New tetracyclic arylcarbonylindols with affinity to serotonine receptors applicable as pharmaceuticals, method of their production and pharmaceutical compositions on their base

FIELD: chemistry.

SUBSTANCE: described is the compound of the general formula , where R1, R2, R3, R4, R5, R6, R7, R8 can be identical or different represent independently hydrogen, halogen, percahalogenalkyl, (C1-C3)alkyl or (C1-C3)alkoxy; R9, R10, R11, R12 R13 and R14 can be identical or different and represent independently hydrogen or (C1-C3)alkyl; "n" is equal to 1 or 2, it is preferable that n be equal to 1; not obligatorily R13 and R14 together with nitrogen atom cab form a 6- term heterocyclic ring, where heterocycle can also be substituted by (C1-C3)alkyl that can have "additional heretoatoms", selected from N and O. Described also are intermediate compounds, the method of their production, pharmaceutical composition and the use of pharmaceuticals intended for treatment of the cases when modulation of the 5-HT receptor activity.

EFFECT: compounds as per this invention are applicable in treatment of disturbances of nervous system.

16 cl, 34 ex

 

The present invention relates to novel tetracyclic to arylcarbamoyl, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, a new intermediate compounds described herein, and the pharmaceutically acceptable compositions.

General formula (I)

The present invention also relates to a method of obtaining compounds of General formula (I), their tautomeric forms, their stereoisomers, their geometric forms, their N-oxides, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, new intermediate compounds described herein, and the pharmaceutically acceptable compositions.

Compounds of General formula (I) of this invention are ligands of 5-HT (serotonin), such as agonists or antagonists.

Thus, compounds of General formula (I) of this invention are suitable for treating diseases in which, in order to get the desired effect, modulate the activity of 5-HT (serotonin). Specifically, the compounds of this invention are suitable for treatment and/or prevention of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophrenic disorders forms, anxiety, migraines, depression, is arkamani, convulsive syndromes, personality disorders, hypertension, autism, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders and sleep disorders.

Compounds of General formula (I) of the present invention is also suitable for the treatment of psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and extrapyramidal motor side effects of other antipsychotic drugs.

Compounds of General formula (I) of the present invention is also suitable for the treatment of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and horii's disease, and vomiting caused by chemotherapy. Compounds of General formula (I) of the present invention is also suitable for modulation of feeding behavior and, thus, are suitable for reducing morbidity and mortality associated with overweight.

In many diseases of the Central nervous system is affected by adrenergic, dopaminergic and serotonergic neurotransmitter system. Serotonin is involved in a number of diseases and conditions that occur in the Central nervous system. These include diseases and conditions associated with sleep, eating, experiencing pain, regulation of body temperature, regulation of blood pressure, depression, anxiety, sizor the company and other physical conditions. (References: Fuller R.W., Drugs Acting on Serotonergic Neuronal Systems Biology of Serotonergic Transmission, John Wiley & Sons Ltd. (1982), 221 to 247; Boullin D.J., Serotonin in Mental abnormalities (1978), 1, 316; J. Barchas et al., Serotonin and Behavior (1973)). Serotonin also plays an important role in peripheral systems, such as gastro-intestinal system, where found, it is an intermediary in many of contractile, secretory, and electrophysiological actions.

Because of the wide distribution of serotonin in the body there are a number of interests and applications in respect of drugs that affect the serotonergic system. In particular, compounds with receptor specific agonism and/or antagonism, and are preferred for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease and horii's disease, and vomiting caused by chemotherapy (reference: who is a M.D. et al., The peripheral actions of 5-Hydroxytryptamine (1989), 246; Saxena P.R. et al., Journal of Cardiovascular Pharmacology (1990), supplement 7, 15).

Major classes of serotonin receptors (5-HT1-7contain fourteen-eighteen separate receptors, classified formally (reference: Glennon et al., Neuroscience and Behavioral Reviews (1990), 14, 35, and D. Hoyer et al., Pharmacol. Rev. (1994), 46, 157-203). Recently discovered details rmacy, concerning the identity, distribution, structure and functions of the subtypes, suggesting that it is possible to identify new podtoplenie substances with improved therapeutic profiles with less side effects. Receptor 5-HT6identified in 1993 (reference: Monsma et al., Mol. Pharmacol. (1993), 43, 320-327, and Ruat M. et al., Biochem. Biophys. Res. Com. (1993), 193, 269-276). Some antidepressants and atypical antipsychotics are associated with receptor 5-HT6with high affinity, and this binding can be a factor in their profile of activities (reference: Roth et al., J. Pharm. Exp. Therapeut. (1994), 268, 1403-1410; Sleight et al., Exp. Opin. Ther. Patents (1998), 8, 1217-1224; Bourson et al., Brit. J. Pharmacol. (1998), 125, 1562-1566; Boess et al., Mol. Pharmacol., 1998, 54, 577-583; Sleight et al., Brit. J. Pharmacol. (1998), 124, 556-562). In addition, the receptor 5-HT6associated with generalized stress and anxiety condition (reference: Yoshioka et al., Life Sciences (1998), 17/18, 1473-1477). Together these studies and observations suggest that compounds antagonistic receptor 5-HT6will be suitable in the treatment of various disorders of the Central nervous system.

U.S. patent 4839377 and U.S. patent 4855314 refer to 5-substituted 3-aminoalkylindoles. It is reported that the compound suitable for the treatment of migraine.

Patent UK 2035310 relates to 3-aminoalkyl-1N-indol-5-thioamides and carboxamides. It is reported that the joint is suitable for the treatment of hypertension, disease Raymond and migraines.

Publication of the European patent 303506 relates to 3-polyhydroxyethyl-5-substituted 1H-indoles. It is reported that the compounds have activity receptor agonists 5-HT1and vasoconstrictor activity and are suitable for the treatment of migraine. Publication of the European patent 354777 relates to the derivatives of sulfonamides N-piperidinecarbonitrile. It is reported that the compounds are agonists of the receptor 5-HT1and have vasoconstrictor activity and are suitable for the treatment of headache.

Publication of the European patent 438230 refers to indorsement five-membered heteroaromatic compounds. It is reported that the compounds have activity agonists of 5-HT1-like receptors and are suitable for the treatment of migraine and other disorders in which is shown a selective agonist of these receptors.

Publication of the European patent 313397 refers to 5-heterocyclic derivatives of indole. It is reported that the compounds have exceptional properties for the treatment and prevention of migraine, hemicrania and headache associated with vascular disorders. It is also reported that these compounds possess exceptional agonism regarding "5-HT1-like" receptors.

Publication of International patent WO 91/18897 refers to 5-heterocy the symbolic derivatives of indole. It is reported that the compounds have exceptional properties for the treatment and prevention of migraine, hemicrania and headache associated with vascular disorders. It is also reported that these compounds possess exceptional agonism regarding "5-HT1-like" receptors.

Publication of the European patent 457701 refers to arylacetamide derivative with high affinity to the serotonin receptors 5-HT1D. It is reported that these compounds are suitable for treating diseases associated with dysfunction of the serotonin receptors, such as migraine.

Publication of the European patent 497512 A2 belongs to a class of derivatives of imidazole, triazole and tetrazole, which are selective agonists for 5-HT1-like" receptors. It is reported that these compounds are suitable for treatment of migraine and associated disorders.

In the published International patent application WO 93/00086 describes a number tetrahydrocarbazole derivatives as agonists of the receptor 5-HT1suitable for treatment of migraine and related conditions.

Publication of international patent WO 93/23396 refers to condensed derivatives of imidazole and triazole as agonists of the receptor 5-HT1suitable for treatment of migraine and other disorders.

Schoeffter et al. in his article "SDZ216-525, a selective and potent 5-N is 1Areceptor antagonist" in European Journal of Pharmacology, 244, 251-257 (1993), mention methyl-4-{4-[4-(1,1,3-trioxo-2H-1,2-benzisothiazol-2-yl)butyl]-1-piperazinil}-1H-indole-3-carboxylate as a selective receptor antagonist 5-HT1A.

Publication of international patent WO 94/06769 relates to derivatives of 2-substituted 4-piperazineethanol, which are substances that are active against serotonin receptors 5-HT1Aand 5-HT1Dsuitable for the treatment of anxiety, depression, migraine, stroke, angina and hypertension.

The present invention relates to novel tetracyclic to arylcarbamoyl, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, a new intermediate compounds described herein, and the pharmaceutically acceptable compositions.

More specifically, the present invention relates to novel tetracyclic to arylcarbamoyl General formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, a new intermediate compounds described herein, and the pharmaceutically acceptable compositions.

General formula (I)

In the above formula, R1, R2, Rsub> 3, R4, R5, R6, R7, R8, R9, R10, R11and R12may be the same or different and represent, each independently, hydrogen, halogen, perhalogenated, substituted or unsubstituted groups such as linear or branched (C1-C3)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, sulfonic acid and its derivatives,

R13and R14may be the same or different and represent, each independently, hydrogen, substituted or unsubstituted groups such as linear or branched (C1-C3)alkyl, (C3-C7)cycloalkyl may, R13and R14together with the nitrogen atom can form a 6 - or 7-membered heterocyclic ring, where the heterocycle may also be substituted and he can have one, two or three double bonds or more heteroatoms, as described above.

"n" is an integer 1 or 2. It is preferable that n was equal to 1.

A partial list of such compounds of General formula (I) include the following compounds:

11-(2-N,N-dimethylaminoethyl)isoindole[2.1-a]indol-6-he;

<> 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-he;

the hydrochloride salt of 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

salt of maleic acid, 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

salt D,L-malic acid 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

the oxalate salt of 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

the citrate salt of 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

11-[(2-N-cyclopropyl-N-methylamino)ethyl]-2-horizontale[2.1-a]indol-6-he;

11-[(2-N-cyclopropyl)ethyl]-2-horizontale[2.1-a]indol-6-he;

2-bromo-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he;

2-chloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he;

4-chloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-2-methylisoxazole[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-2-methoxyindole[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-4-methoxyindole[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-4-triftormetilfosfinov[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-4-utilizando[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-2,4-depersonal[2.1-a]indol-6-he;

2,4-dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he;

3,4-dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he;

1,2,4-trichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-of the;

11-[(2-N,N-dimethylamino)ethyl]-2,4-dimethylisoxazole[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)ethyl]-3,4-dimethylisoxazole[2.1-a]indol-6-he;

1-chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-he;

3-chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-he;

11-[(2-N,N-dimethylamino)propyl]-4-methylisoxazole[2.1-a]indol-6-he;

3-chloro-11-[(2-N-methylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-he;

3-chloro-11-[(2-N-methyl-N-acetylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-he;

3-chloro-11-[(2-N-methylamino)ethyl]-2-methoxyindole[2.1-a]indol-6-he;

3-chloro-11-[(2-N-methylamino)ethyl]-2-sulphamethizole[2.1-a]indol-6-he;

3-iodine-11-[(2-N-methylamino)ethyl]-2-methoxyindole[2.1-a]indol-6-he;

2-bromo-11-[(2-morpholine-1-yl)ethyl]isoindole[2.1-a]indol-6-he;

2-bromo-11-[2-(4-methylpiperazin-1-yl)ethyl]isoindole[2.1-a]indol-6-he;

and stereoisomers, N-oxides, their polymorphs, their pharmaceutically acceptable salt and solvate.

