 209-212. Rats were injected traditional neuroleptic drug - haloperidol, which increases muscle tone. Muscle tone electromehanichesky measured as resistance to passive flexion and extension of the hind legs. (2R,4R)-2({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES reduce muscle tone, increased with haloperidol.

Another typical animal model represents a sensitized brain monkeys in accordance with D..Casey, Psychopharmacology, 1996; 124: 134-140. Monkeys subjected to repeated processing of traditional neuroleptics, are highly sensitive to subsequent introduction of Provo is sure dose neuroleptic drugs. After the introduction of the monkeys immediately demonstrate extrapyramidal motor side effects such as dystonia, dyskinesia, akathisia and bradykinesia that value in accordance with the scoring system. Traditional neuroleptic drug haloperidol entered as a provocative tool. Once you experience the above side effects, enter (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or MES; (2R, 4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, depending on the dose reduces extrapyramidal musculoskeletal side effects.

Late dyskinesia is an adverse effect of long-term treatment with neuroleptics. A typical study the efficacy of compounds in accordance with the invention in relation to the impact on late dyskinesia described below. Conducted a study on 32 patients with schizophrenia (DSM-III-R), aged 25-60 years who were subjected to constant long-term antipsychotic treatment. The hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or placebo was administered as a Supplement to antipsychotic treatment, which remained unchanged during the whole period of study. The dose for lepai treatment drug was determined during a period of 3 weeks in the interval from 2.5 to 20 mg twice a day. After this treatment with medicines kept in conditions of double-blind method within 2 weeks. After a two-week washout period was changed drug. Assessment of tardive dyskinesia using a scale of abnormal involuntary movements (AIMS, see above) and parkinsonism extrapyramidal side effects (UPDRS, see above) was performed before treatment and after the treatment period. Values AIMS during treatment using the hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol were significantly lower than those for placebo.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol. Thus, the invention applies in particular to the use for the manufacture of a medicinal product for the treatment of extrapyramidal symptoms induced by neuroleptics, particularly akathisia and/or tardive dyskinesia, while pharmacologically acceptable salt is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-PI is one-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for the treatment of extrapyramidal symptoms, induced by neuroleptics.

The present invention relates to the use of substituted aminomethylpropanol formula I and their optical isomers and pharmaceutically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of tremor.

Thus, the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a pharmacologically acceptable salt or MES for production of medicines for the treatment of tremor.

Tremor includes all types of jitter, such as essential tremor, activated physiological tremor, cerebellar tremor, orthostatic tremor or tremor induced drugs.

(2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES are useful for the treatment of essential tremor and/or induced by drugs of tremor.

Typical animal models using either genetic mutant animals or models in which the jitter induced by pharmacological agent (for review see: .Wilms and others, Mov. Disord., 1999; 14: 557-571).

Typical genetic models in the mutant animals represent syndrome Campus at pieranski pigs under A. Richter and others (Ex is. Neurology 1995; 134: 205213) or veverska mutant mice in accordance with J.R.Simon and .Ghetti (Mol. NeurobioL, 1994; 9: 183-189). In the model syndrome Campus such mutant pigs demonstrate jitter high frequency, when standing and during movement, but not during rest. Assessment of tremor conducted by accelerometric registration. Veverska mutant mice degenerative atrophy of the cerebellum combined with tremor, gait instability and tipping to the side after a few steps. The instability of gait and tilting lead to significantly reduced locomotor activity, which is measured in distance and time spent standing in normal cells to measure activity.

(2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its pharmaceutically acceptable salt or solvate facilitates syndrome Campus at pieranski pigs, i.e. it reduces the jitter, which makes animals incapable and improves locomotor activity in the mutant veverska mice when standing and moving, improving locomotor activity in the mutant mice.