The present invention also applies to some suitable biologically active metabolites of compounds of General formula (I).

Compounds of General formula (I) of this invention are suitable for treatment and/or prophylaxis of a condition in which the desired modulation of the activity of 5-HT.

The present invention relates to the use of compounds of General formula (I)above, to obtain drugs for their possible applications to the tion in the treatment and/or prevention of certain disorders of the Central nervous system, such as anxiety, depression, convulsive syndromes, obsessive-compulsive disorders, migraine, cognitive memory disorders, for example Alzheimer's disease and age-related decline in cognitive abilities, ADHD (attention deficit/hyperactivity disorder), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, disorders of the schizophrenic form, the syndrome of abuse of drugs, such as cocaine, ethanol, nicotine and benzodiazepines, panic attacks, sleep disorders (including disturbances of circadian rhythm), and also disorders associated with spinal trauma and/or damage the head, such as hydrocephalus. It is also expected that compounds of the invention will be applicable in the treatment of mild cognitive impairments and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's chorea.

It is also expected that compounds of the invention will be applicable in the treatment of certain GI (gastrointestinal) disorders such as IBS (irritable bowel syndrome) or vomiting caused by chemotherapy.

It is also expected that compounds of the invention will be applicable in the modulation of feeding behavior, and such compounds can also be used to reduce morbidity and mortality, tie is the R overweight.

The present invention relates to a method of treatment of a human or animal suffering from certain CNS disorders such as anxiety, depression, convulsive syndromes, obsessive-compulsive disorders, migraine, cognitive memory disorders, for example Alzheimer's disease and age-related decline in cognitive abilities, ADHD (attention deficit/hyperactivity disorder), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, disorders of the schizophrenic form, the syndrome of abuse of drugs, such as cocaine, ethanol, nicotine and benzodiazepines, panic attacks, sleep disorders (including disturbances circadian rhythm), and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. It is also expected that compounds of the invention will be applicable in the treatment of mild cognitive impairments and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's chorea.

The present invention also relates to a method desirable in some instances, modulation of the function of the receptors 5-HT.

The present invention also includes a radiolabelled compound, identical to the compounds defined by the General formula (I), but which in fact the Dean or more atoms are replaced by atoms, having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, bromine, and m is technetium, examples of which are2H,3H,11C,13C,14C,13N15N15O,18F,99mTc31P, S,123I and125I. Compounds of the present invention and pharmaceutically acceptable salts and prodrugs of such compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are included in the scope of this invention.

Radiolabelled compounds of the present invention is useful in the analysis of drugs and/or distribution in the substrate-tissues and employment targets. For example, compounds labeled with radioisotopes suitable, in particular, SPECT (single photon emission computed tomography) and PET (positron emission tomography).

An effective amount of the compounds of General formula (I) or its salt is used to produce medicines of the present invention together with conventional pharmaceutical excipients, carriers and additives.

The present invention also relates to pharmaceutical is the first composition for treatment and/or prevention of disorders - the state, in which the mammal is desired modulation of 5-HT containing

a) a pharmaceutically acceptable carrier,

b) the compound of General formula (I)above, and

(C) the inhibitor of the reuptake of 5-HT or its pharmaceutically acceptable salt;

in which the amount of each active compounds (compounds of General formula (I) and inhibitor reuptake 5-HT) such that their combination is effective in treating such condition.

The present invention also relates to a method of treatment and/or prevention of disorders - a condition in which the mammal is desired modulation of 5-HT, including the introduction of a pharmaceutical composition containing

a) a pharmaceutically acceptable carrier,

b) the compound of General formula (I)above, and

(C) the inhibitor of the reuptake of 5-HT or its pharmaceutically acceptable salt;

in which the amount of each active compounds (compounds of General formula (I) and inhibitor reuptake 5-HT) such that their combination is effective in treating such condition.

The present invention also relates to pharmaceutical compositions for the treatment and/or prevention of disorders - a condition in which the mammal is desired modulation of 5-HT containing

and pharmaceutically acceptable carries the eh,

b) the compound of General formula (I)above, and

(C) on melatonergic ligands or its pharmaceutically acceptable salt;

in which the amount of each active compounds (compounds of General formula (I) and on melatonergic ligand) such that their combination is effective in treating such condition.

The present invention also relates to a method of treatment and/or prevention of disorders - a condition in which the mammal is desired modulation of 5-HT, including the introduction of a pharmaceutical composition containing

a) a pharmaceutically acceptable carrier,

b) the compound of General formula (I)above, and

(C) on melatonergic ligands or its pharmaceutically acceptable salt;

in which the amount of each active compounds (compounds of General formula (I) and on melatonergic ligand) such that their combination is effective in treating such condition.

The present invention also relates to a method for producing the above compounds, their tautomeric forms, their stereoisomers, their geometric forms, their N-oxides, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, new intermediate compounds described herein, and pharmaceutical compositions containing them.

Detailed opisaniemopyta

The present invention relates to novel tetracyclic to arylcarbamoyl, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, a new intermediate compounds described herein, and the pharmaceutically acceptable compositions.

More specifically, the present invention relates to novel tetracyclic to arylcarbamoyl General formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate, a new intermediate compounds described herein, and the pharmaceutically acceptable compositions and to the use of such compounds in medicine.

General formula (I)

In the above formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12may be the same or different and represent, each independently, hydrogen, halogen, perhalogenated, substituted or unsubstituted groups such as linear or branched (C1-C3)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, acyl, and is iloxi, acylamino, monoalkylamines, dialkylamines, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, sulfonic acid and its derivatives,

R13and R14may be the same or different and represent, each independently, hydrogen, substituted or unsubstituted groups such as linear or branched (C1-C3)alkyl, (C3-C7)cycloalkyl, optional, R13and R14together with the nitrogen atom can form a 6 - or 7-membered heterocyclic ring, where the heterocycle may also be substituted and he can have one, two or three double bonds or more heteroatoms, as described above.

"n" is an integer 1 or 2. It is preferable that n was equal to 1.

Suitable groups represented by R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12may be a halogen atom such as fluorine, chlorine, bromine or iodine; perhalogenated, in particular peralagan(C1-C3)alkyl, such as vermeil, deformity, trifluoromethyl, triptorelin, foradil, defloratin and the like; linear or branched (C1-C3)alkyl group such as methyl, ethyl, n-propyl, isopropyl, cyclo(C3-C7)alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, t is cloepfil; (C1-C3)alkoxygroup, such as methoxy, ethoxy, propyloxy, isopropoxy; cyclo(C3-C7)alkoxygroup, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy, Cycloheptane and the like; aryl group such as phenyl or naphthyl, aracelio group, such as benzyl, phenethyl,6H5CH2CH2CH2naphthylmethyl etc., kalkilya group may be substituted, and the substituted kalkilya group represents a group, such as CH3With6H4CH2Hal-C6H4CH2CH3OS6H4CH2CH3OS6H4CH2CH2and the like; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy etc., urlcategory may be substituted; acyl group such as acetyl, propionyl or benzoyl, the acyl group may be substituted; alloctype, such as CH3Soo, CH3CH2Soo,6H5Soo, etc. which may be optionally substituted, allmenalp, such as CH3CONH, CH3CH2CONH, C3H7CONH, C6H5CONH, which may be substituted, (C1-C3)monoalkylamines, such as CH3NH, C2H5NH, C3H7NH, etc. which may be substituted, (C1-C )dialkylamino, such as N(CH3)2CH3(C2H5)N and the like, which may be substituted; alkoxyalkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. which may be substituted; aryloxyalkyl group, such as6H5Och2With6H5Och2CH2naphthylacetyl, etc. which may be substituted; alcoxialchil group, such as6H5CH2Och2With6H5CH2Och2CH2and the like, which may be substituted; and (C1-C6)-alkylthio, sulfonic acid or its derivatives, such as the SO2NH2, SO2NHCH3, SO2N(CH3)2, SO2NHCF3, SO2NHCO(C1-C6)alkyl, SO2NHCO-aryl, where the aryl group has the meanings given above, and sulfonic acid derivatives may be substituted.

R13and R14represents hydrogen, substituted or unsubstituted linear or branched (C1-C3)alkyl, such as methyl, ethyl, n-propyl, isopropyl, cyclo(C3-C7)alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Suitable heterocyclic rings formed by R13and R14together with the nitrogen atom are such heterocycles as pyrrolyl, pyrrolidinyl, piperidinyl, pyridine, 1,2,3,4-tetrahydropyridine, imidazolyl, pyrimidinyl, pyrazinyl, piperazinil, diazoline etc.; heterocyclyl group may be substituted; heteroaryl group such as pyridyl, imidazolyl, tetrazolyl and the like, the heteroaryl group may be substituted; heterocycle(C1-C6)alkyl, such as pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, occasionally etc., heterocycle(C1-C6)alkyl group may be substituted; heteroaryl group, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl etc., heteroalkyl group may be substituted.

In the case of compounds of General formula (I)containing an asymmetric carbon atom, the present invention relates to D-form, L-form and D,L-mixtures, and in the case of several asymmetric carbon atoms and diastereomeric forms of the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. These compounds of General formula (I)containing an asymmetric carbon atom and which, as a rule, get in the form of the racemates, can be separated from one another by conventional means, or any given isomer may be obtained stereospecific or asymmetric synthesis. However, it is also possible to use optically active compound ka is the source, and then the final connection receive, respectively, as active or diastereomers connection.

In the case of compounds of General formula (I), which can be tautomerism, the present invention relates to all possible tautomeric forms and their possible mixtures.

In the case of compounds of General formula (I)containing geometric isomers, the present invention applies to all such geometric isomers.

Suitable pharmaceutically acceptable salts of the acids of accession compounds of General formula (I) can be obtained from the above compounds of the bases of the present invention, which form non-toxic salts accession acids, and these include salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrates, sulphates, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartratami, bitartrate, succinate, maleate, fumarate, gluconate, saharty, benzoate, methanesulfonate, econsultancy, bansilalpet, p-toluensulfonate, palmoate and oxalates.

Suitable pharmaceutically acceptable salts of joining the bases of the compounds of General formula (I) can be obtained from the above compounds-acids of this invention, which form non-toxic salts attaching grounds, and to them relative to the tsya salt, containing pharmaceutically acceptable cations, such as lithium, sodium, potassium, calcium and magnesium salts, salts with organic bases, such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like bases; ammonium salts or substituted ammonium. Understood that pharmaceutically acceptable salts forming part of this invention, are defined, but are not limited to the above list.

In addition, pharmaceutically acceptable salts of the compounds of formula (I) can be obtained by transforming derivatives containing tertiary amino groups into the corresponding salts of Quaternary ammonium bases by methods known from the literature, using agents of quaternization. Possible quaternization agents are, for example, alkylhalogenide, such as modesty methyl, ethylbromide and n-propylchloride, including arylalkylamine, such as benzylchloride or 2-fenilatilamin. In addition to pharmaceutically acceptable salts of the invention include other salts. They can serve as intermediates in the purification of compounds, upon receipt of other salts, or in the identification and characterization of compounds or intermediates.

Pharmaceutically acceptable salts of compounds of formula (I) may exist in the form of a solvate, for example, with water, methanol is, ethanol, dimethylformamide, ethyl acetate and similar solvents. You can also get a mixture of such solvate. The basis of such a MES may be the solvent of crystallization, inert or crystallization or incidental to such a solvent. Such solvate included in the scope of this invention.

The invention also includes pharmaceutically acceptable prodrugs of compounds of formula (I). A prodrug is a drug that is chemically modified and may be biologically inactive in the scene, but which can be degraded or modified under the action of one or more enzymatic or other processes in vivo to its original form. This prodrug should have a different pharmacological profile than the original drug, making possible more easily absorbed through the epithelium of the mucous membranes, best salt formation or better solubility and/or improved system stability (e.g., increased half-life existence in the plasma). Typically, such chemical modifications include the following changes:

1) ester or amide derivatives which can be converted by esterases or lipases;

2) peptides that can be recognized by specific or nonspecific by proteases; Il the

3) derivatives that accumulate at the site of action through a selective membrane in respect of a prodrug, or a modified form of the prodrug; or any combination of the above 1-3.

Conventional procedures for the selection and obtaining the appropriate proletarienne derivatives are described, for example, in H. Bundgard, Design of prodrugs, (1985).

Compounds of General formula (I) can be obtained by any of the methods described below. The present invention also relates to methods of preparing compounds of General formula (I)above, their tautomeric forms, their stereoisomers, their geometric forms, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvate, new intermediate compounds described herein, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14and "n" have the meanings given above, which can be obtained by any of the methods described below.

Scheme 1

Compounds of General formula (I) can be obtained by cyclization of an intermediate compound of the following formula (II)

where X is a halogen, such as chlorine, bromine or iodine, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R 12, R13, R14and "n" have the meanings given above, using as the catalyst derived Pd(0) or Pd(II), for example, tetranitroaniline, (bis-tri-o-tolylphosphino)palladium and the like; followed, if necessary,

i) converting the compounds of formula (I) into another compound of formula (I); and/or

ii) removing any protective groups; and/or

iii) obtaining its pharmaceutically acceptable salt, MES, polymorph or prodrugs.

This cyclization reaction can be performed using a variety of palladium catalysts. The reaction can be influenced by the presence of a base, such as CH3The Cooke. This reaction can be performed in the presence of solvents such as THF, DMF, DMSO, DMA, DME, acetone and the like, and preferably dimethylacetamide. The inert atmosphere can be maintained by using inert gases such as N2, Ar or Not. The reaction temperature may vary from 50°to 200°C, depending on the chosen solvent, and preferably to interact at a temperature of 160°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 10 to 20 hours.

Scheme 2

Compounds of General formula (I) can be obtained by the interaction, in the sequence of stages or in one stage, the link given is th following formula (III)

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12and "n" have the meanings given above, with a suitable alkylating agent such as R13X or R14X or XR13R14X, where X is an easily removable group, such as halogen, hydroxyl and the like; and further, if desirable or necessary, the implementation stages (i), (ii) and/or (iii)above.

Interaction is preferable to carry out in an organic solvent, inert under the reaction conditions, such as acetone, THF or DMF and the like, or their mixture. The inert atmosphere can be maintained by using inert gases such as N2, Ar or Not. The reaction can be influenced by the presence of a base, such as2CO3, Na2CO3, Thea, or a mixture thereof. The reaction temperature may vary from 20°to 200°C, depending on the solvent, and preferably to interact at a temperature in the range from 30°to 150°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.

Scheme 3

Compounds of General formula (I) can be obtained by the interaction of the compounds of the following formula (IV)

where R1, R2, R3, R4, R5, R6, R7, R8and "n" have the meanings given above, with formaldehyde and a compound of the following formula (V)

Other13R14

(V)

where R13and R14have the meanings given above, followed, if desired or necessary, the implementation stages (i), (ii) and/or (iii)above.

The above interaction is preferably carried out at a temperature of 50°C-150°C. the Formaldehyde can be in the form of aqueous solution, i.e. a 40% formalin solution, or in polymeric form, such as paraformaldehyde or trioxymethylene. When using such polymeric forms, add a molar excess of an inorganic acid, for example chloroethanol acid for the regeneration of the polymer of the free aldehyde. The interaction is carried out preferably in an organic solvent, inert under the reaction conditions, such as methanol, ethanol or 3-methylbutanol, etc. or a mixture thereof, and preferably with the use or acetone, or DMF. The inert atmosphere can be maintained by using inert gases such as N2, Ar or Not. The reaction temperature may vary from 20°to 150°C, depending on the chosen solvent, and preferably to interact at a temperature in the range from 30°to 100°C. Long is th reaction can vary from 1 to 24 hours, preferably from 2 to 6 hours.

Scheme 4

Compounds of General formula (I) can be obtained from other compounds of formula (I)containing a group(s) -C(=O) in the side chain, known methods of recovery to the corresponding compounds containing-C(IT,N) or(N,N); followed, if desirable or necessary, the implementation stages (i), (ii) and/or (iii)above.

New intermediate compounds is below the General formula (IV)

where R1, R2, R3, R4, R5, R6, R7and R8may be the same or different and represent, each independently, hydrogen, halogen, perhalogenated, substituted or unsubstituted groups such as linear or branched (C1-C3)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, sulfonic acid and its derivatives.

The present invention also relates to a process for the preparation of intermediate compounds of General formula (IV)comprising the cyclization of compounds of formula (VIII)

where R1, R2, R3 , R4, R5, R6, R7and R8have the meanings given above and X represents halogen, such as chlorine, bromine or iodine, using as a catalyst derived Pd(0) or Pd(II), for example tetranitroaniline, (bis-tri-o-tolylphosphino)palladium and the like, in a suitable solvent.

During the implementation of any of the above sequences of synthesis may be necessary and/or desirable to protect sensitive or reactive groups on any of the relevant molecules. This can be achieved using a conventional protective groups such as the groups described in Protective Groups in Organic Chemistry, Ed J.F.W. McOmie, Plenum Press, 1973; and in T.W. Greene &P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. For example, suitable protective groups for piperazino groups are BOC, COCCl3, COCF3. The protective group can be removed according to known procedures.

The protective group can be removed at a convenient stage in the sequence of reactions using methods known in the art.

Compounds of the present invention may contain one or more asymmetric centers, and thus they can exist as stereoisomers. The stereoisomers of the compounds of the present invention can be obtained in one or more ways below.

i Can use the ü one or more reagents in their optically active form.

ii) In the recovery process together with a metal catalyst can be used optically pure catalyst or a chiral ligand. The metal catalyst may be rhodium, ruthenium, indium and the like metal. Chiral ligands may represent a preferred chiral phosphines (Principles of Asymmetric synthesis, J.E. Baldwin Ed., Tetrahedron series, 14, 311-316).

iii) a Mixture of stereoisomers can be split in the usual ways, such as the formation of diastereomeric salts with chiral acids or chiral amines, or karelinii the aminoalcohols, chiral amino acids. Then the resulting mixture of diastereomers can be divided through methods such as fractional crystallization, chromatography and the like, followed by an additional stage of selection optically active product derived by hydrolysis (Jacques et al., "Enantiomers, Racemates and Resolution", Wiley Interscience, 1981).

iv) a Mixture of stereoisomers can be split in the usual ways, such as microbial separation and splitting of the diastereomeric salts formed with chiral acids or chiral bases.

Chiral acids that can be used can be represented as tartaric acid, almond acid, lactic acid, camphorsulfonic acid, amino acids and other Chiral base that you can use may constitute hin the e alkaloids, brucine or a basic amino acid such as lysine, arginine, etc.

Pharmaceutically acceptable salts forming part of this invention, can be obtained by treating compound of formula (I) 1-6 equivalents of base, such as lithium, ammonium, substituted ammonium, sodium hydride, sodium methoxide, ethoxide sodium, sodium hydroxide, tert-piperonyl potassium, calcium hydroxide, calcium acetate, calcium chloride, magnesium hydroxide, magnesium chloride, etc. Can be used solvents such as water, acetone, ether, THF, methanol, ethanol, tert-butanol, dioxane, isopropanol, isopropyl ether, or a mixture thereof. It is possible to use organic bases such as lysine, arginine, methylbenzylamine, ethanolamine, diethanolamine, tromethamine, choline, guanidine and derivatives thereof. Salt accession acids, for any application, can be obtained by treatment with acids such as tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, benzolsulfonat acid, p-toluensulfonate acid, hydroxynaphthoic acid, methanesulfonate acid, malic acid, acetic acid, benzoic acid, succinic acid, palmitic acid, oxalic acid, chloromethane acid, Hydrobromic acid, sulfuric acid, nitric sour is and etc, in solvents such as water, alcohols, ethers, ethyl acetate, dioxane, DMF or lower alkylene, such as acetone, or mixtures thereof.

Different polymorphs can be obtained by crystallization of the compounds of General formula (I) in different conditions, such as different solvents or solvent mixtures in different proportions for recrystallization, various methods of crystallization, such as slow cooling, rapid cooling or very rapid cooling, or speed cooling during crystallization. Different polymorphs can also be obtained by heating compound, melting connection and otorita it by gradual or fast cooling, heating or melting the compound under vacuum or in an inert atmosphere and cooling in vacuum or in an inert atmosphere. Different polymorphs can be identified by one or more methods, such as differential scanning calorimetry, powder x-ray diffraction, IR spectroscopy, NMR spectroscopy of solid sample and thermal microscopy.

Another aspect of the present invention is a pharmaceutical composition comprising as active ingredient at least one representative compounds of General formula (I), their derivatives, their tautomeric forms, their stereoisomers, their geometric fo the m their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate together with used in pharmacy carriers, auxiliary substances and similar substances.

The pharmaceutical compositions of the present invention can be obtained in the usual way using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention can be introduced into the compositions for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal injection or in a form suitable for administration by inhalation or insufflate.

The dose of the active compounds can vary depending on such factors as the route of administration, age and weight of the patient, nature and severity of the disease, which is treated and similar factors. Therefore, any reference in this description to pharmacologically effective amount of the compounds of General formula (I) correlates with the above factors.