Typical animal model for tremor induced by drugs is a tremor induced oxotremorine (for example, .Hallberg and .Almgren, Acta Physio. Scand., 1987; 129: 407-13; J.G.Clement and W.R.Dyck, J. Pharmacol Meth., 1989; 22: 25-36). Oxotremorine induces jitter, which is assessed through a scale of values. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its pharmaceutically acceptable salts and solvate inhibits the tremor induced by oxotremorine.

The preferred salt of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol. Thus, the invention applies in particular to the use for the manufacture of a medicinal product for the treatment of tremor, in particular essential tremors and/or tremors induced by drugs, with pharmacologically acceptable salt is a hemihydrate of monohydrochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts, or MES, for the treatment of tremor.

The present invention relates to the use of substituted aminomethylpropanol formula I and their optical isomers and pharmaceutically acceptable salt or solvate for the manufacture of medicinal environments is TBA for the treatment of extrapyramidal movement disorders, selected from the group consisting of a syndrome of Gilles de La Tourrettes, ballism, myoclonus syndrome restless legs and Wilson disease.

Thus, the invention applies in particular to the use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a pharmacologically acceptable salt or MES for production of medicines for the treatment of extrapyramidal movement disorders selected from the group consisting of a syndrome of Gilles de La Tourrettes, ballism, myoclonus syndrome restless legs and Wilson disease.

Typical animal model for myoclonus is a myoclonus induced by acute hypoxia in accordance with D.D.Truong and others, Mov. Dsiord., 1994; 9: 201-206). In this post-hypoxic model of myoclonus rats subjected to cardiac delayed for 8 minutes, then bring to consciousness. Millonaria convulsive twitches occur spontaneously, but can also be provoked auditory stimulation, with deterioration in a few days after cardiac delays. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its pharmacologically acceptable salt or solvate depending on the dose reduced the number of spontaneous and provoked by the researcher mykronaushnyk convulsive twitching.

The preferred salt of (2R,4R)-2-({[5-(4-shall terphenyl)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

Thus, the invention applies in particular to 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 Tourrettes, ballism, myoclonus syndrome restless legs, Wilson disease, with pharmacologically acceptable salt is a hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In addition, the invention relates to use of pharmaceutical compositions containing at least one compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or one of its biocompatible salts or solvate for the treatment of extrapyramidal movement disorders selected from the group consisting of a syndrome of Gilles de La Tourrettes, ballism, myoclonus syndrome restless legs, disease, Wilson.

Extrapyramidal movement disorders such as syndrome Steele-Richardson-Olzewski (=progressive supranuclear paralysis), kortiko-basal degeneration, Olivone-cerebellar atrophy syndrome, Shi Dragør, easy chorea, chorea pregnant, cramps in the letter, blepharospasm, the syndrome Mage, extra-sensitive dystonia syndrome of Gilles de La Tourrettes, ballism, myoclonus syndrome restless legs and Wilson disease are not present is like common to conduct regular studies were double-blind. However, the need for the development of medical intervention in this area is urgent, because until now, there is no reasonable available therapies. Thus, open kategorirovanie observation on few selected patients represent an appropriate way to demonstrate the effectiveness of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES.

All pharmaceuticals used for the treatment of extrapyramidal movement disorders and/or treatment adverse side effects of antiparkinsonian medications for extrapyramidal motor disorders, including drug combinations, can be used as pharmaceuticals in the treatment of human or veterinary medicine.

The composition of the invention preferably injected parenterally or even better orally, although other routes of administration, such as rectal administration, are not excluded.