For oral administration the pharmaceutical compositions may take the form of, for example, tablets or capsules, obtained by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., swollen corn starch, polyvinylpyrrolidone or hypromellose), the floor is Italy (for example, lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g. magnesium stearate, talc or silica), substances that contribute to dispersal (e.g., potato starch or matrikamantra)or wetting agents (e.g. sodium lauryl sulphate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for compounds with water or other suitable vehicle before use. Such liquid preparations can be obtained by conventional means with pharmaceutically acceptable additives such as suspendresume substances (for example, morbity syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or Arabian gum), non-aqueous vehicles (e.g. almond oil, ester oils or ethanol) and preservatives (e.g. methyl or propyl-p-oxybenzoates or sorbic acid).

For buccal administration of composition may take the form of tablets or lozenges, obtained in the usual way.

Active compounds of the invention can be introduced into the compositions for parenteral administration by injection, including known methods catheteriza and or infusion. Compositions for injection can be presented in a standard dosage form, for example in ampoules or in mnogochasovykh containers with added preservative. Such compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain substances that are added to the composition, such as suspendida, stabilizing and/or dispersing agents. On the other hand, the active ingredient may be in powder form for recovery before applying with suitable carriers, for example, sterile pyrogen-free water.

Active compounds of the invention can also be entered in the composition of the rectal compositions such as suppositories or retention enemas, e.g. containing conventional basis suppositories, such as cocoa butter or other glycerides.

For intranasal or administration by inhalation, the active compounds of the invention are usually delivered in the form of an aerosol spray from an aerosol container or a spray or capsules using an inhaler or insufflator. In the case of an aerosol suitable propellant, e.g. DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, and the standard dose can be measured using the installed valve to deliver dosiro the frame number. Drug for aerosol containers or nebulizer may contain a solution or suspension of active compound, while in the case of capsules, it should be preferably in powder form. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may contain a mixture of powders of the compounds of the invention and a suitable base such as lactose or starch.

The proposed dose of the active compounds of the present invention for oral, parenteral, nasal or buccal administration for the average adult human for the treatment of the conditions listed above, is 0.1-200 mg of the active ingredient at the standard dose, which you can enter, for example, 1-4 times per day.

Aerosol compositions for treating conditions specified above (e.g., migraine), the average adult human are preferably so that each measured dose or "unbounded" of aerosol contains 20 μg to 1000 μg of the compound of the invention. The total daily dose of the aerosol will be in the range from 100 μg to 10 mg of Introduction can be done several times a day, for example 2, 3, 4, or 8 times, giving each time, for example, 1, 2 or 3 doses.

The affinity of the compounds of this invention to various serotonin receptors assessed with ispolzovaniem analyses linking radio described below.

Analyses of the binding of radio-for the different subtypes of receptors 5-ht

i)Analysis for NT1A

Materials and methods:

Source receptor: human recombinant, expressed in cells of SOME 293

Radioligand: [3H]-8-OH-DPAT (221 CI/mmol)

The final concentration of ligand, [0.5 nm]

Standard connection: 8-OH-DPAT

Positive control: 8-OH-DPAT

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH 7.4)containing 10 mm MgSO4, 0.5 mm etc and 0.1% ascorbic acid at room temperature for 1 hour. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site NC1A.

References:

- Hoyer D., Engel G., et al. Molecular Pharmacology of 5HT1and 5-HT2Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [3H]-5HT, [3H]-8-OH-DPAT, [125I]-Iodocyanopindolol, [3H]-Mesulergine and [3H]-Ketanserin. Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications.

- Schoeffter P. and D. Hoyer How Selective is GR 43175? Interactions with Functional 5-HT1A, 5HT1B, 5-HT1C, and 5-HT1DReceptors. Naunyn-Schmiedeberg''s Arch. Pharmac. 340: 135-138 (1989) with modifications.

ii)Analysis for NT1B

Mate is ialy and methods:

Source receptors: rat veins membrane

Radioligand: [125I]-idianapolis (2200 CI/mmol)

The final concentration of ligand [0,15 nm]

Non-specific determinants: serotonin [10 μm]

Standard connection: serotonin

Positive control: serotonin

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH 7.4)containing 60 μm (-)-isoproterenol, at 37°C for 60 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site NC1B.

References:

- Hoyer D., Engel G., et al. Molecular Pharmacology of 5HT1and 5-HT2Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [3H]-5HT, [3H]-8-OH-DPAT, [125I]-Iodocyanopindolol, [3H]-Mesulergine and [3H]-Ketanserin.Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications.

- Schoeffter P. and D. Hoyer How selective is GR 43175? Interactions with Functional 5-HT1A, 5HT1B, 5-HT1C, and 5-HT1Receptors.Naunyn-Schmiedeberg''s Arch. Pharmac.340: 135-138 (1989) with modifications.

iii)Analysis for NT1D

Materials and methods:

The source of receptors: the cortical substance of the person

Radioligand: [3N]-5-carboxamidotryptamine (20-70 CI/mmol)

End oncentrate ligand [2.0 nm]

Non-specific determinants: 5-carboxamidotryptamine (5-ST) [1,0 µm]

Standard connection: 5-carboxamidotryptamine (5-ST)

Positive control: 5-carboxamidotryptamine (5-ST)

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH of 7.7)containing 4 mm CaCl2, 100 nm 8-OH-DPAT, 100 nm mesulergine, 10 nm of pargyline and 0.1% ascorbic acid, at 25°C for 60 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site cloned T1D.

References:

- Waeber C., Schoeffter, Palacios J.M. and D. Hoyer Molecular Pharmacology of the 5-HT1DRecognition Sites: Radioligand Binding Studies in Human, Pig, and Calf Brain Membranes. Naunyn-Schmiedeberg''s Arch. Pharmacol. 337: 595-601 (1988) with modifications.

iv)Analysis for NT2A

Materials and methods:

The source of receptors: the cortical substance of the person

Radioligand: [3H]-ketanserin (60-90 CI/mmol)

The final concentration of ligand [2.0 nm]

Non-specific determinants: ketanserin [3.0 mm]

Standard connection: ketanserin

Positive control: ketanserin

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH 7.5) at room temperature is round for 90 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site NC2A.

References:

- J.E. Leysen, Niemegeers C.J., Van Nueten J.M. and Laduron P.M. [3H]Ketanserin: A Selective Tritiated Ligand for Serotonin2Receptor Binding Sites. Mol. Pharmacol. 21: 301-314 (1982) with modifications.

- Martin, G.R. and Humphrey, P.P.A. Classification Review: Receptors for 5-HT: Current Perspectives on Classification and Nomenclature. Neuropharmacol. 33(3/4): 261-273 (1994).

v)Analysis for NT2C

Materials and methods:

Source receptor: membrane of choroid plexus pigs

Radioligand: [3N]-mesulergine (50-60 CI/mmol)

The final concentration of ligand [1.0 nm]

Non-specific determinants: serotonin [100 μm]

Standard connection: mianserin

Positive control: mianserin

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH of 7.7)containing 4 mm CaCl2and 0.1% ascorbic acid, at 37°C for 60 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions feel soy is inane with the binding site NC 2C.

References:

- A. Pazos, D. Hoyer, and J. Palacios. The Binding of Serotonergic Ligands to the Porcine Choroid Plexus: Characterization of a New Type of Serotonin Recognition Site. Eur. Jrnl. Pharmacol. 106: 539-546 (1985) with modifications.

- Hoyer, D., Engel, G., et al. Molecular Pharmacology of 5HT1and 5-HT2Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [3H]-5HT, [3H]-8-OH-DPAT, [125I]-Iodocyanopindolol, [3H]-Mesulergine and [3H]-Ketanserin. Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications.

vi)Analysis for NT3

Materials and methods:

Source receptor: cell N1E-115

Radioligand: [3N]-GR 65630 (30-70 CI/mmol)

The final concentration of ligand [0.35 nm]

Non-specific determinants: MDL-72222 [1,0 µm]

Standard connection: MDL-72222

Positive control: MDL-72222

Conditions of incubation:

The reaction is carried out in 20 mm HEPES (pH 7.4)containing 150 mm NaCl, at 25°C for 60 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site NC3.

References:

- S.C.R. Lummis, Kilpatrick G.J. Characterization of 5HT3Receptors in Intact N1E-115 Neuroblastoma Cells. Eur. Jrnl. Pharmacol. 189: 223-227 (1990) with modifications.

- Hoyer D. and Neijt H.C. Identification of Serotonin 5-HT3Recognition Sites in Membranes of N1E-115 Neuroblastoma Cells by Radioligand Binding. Mol. Pharmacol. 33: 303 (1988).

- M.B. Tyers 5-HT3Receptors and therapeutic Potential of 5HT3Receptor Antagonists. Therapie. 46:431-435 (1991).

vii)Analysis for NT4

Materials and methods:

Source receptor: veins of the membrane of the Guinea pig

Radioligand: [3N]-GR-113808 (30-70 CI/mmol)

The final concentration of ligand, [0,2 nm]

Non-specific determinants: serotonin (5-HT) [30 µm]

Standard connection: serotonin (5-HT)

Positive control: serotonin (5-HT)

Conditions of incubation:

The reaction is carried out in 50 mm HEPES (pH 7.4) at 37°C for 60 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site NC4.

Literary reference:

- Grossman Kilpatrick, C., et al. Development of a Radioligand Binding Assay for 5HT4Receptors in Guinea Pig and Rat Brain. Brit. J Pharmco. 109: 618-624 (1993).

viii)Analysis for NT5A

Materials and methods:

Source receptor: human recombinant, expressed in cells of SOME 293

Radioligand: [3N]-LSD (60-87 CI/mmol)

The final concentration of ligand [1.0 nm]

Non-specific determinants: mesilate methiothepin [1,0 µm]

Standard connection: mesilate methiothepin

Positive to ntrol: mesilate methiothepin

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH 7.4)containing 10 mm MgSO4and 0.5 mm etc, at 37°C for 60 minutes. The reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test compound with the binding site cloned T5A.

Literary reference:

- Rees, S., et al. FEBS Letters, 355: 242-246 (1994) with modifications

ix)Analysis for NT6

Materials and methods:

Source receptor: human recombinant, expressed in cells of SOME 293

Radioligand: [3N]-LSD (60-80 CI/mmol)

The final concentration of ligand [1.5 nm]

Non-specific determinants: mesilate methiothepin [0,1 µm]

Standard connection: mesilate methiothepin

Positive control: mesilate methiothepin

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH 7.4)containing 10 mm MgCl2and 0.5 mm etc, for 60 minutes at 37°C. the Reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test(s) connection(s) is the binding site cloned serotonin NT 6.

Literary reference:

- F.J. Monsma Jr., et al., Molecular Cloning and Expression of a Novel Serotonin Receptor with High Affinity for Tricyclic Psychotropic Drugs. Mol. Pharmacol. (43): 320-327 (1993).

x)Analysis for NT7

Materials and methods:

Source receptor: human recombinant, expressed in cells SNO

Radioligand: [3N]-LSD (60-80 CI/mmol)

The final concentration of ligand [2.5 nm]

Non-specific determinants: 5-carboxamidotryptamine (5-ST) [0,1 µm]

Standard connection: 5-carboxamidotryptamine

Positive control: 5-carboxamidotryptamine

Conditions of incubation:

The reaction is carried out in 50 mm Tris-HCl (pH 7.4)containing 10 mm MgCl2and 0.5 mm etc, for 60 minutes at 37°C. the Reaction is complete by rapid filtration under vacuum filters fiberglass. Determine the radioactivity of a substance, the detainee on the filters, and compared to control values in order to install any interactions of test(s) connection(s) with the binding site cloned serotonin NT7.

Literary reference:

- Y. Shen, E. Monsma, M. Metcalf, P. Jose, M Hamblin, D. Sibley, Molecular Cloning and Expression of a 5-hydroxytryptamine7 Serotonin Receptor Subtype. J. Biol. Chem. 268: 18200-18204.

Further description illustrates the method of obtaining differently substituted compounds of General formula (I) according to the methods described in this description. Such variants is repodata for illustration purposes only and therefore should not be construed as limiting the scope of the invention.

Commercial reagents are used without additional purification. Room temperature means a temperature of 25-30°C. the melting Temperature is not corrected. IR spectra were obtained using KBr and in the solid state. Unless otherwise stated, all mass spectra obtained using ESI conditions. Spectra1H-NMR spectrum recorded at 300 MHz on a Bruker instrument. As solvent using deuterated chloroform (99.8% of D). TMS used as an internal standard. The values of chemical shifts result in (δ)-values in ppm. For the NMR signals of the multiplet use the following abbreviations: s = singlet, Ushs = broadened singlet, d = doublet, t = triplet, K = Quartet, qui = quintet, g = septet, DD = double doublet, dt = double triplet, TT = triplet of triplets, m = multiplet. NMR, mass adjusted on the background peaks. The specific rotation was measured at room temperature using line D of sodium (589 nm). Chromatography means column chromatography is carried out using silica gel of 60-120 mesh and under conditions of nitrogen pressure (flash chromatography).

Description 1. N,N-Dimethyl-1-(2'-bromobenzoyl)tryptamine (D1)

A suspension of potassium hydride (15.0 mmol, 2.0 g (30% suspension in mineral oil, washed with THF before use)) in 30 ml THF is stirred and cooled to 10°C. To polycentropodidae solution gradually, within 15 min, keeping the temperature below 10°C, add a solution of N,N-dimethyltryptamine (15 mmol) in THF. Then after that, under a layer of nitrogen is added a solution of 2-bromobenzonitrile in THF (15 mmol, in 10 ml THF) and maintain the reaction temperature below 10° (exothermic reaction). Then the reaction mixture was kept at 20-25°even within 2-4 hours. Upon completion of reaction (TLC) the excess THF is distilled off and the concentrate is diluted with a mixture of water with ice, and extragere with ethyl acetate. United an ethyl acetate layer washed with water, dried over sodium sulfate and evaporated under reduced pressure at a temperature below 50°C.

The crude residue is purified column chromatography on silica gel using as mobile phase a mixture of 30% methanol in ethyl acetate and receive the intermediate compound N,N-dimethyl-1-(2'-bromobenzoyl)tryptamine, which identify the analyses by IR, NMR and mass spectrometry.

Description 2-21 (D2-D21)

Various intermediate indoles enter into interaction with substituted 2-bromobenzylcyanide according to the procedure described in step 1. The compounds identified by the analyses by IR, NMR and mass spectrometry. Among such compounds include the compounds listed below.

With the list 1
DescriptionMass ions (M+N)+
D12-[1-(2-Bromobenzoyl)indol-3-yl]ethyl-N,N-dimethylamine371
D22-[1-(2-Bromobenzoyl)-5-bromoindole-3-yl]ethyl-N,N-dimethylamine449
D32-[1-(2-Bromobenzoyl)-5-Clorinda-3-yl]ethyl-N,N-dimethylamine405
D42-[1-(2-Bromobenzoyl)-5-Florinda-3-yl]ethyl-N,N-dimethylamine389
D52-[1-(2-Bromobenzoyl)-5-methylindol-3-yl]ethyl-N,N-dimethylamine385
D62-[1-(2-Bromobenzoyl)-5-methoxyindol-3-yl]ethyl-N,N-dimethylamine401
D72-[1-(2-Bromobenzoyl)-7-ethylindole-3-yl]ethyl-N,N-dimethylamine399
D82-[1-(2-Bromobenzoyl)-7-Clorinda-3-yl]ethyl-N,N-dimethylamine405
D92-[1-(2-Bromobenzoyl)-7-methoxyindol-3-yl]ethyl-N,N-dimethylamine401
D102-[1-(2-Bromobenzoyl)-7-cryptomaterial-3-yl]ethyl-N,N-dimethylamine439
D112-[1-(2-Bromobenzoyl)-5,7-dichloride-3-yl]ethyl-N,N-dimethylamine439
D122-[1-(2-Bromobenzoyl)-6,7-dichloride-3-yl]ethyl-N,N-dimethyln is n 439
D132-[1-(2-Bromobenzoyl)-5,7-differental-3-yl]ethyl-N,N-dimethylamine407
D142-[1-(2-Bromobenzoyl)-5,7-dimethylindole-3-yl]ethyl-N,N-dimethylamine399
D152-[1-(2-Bromobenzoyl)-6,7-dimethylindole-3-yl]ethyl-N,N-dimethylamine399
D162-[1-(2-Bromobenzoyl)-4-chloro-7-methylindol-3-yl]ethyl-N,N-dimethylamine419
D172-[1-(2-Bromobenzoyl)-6-chloro-7-methylindol-3-yl]ethyl-N,N-dimethylamine419
D182-[1-(2-Bromobenzoyl)-4,5,7-trichloride-3-yl]ethyl-N,N-dimethylamine473
D192-[1-(2-Bromobenzoyl)indol-3-yl]-1-hydroxyethyl-N,N-dimethylamine387
D201-(2-Bromobenzoyl)-5-bromo-3-(2-(morpholino-1-yl)ethyl)-1H-indole491
D211-(2-Bromobenzoyl)-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indole504

Example 1. 11-(2-N,N-Dimethylaminoethyl)isoindole[2.1-a]indol-6-he

In a 100-ml 3-necked round-bottom flask is charged with 1-(2'-bromobenzoyl)-N,N-dimethyltryptamine (0,286 mol) with N,N-dimethylacetamide (40 ml), potassium acetate (0,286 mol, 0,281 g) and dichloro-bis(tri-o-tolylphosphino)palladium (0,0143 mol, 0,0126 g). The reaction mixture was kept in the atmosphere is nitrogen and heat at 160° With stirring for 16 hours. Upon completion of reaction (TLC) the excess of dimethylacetamide is evaporated under reduced pressure.

The resulting residue is purified column chromatography on silica gel using as eluent a mixture of 20% methanol in ethyl acetate and get named in the title compound, which identify the analyses by IR, NMR and mass spectrometry. The final desired compound of General formula (I) can be cleaned additionally, receiving its salt accession acids. IR spectrum (cm-1): 2939, 2779, 1721, 1446; MS (m/z): 291 (M+H)+;1H-NMR (δ ppm): of 2.38 (6H, s), 2.57 m-2,69 (2H, m), 3.00 and-3,10 (2H, m), 7,12-of 7.90 (8H, m).

Example 2. 11-[(2-N,N-Dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 112-117; IR spectrum (cm-1): 2940, 2780, 1730, 1466, 1446; MS (m/z): 309 (M+H)+;1H-NMR (δ ppm): at 2.36 (6H, s), 2.57 m-to 2.65 (2H, m), 2.95 and 3.00 for (2H, m), 6,93-7,81 (7H, m).

Example 3. Hydrochloride 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it

Compound of example No. 2 (199 mg) was dissolved in 30 ml of ether. To the resulting clear solution was added a mixture of isopropyl alcohol - hydrochloric acid (10 ml). Immediately separated white precipitate, which is filtered off, washed with EPE is om and dried. Interval TPL (°) >250 (decomp.).

Example 4. Salt of maleic acid, 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it

Compound of example No. 2 (205 mg) was dissolved in 30 ml of ether. To the resulting clear solution was added a solution of maleic acid (82 mg, dissolved in a mixture of 30 ml of ether + 5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 180-182 (decomp.).

Example 5. Salt D,L-malic acid 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it

Compound of example No. 2 (208 mg) was dissolved in 30 ml of ether. To the resulting clear solution was added a solution of D,L-malic acid (106 mg, dissolved in a mixture of 30 ml of ether + 5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 170-173.

Example 6. Oxalate 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it

Compound of example No. 2 (203 mg) was dissolved in 30 ml of ether. To the resulting clear solution was added a solution of oxalic acid (94 mg, dissolved in a mixture of 30 ml of ether + 5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 244-246 (decomp.).

Example 7. Citrate 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it

Compound of example No. (201 mg) was dissolved in 30 ml of ether. To the resulting clear solution was added a solution of citric acid (134 mg, dissolved in a mixture of 30 ml of ether + 5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 178-180.

Example 8. 2-Bromo-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval MP (°C): 118-121; IR spectrum (cm-1): 2942, 2759, 1718, 1444, 882, 761; MC (m/z): 369 (M+H)+, 371 (M+3)+;1H-NMR (δ ppm): at 2.36 (6H, s), 2.57 m-to 2.65 (2H, m), 2.95 and 3.00 for (2H, m), 7,29-to 7.77 (7H, m).

Example 9. 2-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2925, 2765, 1723, 1446, 1381, 758, 700; MC (m/z): 325 (M+H)+;1H-NMR (δ ppm): 2,32 (6H, s), 2,54-2,62 (2H, m), was 2.76-2,84 (2H, m), 7,27-7,73 (7H, m).

Example 10. 4-Chloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2942, 2779, 1746, 1417, 1343, 782, 700; MC (m/z): 325 (M+H)+;1H-NMR (δ ppm): 2,90 (6H, s), 3.27 to and 3.31 (2H, m), 3,52 is 3.57 (2H, m), 7,07-8,09 (7H, m).

Example 11. 11-[(2-N,N-Dimethylamino)ethyl]-2-methylisoxazole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 116-128; IR spectrum (cm-1): 2941, 2761, 1714, 1611, 1468; MC (m/z): 305 (M+H)+;1H-NMR (δ ppm): 2,39 (6H, s), 2,42 (3H, s), 2.57 m) was 2.76 (2H, m), 2,99-of 3.07 (2H, m), 7,07-to 7.67 (7H, m).

Example 12. 11-[(2-N,N-Dimethylamino)ethyl]-2-methoxyindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2941, 2773, 1466, 1371, 1237; MC (m/z): 321 (M+H)+;1H-NMR (δ ppm): 2,39 (6H, s), 2,60 of 2.68 (2H, m), 2,98-of 3.06 (2H, m), 3,85 (3H, s), 6,84-7,66 (7H, m).

Example 13. 11-[(2-N,N-Dimethylamino)ethyl]-4-methoxyindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2941, 2773, 1728, 1466, 1230; MC (m/z): 321 (M+H)+.