Acceptable excipients are organic or inorganic substances which are acceptable for enteral (for example oral), parenteral or the local administration and which do not react with the compound of the formula I in accordance with paragraph 1, such as (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino)-methyl)-chroman-4-ol and/or one of its biocompatible salts or solvate, and include, for example, water, vegetable oils, benzyl alcohols, alkalophile, glycols, glyceryltrinitrate, gelatin, carbohydrates, such as lactose or starch, start magnesium, talc, vaseline. Forms used for oral administration, in particular, are tablets, pills, tablets, coated in sugar, capsules, powders, granules, syrups, medicine or drops, forms for rectal injection are, in particular, suppositories, forms for parenteral administration are, in particular, solvents, preferably fatty or aqueous solutions, and also suspensions, emulsions or implants, and forms for local injection are transdermal patches, ointments, creams or powders. The compounds of formula I in accordance with paragraph 1 and/or their pharmaceutically acceptable salt and solvate can be dried, which results in liofilizatow used, for example, to obtain injectable products. The above-mentioned preparations can be sterilized form and/or may include excipients, such as agents that promote slippage tablets, preservatives, stabilizers and/or smace the surrounding agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, agents, giving coloring, flavoring and/or other active ingredients, for example one or more vitamins.

Drugs can, if it is desirable to be designed to provide slow release of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino)-methyl)-chroman-4-ol or its biocompatible salts or MES.

EXAMPLES

Example 1: (2R,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol

The heated suspension of 3.5 g of (2R,4R/S)-2-chloromethyl-4-hydroxychromone in 200 ml of acetonitrile was treated with 4.5 g of triethylamine to obtain a yellow solution. To this solution was added 4 g of sodium bicarbonate and 4 g of the hydrochloride of 3-(4-forfinal)-pyridyl-5-methylamine in 100 ml of acetonitrile. The reaction mixture was subjected to reflux during the night to obtain a red solution. The mixture was subjected to evaporation, the obtained residue was transferred into ethyl acetate, washed with water and dried with sodium sulfate. The organic solution is evaporated to a dry residue. The obtained residue was purified using chromatography. The purified compound was converted into the hydrochloride (2R,4R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol in ethanol. The freezing point is 165°C. the Yield was 800 mg To the ome N-monoalkylamines compound was obtained N-dialkylamino connection and the source material.

Example 2:(2R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol

1. 300 mg of (2R/S)-2-[5-(4-forfinal)-3-pyridylmethylamine]-7-methoxypropane was treated with 25 ml of Hydrobromic acid (48% in water) at a temperature of 130°C. the Obtained red solution was neutralized and subjected to processing as described in Example 1. Received 130 mg hydrobromide (2R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-7-ol;

Rf=0.27 in a mixture of ethyl acetate/methanol 8/2.

Similarly, the connection was received as maleate 2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl) chroman-7-ol.

2. Analogously to Example 2.1, (2R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-8-methoxypropan were subjected to treatment with hydrogen bromide to obtain hydrobromide (2R/S)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-8-ol.

Example 3:

Within 2 hours in small portions was added to borohydride sodium in the number 26,0 g to a stirred mixture of 20.0 g of compound of formula VII in 250 ml of methanol. After stirring the mixture for 1 hour at room temperature was added 500 ml of water and 800 ml of ethyl acetate. The organic layer was separated and solvent was removed and the residue was subjected to conventional processing. After crystallization from toluene received enantiomeric and diastereoisomeric net connection fo the mules VIII.

Example 4:

A solution of 3.7 g of the aldehyde VIA and 3.3 g of amine V (obtained according to WO 02/20507, Example 3 (2), of the compounds of formula (VIII) and a catalytic amount of p-toluensulfonate acid in 280 ml of toluene was subjected to boiling under reflux for three hours using a water separator. The mixture was left to cool at room temperature before adding 100 ml of methanol. Within 30 minutes to a stirred mixture was added 4.0 g of sodium borohydride in small portions. After stirring the mixture for one hour at room temperature was added 100 ml of water and 200 ml of ethyl acetate. Separated the organic layer, the solvent was removed and the residue was subjected to conventional processing methods. Thus was obtained the free base of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.

In order to prepare the corresponding hydrochloride, the product was dissolved in 100 ml of ethanol and treated with 14,27 ml of IN hydrochloric acid solution in water. Remove the solvents and the residue was recrystallized from 50 ml of ethanol. Thus obtained compound (2R,4R)-2({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol as a hemihydrate of monochloride in enantiomerically pure form.

Example 5:

The affinity of the receptor 5-HT1Amaybe the definition is Lena in vitro using experiments on radioligand binding in accordance with Cossery JM, etc. (Eur. J. Pharmacol. 1987; 140: 143-155). Functional agonistic properties on the receptor 5HT1Acan be determined in vitro in a GTP-gamma-S analysis (Newman-Tancredi a, and others, Eur. J. Pharmacol. 1996; 307: 107-111). A standard animal model for determination of 5-HT1Aagonistic properties is a test of ultrasonic treatment on rats (e.g., de J Fry and others, Eur. J. Pharmacol. 1993; 249: 331-339; Sanchez C, Behav. Pharmacol. 1993; 4: 269-277). The affinity for the dopamine receptor D4 may be determined in vitro using experiments on radioligand binding in accordance with Klokow M and others (Drug Res. 1986; 36: 197-200). The compound (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}methyl)-chroman-4-ol is associated with 5-HT1Areceptors with the value of the IC50that is 10 nm, and D4 receptors with the value of the IC5012 nm. In addition, there is no or there is a very weak binding to D2 receptors. Its agonistic properties against 5-HT1Aconfirmed in vitro in a GTP-gamma-S test, which gives the value of the ED5033 nm and in vivo using ultrasound with the value of the ED502 mg/kg

The following examples relate to pharmaceutical products.

Example: Vials

A solution of 100 g of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES, and 5 g of disodium hydrogen phosphate in 3 l of bidis is fillerbunny water brought to pH of 6.5 using 2N hydrochloric acid, sterilized through a filter, filled the vials were subjected to freeze-drying under sterile conditions and sealed under sterile form. Each vial contains 5 mg of active ingredient.

Example: Suppositories

A mixture of 20 g of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES melted with 100 g of soya lecithin and 1400 g of cocoa butter, the mixture was poured into molds and left to cool. Each suppository contains 20 mg of the active ingredient.

Example: Solution

The solution was prepared from 1 g of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES, 9,38 g NaH2PO4•2H2O, 28,48 g of Na2HPO4•12H2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH value was adjusted to 6.8, and the solution was brought to 1 l and sterilized using radiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES mixed with 99.5 g of vaseline under sterile conditions.

Example E-1: Tablets

A mixture of 1 kg of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt resolute, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate were subjected to pelletizing the usual way so that each tablet contained 10 mg of the active ingredient.

Example E-2: Tablets

A mixture of 20 g of the hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, 1 kg, 1-stage, 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 were subjected to pelletizing the usual way so that each tablet contained 0.2 mg of hemihydrate of monochloride (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol, 10 mg of 1-DOPA and 2.5 mg benserazide.

Example F: Tablets, coated sugar

The mixture was subjected to pelletizing analogously to Example E, the pill consistently covered in the usual way using a coating of sucrose, potato starch, talc, tragakant and coloring matter.

Example G: capsules

2 kg (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES filled hard gelatin capsules in a conventional way so that each capsule contained 20 mg of the active ingredient.

Example N: Ampoules

A solution of 1 kg of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or a physiologically acceptable salt or MES in 60 l of bidis is fillerbunny water, which was sterilized with a filter filled capsules were subjected to freeze-drying under sterile conditions and sealed under sterile form. Each ampoule contains 10 mg of active ingredient.

Example I: Aerosol for inhalation

14 g of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino)-methyl)-chroman-4-ol or a physiologically acceptable salt or MES was dissolved in 10 l of isotonic NaCl solution, the solution was filled available commercial aerosol containers with inflation. The slurry is sprayed into the mouth or nose. One pumping (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg

1. The use of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol or its pharmaceutically acceptable salt or solvate for the manufacture of a medicinal product for the treatment of catalepsy.