Example 14. 11-[(2-N,N-Dimethylamino)ethyl]-4-triftormetilfosfinov[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 359 (M+N)+.

Example 15. 11-[(2-N,N-Dimethylamino)ethyl]-4-utilizando[2.1-a]and the Dol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 319 (M+N)+.

Example 16. 11-[(2-N,N-Dimethylamino)ethyl]-2,4-depersonal[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 327 (M+N)+.

Example 17. 2,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 359 (M+N)+.

Example 18. 3,4-Dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 359 (M+N)+.

Example 19. 1,2,4-Trichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 393 (M+N)+.

Example 20. 11-[(2-N,N-Dimethylamino)ethyl]-2,4-dimethylisoxazole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some necri the ranks of changes to get the above derivative. Interval TPL (°C): 100-102; IR spectrum (cm-1): 2942, 2758, 1721, 1449, 1242; MC (m/z): 319 (M+H)+;1H-NMR (δ ppm): at 2.36 (3H, s), of 2.38 (6H, s), 2,61-to 2.65 (2H, m), 2,84 (3H, m), 2,97-3,00 (2H, s), 6.87 in to 7.75 (6H, m).

Example 21. 11-[(2-N,N-Dimethylamino)ethyl]-3,4-dimethylisoxazole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 119-121; IR spectrum (cm-1): 2941, 2762, 1719, 1305; MC (m/z): 319 (M+H)+;1H-NMR (δ ppm): 2,35 (3H, s), 2,38-to 2.40 (6H, s), 2,61-to 2.65 (2H, m), of 2.86 (3H, m), 2,98-of 3.06 (2H, s), 6,98-7,76 (6H, m).

Example 22. 1-Chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 339 (M+N)+.

Example 23. 3-Chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 339 (M+H)+.

Example 24. 11-[(2-N,N-Dimethylamino)propyl]-4-methylisoxazole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 305 (M+H)+.

Example 25. 2-Bromo-11-[(2-morph the Lin-1-yl)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (° (C): 148-151; IR spectrum (cm-1): 2956, 2806, 1733, 1438, 1360; MS (m/z): 411 (M+N)+;1H-NMR (δ ppm): 2,56-2,63 (4H, t), 2,63-a 2.71 (2H, m), 2,98-of 3.06 (2H, m), 3,74-of 3.78 (4H, t), 7,31-7,79 (7H, m).

Example 26. 2-Bromo-11-[2-(4-methylpiperazin-1-yl)ethyl]isoindole[2.1-a]indol-6-he

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (° (C): 146-150; IR spectrum (cm-1): 2940, 2790, 1725, 1440, 1357, 801, 703; MS (m/z): 424 (M+N)+;1H-NMR (δ ppm): 2,28 of-2.32 (3H, t), 2,52-2,75 (10H, m), 2,98 was 3.05 (2H, m), 7,30 for 7.78 (7H, m).

Example 27: 11-[(2-N,N-dimethylamino)propyl]-2-methoxyindole[2,1-a]indol-6-he

Using methodology similar to that described in example 27, in certain non-critical variations have been derived above.

The melting range: 77,0-88,9°C;

IR spectra (cm-1): 2934, 1716, 1613, 1480, 1444, 1363, 1230, 1032, 763;

1H NMR (M. D.): equal to 1.03-1.05 (3H, d, J=6.48 in Hz), 2,43 (6N, (C), 2,69 is 2.75 (1H, m), 2.95 and-a 3.01 (1H, m), 3,09-3,14 (1H, m), 3,85 (3H, s), 6,86-of 6.90 (2H, m), 7,28-to 7.32 (1H, dt, J=7,49, 1,00 Hz), 7,46-7,51 (1H, dt, J=7,43, 1,00 Hz), 7,53-of 7.55 (1H, d, J=7,52 Hz), 7,73-to 7.77 (2H, m).

Mass spectrometry (m/z): 335,3 (M+N)+.

Example 28: 11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2,1-a]indol-6-he

When is the use of techniques similar to that described in example 1 (in the application under the PCT applicants), for some non-critical variations have been derived above.

IR spectra (cm-1): 2925, 1736, 1637, 1410, 1337, 1101, 928;

1H NMR (M. D.): 2,41 (6N, (C), 2,62-of 2.66 (2H, m), is 2.88 (3H, c), 3,03-of 3.07 (2H, m), 7,06-7,07 (2H, m), 7,21-of 7.23 (1H, m), 7,31-7,33 (1H, m), 7,51-7,53 (1H, m), 7,56-7,58 (1H, d, 7,52 Hz), 7,73 to 7.75 (1H, d, J=7,52 Hz).

Mass spectrometry (m/z): 305,3 (M+N)+.

Experimental data on the pharmacological action of the compounds.

Example 1: model of the problem with the recognition of the object

Improve cognitive ability properties of the compounds of this invention were evaluated using the model of cognition in animals: a model problem with the recognition of the object.

As experimental animals used male Wister rats (230-280 g)obtained in the company of N. I. N. (National Institute of Nutrition, Hyderabad, India). Each cell was placed four animals. Within one day before the test animals 20% were deprived of food during the whole experiment gave them plenty of water and they endured a 12-hour cycle of light/dark. In addition, rats were allowed to habituate to the individual places within 1 hour in the absence of any objects.

One hour before the experiment with a familiar object (T1) and on carrying out selection (T2) one group is C 12 rats orally injected medium (1 ml/kg), and another group of animals either orally or administered intraperitoneally injected with a connection vpisivaushiesya formula (I).

The experiment was performed in made of acrylic resin chamber open field with dimensions of 50×50×50 see the familiarization phase (T1) rats were individually placed in the chamber open field for 3 minutes, in which two adjacent angles at a distance of 10 cm from the walls placed two identical objects (bottles, plastic height 12.5cm × diameter 5.5 cm), where one was covered with yellow sticky masking tape, (A1 and A2). Upon expiration of 24 hours after the experiment (T1) for testing long-term memory of the same rats were placed on the same place where they were housed in experiment T1. Rats from a phase of elections (T2) gave the opportunity to explore the camera open field for 3 minutes in the presence of one familiar object (A3) and a new object (b) (glass bottle amber color, with a height of 12 cm and a diameter of 5 cm). Familiar objects were characterized by similar textures, colors and sizes. In the experiment, T1 and T2 research each object (defined as Obrucheva, licking, chewing or vibrissae movement while handling the nose in the direction of an object at a distance less than 1 cm) were recorded separately using secondome the and. Sitting on the object was not considered as a research activity, however, it was observed rarely.

T1 represents the total time spent on the study of familiar objects (A1+A2).

T2 represents the total time spent on the study of the familiar object and a new object (A3+b).

Test detection was performed as described in the work Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats - Behavioral data, Behav. Brain Res., 31, 47-59.

Some representative compounds showed a positive effect, indicating improved the detection of a new object, namely increased research time in the case of a new object and an increased index of discernment.

Number exampleNORT Index of differentiation (DI)=process (Wednesday) 30 mg/kg, orallyConclusion
27.0,67Activity
28.0,6Activity

Example 2: water maze

The apparatus with the water maze consisted of a circular pool (diameter 1.8 m, height 0.6 m), constructed from black Perspex (TSE systems, Germany)filled with water (24±2° (C) and located under the wide angle camera DL the track of the animal. In the centre of one of the four imaginary quadrants, which remained constant for all rats had a platform from Perspex area of 10 cm2located 1 cm below the water surface. Black Perspex used in the construction of the maze and platform, inside the labyrinth has not created any tips that determine the behavior of wymagany. In contrast, the premise for the study had several significant visual cues outside the maze, contributing to the formation of spatial maps, necessary for training wymagania. Used automated tracking system [Videomot 2 (5.51), TSE systems, Germany]. This program analyzes the video images obtained using a digital camera and a card receiving images, which were determined by the path length, swimming speed and the number of entries and duration of sailing time spent in each quadrant of the water maze.

Number exampleCirculation caused by scopolamine
27.≥30 mg/kg, orally
28.≥30 mg/kg, orally

Example 3: the response of the receptor binding 5-HT6person

Compounds can be tested in accordance with the trail the next major methods.

Materials and methods:

Source receptor: human recombinant, expressed in cells NC

Radioligand: [3H] LSD (60-80 CI/mmol)

The final concentration of ligand [1,5 nmol/l]

Nonspecific binding region: meteodependent - [0,1 µmol/l]

Reference compound: meteodependent

Confirming control: meteodependent

Conditions of incubation:

The reaction was carried out for 60 minutes at 37°With 50 mmol/l TRIS-HCl (pH 7.4) with 10 mmol/l MgCl2, 0.5 µmol/l EDTU. Passing the reaction was stopped due to a rapid vacuum filtration onto glass fiber filters. The radioactivity trapped on the filters was determined and compared with reference values in order to ascertain any interactions of test compound (compounds) and cloned center associate 5-HT6serotonin.

Number exampleCI (µmol/l)
1.is 0.135
9.0,393

Reference literature: Monsma F. J. Jr., et al., Molecular Cloning and Expression of a Novel Serotonin Receptor with High Affinity for Tricyclic Psychotropic Drugs. Mol. Pharmacol. (43): 320-327 (1993).

Example 4: pharmacokinetic study for rodents

As the experiment is selected animals used male Wistar rats (230-280 g), received in the company of N. I. N. (National Institute of Nutrition, Hyderabad, India).

Each cell was placed from three to five animals. Within one day before the test animals 20% were deprived of food during the whole experiment gave them plenty of water and they endured a 12-hour cycle of light/dark. One group of rats was injected connection NCE (new chemical structures) (3-50 mg/kg) orally, and another group of animals were administered the same connection intravenously.

At each point in time did the blood collection from the jugular vein. The plasma was kept frozen at - 20°C until analysis. Concentration of the compound NCE in plasma was determined by using the method LC-MS/MS.

Scheduled points in time: before the introduction of dose, 0,25, 0,5, 1, 1,5, 2, 3, 4, 6, 8, 10, 12 and 24 hours after dose (n=3). The number of NCE compounds was determined in plasma using the approved method LC-MS/MS using the technique of solid-phase extraction. The number of NCE compounds were evaluated in the calibration range 2-2000 ng/ml in plasma and brain homogenate. Samples for testing were analyzed using calibration samples in the batch, and sample quality control, distributed over the party.

In accordance with decompartmentalise model using the software WinNonlin version 4.1 escitalopram.medications parameters Cmax, Tmax, AUCt, T1/2and biological availability.

Room use paLine/rodDose (mg/kg)WednesdayRoute of administrationCmax (ng/ml)TM (h)AUXt(ng. h AU/ml)T1/2(h)Bioavailability (%)
1 1.Wistar /male50Water (PEG 50%)Oral1027±6452,6±1,18716±61279,1±7,867,26
W istar /male10Water (PEG 50%)Intravenous1396±5980,09±0,12591±7962,56±0,6

Example 5: model of the problem with the recognition of the object

Improve cognitive ability properties of the compounds of this invention were evaluated using the model of cognition in animals: a model problem with the recognition of the object.