2. Pharmaceutical composition for the treatment of catalepsy, comprising as an active ingredient pharmaceutically effective amount of (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol in combination with one or more pharmaceutically acceptable excipients.

3. (2R,4R)-2-({[5-(4-forfinal)-pyridine-3-ylmethyl]-amino}-methyl)-chroman-4-ol.



 

Same patents:

FIELD: organic chemistry, chemical technology.

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EFFECT: improved method of synthesis.

14 cl, 5 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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EFFECT: valuable biological and biochemical property of compounds.

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FIELD: organic chemistry, medicine, pharmacy.

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17 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

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26 cl, 2 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel benzofuran derivatives comprising group of carbamoyl type of the formula [1]: wherein cycle Z represents group of the formula or A represents a simple bond or group of the formula -NH-; Y represents lower alkylene group, cycloalkanediyl group, phenyl group or piperidyl group; R4 and R5 are similar or different, and each represents hydrogen atom, unsubstituted lower alkyl group, lower alkyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, lower alkyl group substituted with hydroxyl group, lower alkyl group substituted with lower alkoxy group, or lower alkyl group substituted with pyridyl group; or R4 and R5 represent tetrahydropyranyl; or R4 and R are bound by ends to form in common with adjacent nitrogen atom and represent pyrrolidinyl group, morpholinyl group, pyrrolidinyl group substituted with (hydroxy)(lower alkyl) group, pyrrolidinyl group substituted with hydroxyl group, thiomorpholinyl group, piperidinyl group, piperdinyl group substituted with hydroxyl group, piperazinyl group substituted with (hydroxy)(lower alkyl) group, piperidinyl group substituted with (hydroxy)(lower alkyl) group, piperazinyl group substituted with lower alkyl group, pyrrolidinyl group substituted with lower alkoxycarbonylamino group, piperidinyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, or piperidinyl group substituted with lower alkoxycarbonyl group; R1 represents hydrogen atom, halogen atom or lower alkyl group; cycle B of the formula: represents benzene cycle optionally substituted with one or two groups chosen independently from halogen atom, optionally substituted lower alkyl group, hydroxy group, lower alkoxy group optionally substituted with alkoxycarbonyl group or amino group; carbonyl group optionally substituted with lower alkoxy group, hydroxyl group, amino group optionally substituted with 1-2 alkyl groups, morpholinyl or pyrrolidyl group; optionally substituted amino group; R3 represents hydrogen atom or lower alkyl group. Also, invention relates to it's a pharmaceutically acceptable salt that are useful as Fxa inhibitors. Also, invention relates to a pharmaceutical composition based on these compounds and their using in treatment of thrombosis.

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18 cl, 22 tbl, 143 ex

FIELD: organic chemistry, medicine, pharmacy.

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 represents hydrogen atom or linear or branched (C1-C4)-alkyl group; R2 represents hydrogen atom or linear or branched (C1-C4)-alkyl group; R3 represents phenyl, thienyl or furyl group that are substituted optionally with one or more linear or branched (C1-C4)-alkyl group, linear or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 represent independently of one another hydrogen atom, (C3-C6)-cycloalkyl group, linear or branched (C1-C4)-alkyl group comprising optionally amino-group or amino-group substituted with one or two linear or branched (C1-C4)-alkyl groups, hydroxy-group, carboxy-group or alkoxy-group substituted with linear or branched (C1-C4)-alkyl group; or R4 represents hydrogen atom or linear or branched (C1-C4)-alkyl group or benzyl group; R5 represents hydrogen atom, group -SO2OH or formyl group, or R4 and R5 in common with nitrogen atom form group of the general formula (a): wherein R7 and R8 represent independently one another hydrogen atom, linear or branched (C1-C4)-alkyl group; R6 represents phenyl, benzyl, thienyl or furyl group that are substituted optionally with methylenedioxy-group or one or more linear or branched (C1-C4)-alkyl group, linear or branched (C1-C4)-alkoxy-group or halogen atom; X represents group -NH or oxygen atom; Z represents oxygen atom, sulfur atom, group -CH2, group -NH or group -NR11 wherein R11 represents hydrogen atom, linear or branched (C1-C4)-alkyl group, group -SO2OH, linear or branched (C1-C4)-acyl group; n = 0, 1 or 2; m = 1, 2 or 3; o = 1, 2 or 3; p = 0 or 1; r = 0 or 1, and their salts and solvates. Also, invention relates to a method for synthesis of compounds of the general formula (I), to a pharmaceutical composition, its using and to compounds of the general formulas (I''), (II''), (III''), (IV''), (V''), (VI''), (VII''), (VIII'') and (XIII'') given in the invention description. Invention provides synthesis of novel biologically active compounds that are ligands of adenosine A3 receptors but as antagonists preferably.