As experimental animals used male Wister rats (230-280 g)obtained in the company of N. I. N. (National Institute of Nutrition, Hyderabad, India). Each cell was placed four animals. Within one day before the test animals at 20% is isali food and in the course of the experiment they were given plenty of water and they endured a 12-hour cycle of light/dark. In addition, rats were allowed to habituate to the individual places within 1 hour in the absence of any objects.

One hour before the experiment with a familiar object (T1) and on carrying out selection (T2) and one group of 12 rats orally injected medium (1 ml/kg), and another group of animals either orally or administered intraperitoneally injected with a connection vpisivaushiesya formula (I).

The experiment was performed in made of acrylic resin chamber open field with dimensions of 50×50×50 see the familiarization phase (T1) rats were individually placed in the chamber open field for 3 minutes, in which two adjacent angles at a distance of 10 cm from the walls placed two identical objects (bottles, plastic height 12.5cm × diameter 5.5 cm), where one was covered with yellow sticky masking tape, (A1 and A2). Upon expiration of 24 hours after the experiment (T1) for testing long-term memory of the same rats were placed on the same place where they were housed in experiment T1. Rats from a phase of elections (T2) gave the opportunity to explore the camera open field for 3 minutes in the presence of one familiar object (A3) and a new object (b) (glass bottle amber color, with a height of 12 cm and a diameter of 5 cm). Familiar objects were characterized by similar textures, colors and sizes. In Ho the e experiment T1 and T2 research each object (defined as Obrucheva, licking, chewing or vibrissae movement while handling the nose in the direction of an object at a distance less than 1 cm) were recorded separately using a stopwatch. Sitting on the object was not considered as a research activity, however, it was observed rarely.

T1 represents the total time spent on the study of familiar objects (a1+A2).

T2 represents the total time spent on the study of the familiar object and a new object (A3+b).

Test detection was performed as described in the work Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats - Behavioral data, Behav. Brain Res., 31, 47-59.

Some representative compounds showed a positive effect, indicating improved the detection of a new object, namely increased research time in the case of a new object and an increased index of discernment.

Number exampleNORT Index of differentiation (DI)=process (environment)Conclusion
30 mg/kg, orally
1.0,64Activity

Example 6: water maze

Apparats water maze consisted of a circular pool (diameter 1.8 m, height 0.6 m), constructed from black Perspex (TSE systems, Germany)filled with water (24±2° (C) and located under the wide angle video camera to track the animal. In the centre of one of the four imaginary quadrants, which remained constant for all rats had a platform from Perspex area of 10 cm2located 1 cm below the water surface. Black Perspex used in the construction of the maze and platform, inside the labyrinth has not created any tips that determine the behavior wymagania. In contrast, the premise for the study had several significant visual cues outside the maze, contributing to the formation of spatial maps, necessary for training wymagania. Used automated tracking system [Videomot 2 (5.51), TSE systems, Germany]. This program analyzes the video images obtained using a digital camera and a card receiving images, which were determined by the path length, swimming speed and the number of entries and duration of sailing time spent in each quadrant of the water maze.

Number exampleCirculation caused by scopolamine
1.≥30 mg/kg, orally
/p>

1. The compound of General formula (I)

where R1, R2, R3, R4, R5, R6, R7, R8may be the same or different and represent, each independently, hydrogen, halogen, perhalogenated, (C1-C3)alkyl or (C1-C3)alkoxy;

R9, R10, R11, R12, R13and R14may be the same or different and represent, each independently, hydrogen or (C1-C3)alkyl;

n is an integer 1 or 2, preferably n was equal to 1;

optional R13and R14together with the nitrogen atom can form a 6-membered heterocyclic ring, where the heterocycle may also be substituted (C1-C3)alkyl, and he may have additional heteroatoms selected from N and O;

its pharmaceutically acceptable salt.

2. The compound according to claim 1, which is selected from the group consisting of

11-(2-N,N-dimethylaminoethyl)isoindole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

salt hydrochloride 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

salt of maleic acid, 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

salt D,L-malic acid 11-[(2-N,N-dimethylamino)ethyl]-2-ftory is indolo[2.1-a]indol-6-it;

salt oxalate 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

salt citrate 11-[(2-N,N-dimethylamino)ethyl]-2-horizontale[2.1-a]indol-6-it;

2-bromo-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-it;

4-chloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-2-methylisoxazole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-2-methoxyindole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-4-methoxyindole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-4-triftormetilfosfinov[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-4-utilizando[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-2,4-depersonal[2.1-a]indol-6-it;

2,4-dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-it;

3,4-dichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]-indole-6-it;

1,2,4-trichloro-11-[(2-N,N-dimethylamino)ethyl]isoindole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-2,4-dimethylisoxazole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)ethyl]-3,4-dimethylisoxazole[2.1-a]indol-6-it;

1-chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-it;

3-chloro-11-[(2-N,N-dimethylamino)ethyl]-4-methylisoxazole[2.1-a]indol-6-it;

11-[(2-N,N-dimethylamino)propyl]-4-methylisoxazole[2.1-a]indol-6-it;

2-bromo-11-[(2-morpholine-1-yl)et the l]isoindole[2.1-a]indol-6-it;

2-bromo-11-[2-(4-methylpiperazin-1-yl)ethyl]isoindole[2.1-a]indol-6-it;

and its pharmaceutically acceptable salts.

3. Pharmaceutical composition having properties modulation of 5-HT receptors containing any of the pharmaceutically acceptable carrier, diluent(s), excipient(s) together with a therapeutically effective amount of a compound according to claim 1, its pharmaceutically acceptable salts.

4. The pharmaceutical composition according to claim 3 in the form of tablets, capsules, powders, lozenges, suppositories, syrup, solution, suspension, or injection, administered at a single standard dose or a few standard doses.

5. The use of compounds of General formula (I) according to claim 1 for obtaining a drug intended for the treatment when the desired modulation of the activity of 5-HT.

6. The use of the pharmaceutical composition according to claim 3 to obtain drugs intended for treatment, when the desired modulation of the activity of 5-HT.

7. The use of compounds according to claim 1 for obtaining a medicinal product for the treatment and/or prevention of clinical conditions, which shows selective effects on the receptors 5-HT.

8. The use of compounds according to claim 1 for the treatment and/or prevention of clinical conditions such as anxiety, depression, convulsive syndromes, obsessive-compulsive the e disorders, migraine, cognitive memory disorders, ADHD (attention deficit/hyperactivity disorder), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, disorders of the schizophrenic form, the syndrome of abuse of drugs, panic attacks, sleep disorders and also disorders associated with spinal trauma and/or head injury.

9. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment of moderate cognitive impairment and other neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and horei Huntington.

10. The use of compounds according to claim 1 for the manufacture of a medicinal product for the treatment of certain GI (gastrointestinal) disorders such as IBS (irritable bowel syndrome) or vomiting caused by chemotherapy.

11. The use of compounds according to claim 1 for the manufacture of a medicine for reducing morbidity and mortality associated with overweight.

12. The compound of General formula (I), its pharmaceutically acceptable salt for a medicinal product intended for the treatment when the desired modulation of the activity of 5-HT.

13. The method of obtaining compounds of General formula (I) according to claim 1, comprising the cyclization of compounds of the following formula (II)

where X is a halogen, such as chlorine, bromine or iodine, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14and n have the meanings specified above, using as the catalyst derived Pd(0) or Pd(II).

14. The method according to item 13, including the implementation of the following optional stage - removing any protective groups.

15. New intermediate compounds of General formula (IV)

where R1, R2, R3, R4, R5, R6, R7and R8may be the same or different and represent, each independently, hydrogen, halogen, perhalogenated, (C1-C3)alkyl, (C1-C3)alkoxy.

16. The method of production of new intermediate compounds of General formula (IV)comprising the cyclization of compounds of formula (VIII)

where R1, R2, R3, R4, R5, R6, R7and R8have the meanings given above and X represents halogen, such as chlorine, bromine or iodine, using as a catalyst derived Pd(0) or Pd(II).



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: this invention describes new crystal forms of tryazol[4,5-d]pyrimidine formula I , composition methods and based pharmaceutical formulations. Compounds develop high efficiency as antagonist P2T, can be applied for medical prevention and treatment of arterial thrombotic complication, as well as tumour growth and extension.

EFFECT: compounds show high metabolic stability and bioavailability.

22 cl, 5 ex, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to organic substances production and can be applied for production of herbicides and other bioactive compounds. Production of 2-sulphanilamine-1,2,4-triazolo[1,5-a]pyrimidine of general formula , where R1 is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group, R is phenylic, 4-methyl phenylic, 4-chlorophenylic, methoxyphenylic group, R is metal, phenylic, 4-methyl phenylic, 4-chlorophenylic group is sulphurization of 2-amino-4,7-dihydro-1,2,4-triazolo [1,5-a]pyrimidines (II) by sulphochlorides (III) in pyrimidine and oxidation of produced 2-sulphanilamine-4,7-dihydro-1,2,4-triazolo[1,5-a] pyrimidines (IV) by bromine in acetic acid with sodium acetate occurrence.

EFFECT: method allows to produce compounds using low-price and reasonable raw materials without any complicated processing steps applied.

1 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds, which contain pyrrolo[1,2-а][1,4]diazepine fragment, annelated to aromatic and heteroaromatic ring. Method for preparation of derivatives of pyrrolo[1,2-а][1,4]diazepine of general formula I, where А =

, is described. The said derivatives may be of use as substances with potential CNS activity, or with analgesic, antimicrobial and antifungal effect. Method implies recyclization of furan ring of 5-methyl-furfurylamides of general formula 2, , where А stands for above shown groups, by exposure to temperature of 60-70°С in the mixture of glacial acetic acid and strong hydrochloric acid in volumetric ratio 1:0.15 for 10-15 minutes.

EFFECT: provides for simultaneous formation of pyrrole and diazepine rings and improves yield of end products due to less number of process steps.

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the general formula (I): wherein R0 represents hydrogen atom; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and each represents independently hydrogen atom, halogen atom, perhalogenalkyl, substituted or unsubstituted groups, such as linear or branched (C1-C12)-alkyl, (C3-C7)-cyclaoalkyl, (C1-C12)-alkoxy, cyclo-(C3-C7)-alkoxy group, hydroxyalkyl; R13 and R14 can be similar or different and each represents independently hydrogen atom, substituted or unsubstituted groups, such as linear or branched (C1-C4)-alkyl, (C3-C7)-cycloalkyl, optionally, R13 and R14 in common with nitrogen atom can form 5-6-membered heterocyclic ring wherein heterocycle can be substituted also, and it can comprise one, two or three double bonds or "additional heteroatoms" chosen from nitrogen atom (N); "n" means a whole number in the range 1-6, and pharmaceutical compositions based on its. Indicated compounds are ligands of 5-HT (serotonin) and can be used in treatment in cases if modulation of activity of 5-HT and melatonin is desirable.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

21 cl, 31 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

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4]pyrazole dihydrochloride of the formula (I): . This compound is synthesized by interaction of 1-(2-piperazinoethyl)-5-phenyl-4-(4-chlorobenzoyl)-3-hydroxy-3-pyrrolin-2-one dihydrochloride with hydrazine hydrate. Synthesized compound can be used in medicine as agent decreasing arterial blood pressure and blood coagulation. Invention provides synthesis of a novel compound not described early that possesses hypotensive and anti-coagulant effect simultaneously.

EFFECT: valuable medicinal properties of compound.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or their pharmaceutically acceptable salts possessing the inhibitory effect on activity of tyrosine kinase. Proposed compounds can be used in treatment of proliferative disease, such as tumor. In the formula (I) each R1 and R2 means independently of one another hydrogen atom, methyl, ethyl, isopropyl, hydroxyethyl, piperidine-1-ylmethylcarbonyl, pyrrolidine-1-ylmethylcarbonyl, morpholine-4-ylmethylcarbonyl, 4-methylpiperazine-1-ylmethylcarbonyl, N,N-dimethylaminomethylcarbonyl, 4-ethylpiperazine-1-ylmethylcarbonyl, piperidine-1-ylethylcarbonyl, N,N-diethylaminoethylcarbonyl, N,N-dimethylaminopropylcarbonyl, 2-pyridylcarbonyl, tetrahydropyrane-4-yl, morpholine-4-ylethyl, N,N-diethylaminoethyl, tert.-butyl; or R1 and R2 in common with nitrogen atom to which they are bound form 4-ethylpiperazine-1-yl, pyrrolidine-1-yl, 4-methylpiperazine-1-yl, piperidine-1-yl, morpholine-4-yl, 3,5-dimethylpiperazine-1-yl; R3 is chosen from 3-chloro-4-fluorophenyl, phenyl, 4-benzyloxyphenyl, 3-hydroxy-4-methylphenyl, 3-hydroxy-4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 3-methoxyphenyl, benzo[1,3]dioxol-5-yl, 6-methoxypyridine-3-yl, 2-methoxypyridine-4-yl, pyridine-2(1H)-one-5-yl, pyridine-2(1H)-one-4-yl, 3-methoxyphenyl, 3-methylphenyl, pyridine-2(1H)_one-4-yl; G means -CH2-; Q means -NH-; X absents or means -CH(CH3)-, -CH2- under condition that if X absents then R3 is bound by ring carbon atom. Also, invention relates to variants of methods for synthesis of compounds of the formula (I), preparing a pharmaceutical composition and using compounds proposed.

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

13 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: here, described are new derivatives of 1H-1,2,4-triazole-3-carbozamide of the general formula (I) , wherein R is phenyl, possibly replaced by 1-2 halogen atoms, R1 is phenyl possibly replaced by 1-2 halogen atoms or trifluotomethyl group, or pyridile radical; R2 represents a hydrogen atom; R3 - C1-6-alkyl, C2-8-alcoxy, C3-8-cycloalkyl, possibly replaced with C1-3-zalkyl or ethynil, C2-8-bicycloalkyl, C4-8-alkenil, C3-8-trifluoroalkyl or C2-8-fluoroalkyl group or C3-8-cycloalkyl, group NR4R5, where R4 and R5 together with nitrogen atom to which they are coupled, form a monocyclic or bicyclic heterocyclic fragment with 5-8 ring atoms, the heterocyclic group of the above fragment contains one or two heteroatoms, selected from the group N and O, possibly replaced with C1-3-alkyl or R2 and R3 together with nitrogen atom to which they are coupled form 1,4'-bipyperidine radical, their pharmaceutically acceptable salts.

EFFECT: pharmaceutical composition is used for treatment of disturbances involving neurotransmission of cannabinoids.

5 cl, 43 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (I) Formula I , where: X is the following radical: , L is separately selected from -C(R)(R")-, -CO-, NR'-; n equals zero, unity, two, three, four, five, six, seven, eight, nine or ten; R, R' and R" are separately selected from hydrogen, alkyl; D is separately selected from -C(R9)- or -N-; A1 A2, A3, A4, A5, A6, A7, A8, E and G are separately selected from -CO-, -C(R10)(R11)-, =C(R10)-; R1, R2, R3, R9, R10 and R11 are separately selected from hydrogen, alkyl, alkoxyl, hydroxyl, haloge-nalkyl, halogen. The invention relates also to pharmaceutical compositions based on the above substances, to the use of these compounds for production of a pharmaceutical and to the method of treatment of cognitive disturbances. EFFECT: compounds are useful in treatment of cognitive disturbances.

12 cl, 2 tbl, 24 ex.

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of piperidine of the formula I: or to any of its isomers, or to any mixture of its isomers, or to its pharmaceutically acceptable salt, where R1 is a hydrogen or alkyl, R3 is -CH2-O-Rc; where Rc is alkyl or cycloalkylalkyl; R4 is , where Ra and Rb act, independently, as halogens. The invention relates also to pharmaceutical composition and to use compounds based on formula I, that feature inhibiting activity of recapture of neuromediator monoamines in central nervous system. EFFECT: production of new biologically active compounds and pharmaceutical compositions on their base.

10 cl, 5 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention involves compositions of lamotrigine and its pharmaceutically acceptable derivative of prolonged release. Composition includes: 1) nucleus with lamotrigine or its pharmaceutically acceptable derivative; 2) outer coating of nucleus thickness of which is selected so that it is actually resistant for ambient liquids and actually resistant for release of lamotrigine or its pharmaceutically acceptable derivative, and 3) mentioned outer coating has one or more pores from outer face of coating through essentially all the coating without penetration to mentioned nucleus enabling release of lamotrigine or its pharmaceutically acceptable derivative from nucleus into ambient liquid. Mentioned pores have area or integrated area from approximately 10 to approximately 60% of front-face area of mention composition. And release of lamotrigine or its pharmaceutically acceptable derivative is performed essentially trough mentioned pores. Outer surface at that dissolves in the event ambient pH exceeds 5. Composition provides prolonged release of lamotrigine by two procedures: slower release due to initial release of lamotrigine through the pore, and faster release in further step due to dissolving of outer coating.

EFFECT: elimination of side effects accompanying lamotrigine-based or its pharmaceutically acceptable derivatives therapy.

5 cl, 7 dwg, 9 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention involves compositions of lamotrigine and its pharmaceutically acceptable derivative of prolonged release. Composition includes: 1) nucleus with lamotrigine or its pharmaceutically acceptable derivative; 2) outer coating of nucleus thickness of which is selected so that it is actually resistant for ambient liquids and actually resistant for release of lamotrigine or its pharmaceutically acceptable derivative, and 3) mentioned outer coating has one or more pores from outer face of coating through essentially all the coating without penetration to mentioned nucleus enabling release of lamotrigine or its pharmaceutically acceptable derivative from nucleus into ambient liquid. Mentioned pores have area or integrated area from approximately 10 to approximately 60% of front-face area of mention composition. And release of lamotrigine or its pharmaceutically acceptable derivative is performed essentially trough mentioned pores. Outer surface at that dissolves in the event ambient pH exceeds 5. Composition provides prolonged release of lamotrigine by two procedures: slower release due to initial release of lamotrigine through the pore, and faster release in further step due to dissolving of outer coating.

EFFECT: elimination of side effects accompanying lamotrigine-based or its pharmaceutically acceptable derivatives therapy.

5 cl, 7 dwg, 9 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention involves compositions of lamotrigine and its pharmaceutically acceptable derivative of prolonged release. Composition includes: 1) nucleus with lamotrigine or its pharmaceutically acceptable derivative; 2) outer coating of nucleus thickness of which is selected so that it is actually resistant for ambient liquids and actually resistant for release of lamotrigine or its pharmaceutically acceptable derivative, and 3) mentioned outer coating has one or more pores from outer face of coating through essentially all the coating without penetration to mentioned nucleus enabling release of lamotrigine or its pharmaceutically acceptable derivative from nucleus into ambient liquid. Mentioned pores have area or integrated area from approximately 10 to approximately 60% of front-face area of mention composition. And release of lamotrigine or its pharmaceutically acceptable derivative is performed essentially trough mentioned pores. Outer surface at that dissolves in the event ambient pH exceeds 5. Composition provides prolonged release of lamotrigine by two procedures: slower release due to initial release of lamotrigine through the pore, and faster release in further step due to dissolving of outer coating.

EFFECT: elimination of side effects accompanying lamotrigine-based or its pharmaceutically acceptable derivatives therapy.

5 cl, 7 dwg, 9 tbl, 6 ex

FIELD: medicine; psychiatry.

SUBSTANCE: method is implemented as follows: for 30 days pharmacotherapy is administered: 20-25 mg a day intramuscularly of 0.5% solution of benzodiazepine anxyolitic of diazepam, 300-400 mg of antioxidant mexidol intravenously by drop infusion during the first 10-15 days and 125-150 mg in tabloid form during the next 15-20 days, 15 intramuscular injections of 1 - 1.2 ml of 0.1% solution of immunocorrector timogene. Hyperbaric oxygenation is administered at the same time with excessive pressure 0.8 - 1.0 atm at compression and decompression speed of 0.1 atm per minute by isopressure method for 40 minutes 2 times a day during the first 15 days and once a day during the next 15 days.

EFFECT: combination of pathogenic means for efficient and safe treatment of subacute reactive psychosis by complex impact of neuro-homeostasis.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.

EFFECT: compounds possess inhibiting activity.

13 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to 4-pyperazinyl-benzen-sulfanylindols with the general formula I , where: R1 and R2 each independently means hydrogen, halogen, alcoxy, R3 and R4 each independently means hydrogen, halogen, alkyl, n is equal to 0 to 4, R6 in each particular case means hydrogen or halogen, R7 and R8 each means hydrogen, R9 means hydrogen, alkyl, or individual isomer, racemic or non-racemic mixture of isomers or their pharmaceutically acceptable salt or solvate. The pharmaceutical compositions are described based on compound I.

EFFECT: compounds can be efficiently used in treatment of certain diseases of central nervous system.

14 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: this invention relates to derivatives of cyclopropylthropine of the general formula I wherein X- is a one-charge anion, A and B represent -CH=CH-, R means hydrogen, hydroxygroup, -C1-C4alkyl, R1 and R2 have identical or different values and designate - C1-C5alkyl, R3, R4, R3' and R4' have identical or different values and designate hydrogen or halogen, Rx and Rx' jointly designate a simple bond or bridge group -O-, not obligatorily in the form of their pharmacologically acceptable acid-additive salts. The compounds of formula I are antagonists of muscarine receptor of subtype 3, which allows an assumption that they may be used as anticholinergic preparation. Intermediate compound are also described used in synthesis of the compounds I, pharmaceutical compositions based on the compounds I and the use of the latter for treatment of asthma, chronic obstructive disease of lungs.

EFFECT: new compounds possess useful biological properties.

9 cl, 7 ex

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