EFFECT: valuable biological properties of compounds.

20 cl, 1 tbl, 40 ex

FIELD: organic chemistry, chemical technology.

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

11 cl, 9 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes novel 2-amino-4-bicycloamino-1,3,5-triazines of the general formula (I): wherein R1 and R2 mean independently hydrogen atom, amino-group, (C1-C6)-alkyl, (C1-C4)-alkanoyl, phenylalkyl c 1-6 carbon atoms in alkyl moiety and possibly substituted with halogen atom; or R1 and R2 in common with nitrogen atom to which they are bound form morpholino-group; R3 means hydrogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, hydroxy-, amino-, di-(C1-C4-alkyl)amino-, cyano-group, phenyl, (C1-C4)-alkoxy-, carboxy-group or (C3-C9)-cycloalkyl that can be substituted with halogen atom, phenyl possibly substituted with halogen atom, (C1-C6)-alkyl, hydroxy-group or phenyl, amino-, di-(C1-C4-alkyl)amino-, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, or (C2-C6)-alkenyl; R4 and R5 mean independently hydrogen atom, (C1-C4)-alkyl or (C1-C4)-alkanoyl; R6 means independently (C1-C6)-alkyl, (C1-C6)-alkoxy-group or halogen atom; Y1 means a direct bond or -CH2-; Y2 means group -CRaRb wherein Ra and Rb mean independently hydrogen atom or (C1-C6)-alkyl; Y3 means a direct bond, Y2-independent group -CRaRb wherein Ra and Rb mean independently hydrogen atom or (C1-C6)-alkyl, or bivalent group of the formula -O-, -S-; m means 1, 2 or 3; n means 0, 1, 2, 3 or 4, or their salts. Novel compounds possess herbicide activity with the effectiveness 60-100%, for example, in rice plantings and wherein damages of cultivate plants do not exceed 10%.

EFFECT: valuable herbicide properties of compounds.

7 cl, 1 tbl, 4 ex

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

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

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated pyrrolo[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers, pharmaceutically acceptable salts and/or hydrates that can be used, for example, in treatment and prophylaxis of different neurodegenerative diseases, such as Alzheimer's syndrome. In the general formula (1): a dotted line with accompanying unbroken line represents ordinary or double bond; R1 and R2 represent independently of one another substitutes of amino group chosen from hydrogen atom, possibly substituted (C1-C6)-alkyl substituted possibly with aryl, possibly substituted phenyl, possibly substituted carbonylamino or thiocarbonylamino group, substituted acyl, possibly substituted aryl sulfonate wherein substituted in indicated R1 and R2 are chosen from (C1-C6)-alkyl, halogen atoms, nitro, carboxy, alkoxy group, aryl; R1n represents one or some similar or different substituted of cyclic system chosen from hydrogen atom, alkyl, aryl, cyano group, halogen atom, 5-6-membered nitrogen-containing heteroaryl. Also, invention relates to methods for synthesis of these compounds, pharmaceutical compositions and their using, and to using compounds in libraries with their using.

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

20 cl, 2 tbl, 12 ex

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