Novel tetracyclic arylsulfonyl-indoles with affinity for serotonin receptors, accetable as medications, method of their obtaining and pharmaceutical compositions containing them

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be similar or different and represent, each independently, hydrogen, halogen, hydroxyl, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or neighbouring groups R2 and R3 together with carbon atoms to which they are bound, can form benzol ring; R13 and R14 can be similar or different and represent each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13 and R14 together with nitrogen atom can form 5-, 6-member heterocyclic ring, where heterocycle also can be substituted (C1-C6)alkyl, and it can have "additional heteroatoms", selected from O, N; "n" is an integer in interval from 1 to 4, and carbon chain, to which it relates is linear.

EFFECT: compound possess the characteristic of activity modulators 5-HT and can be applied for treatment of such diseases as anxiety, depression, convulsive syndromes, migraine.

15 cl, 67 ex

 

The present invention relates to novel tetracyclic to arylsulfonamides, their derivatives, their analogs, 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 derivatives, their analogs, 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 the desired modulation of 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, is ravage, migraines, depression, drug addiction, 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, d is a major depression, anxiety, schizophrenia, 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 is interest in drugs that affect the serotonergic system and its application. 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., Phrmacol. Rev. (1994), 46, 157-203). The last detected information relating to 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 is Amida and carboxamides. It is reported that the compound suitable for the treatment of hypertension, diseases of 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.

PU the published International patent application WO 91/18897 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 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 P. et al. in his article "SDZ216-525, a selective and potent T 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 arylsulfonamides, their derivatives, their analogs, 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 arylsulfonamides General formula (I), their derivatives, their analogs, 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.

Of the 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, oxo, thio, perhalogenated, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl, geterotsiklicheskikh, heteroalkyl, heteroaromatic, heteroaromatic, geterotsiklicheskikh, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, arylamino, diarylamino, aralkylamines, alkoxycarbonyl, aryloxyalkyl, arelaxation, geterotsiklicheskikh, heteroarylboronic, hydroxyalkyl, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, arachidonoylethanolamine, aminocarbonyl, alkylaminocarbonyl, dialkylaminomethyl, alkylamino, alkylguanine, dialkyl Andino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphoric acid and its derivatives; or the adjacent groups, such R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the carbon atoms to which they are attached, may form a 5-, 6 - or 7-membered cycle which may optionally contain one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and combinations of double bond and heteroatoms; or R9and R10or R11and R12together represent a double bond attached to the oxygen or sulfur; or R9and R10or R11and R12together with the carbon atoms to which they are attached, may form a 3-, 4-, 5 - or 6-membered cycle which may optionally contain one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and also includes a combination of one or more double bonds with heteroatoms, the values of which are indicated above.

R13and R14may be the same or different and represent, each independently, hydrogen, substituted or unsubstituted groups such as Lina is hydrated or branched (C 1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C2-C12)alkanoyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, aryl, aralkyl, heteroaryl, geterotsiklicheskikh; optional, R13and R14together with the nitrogen atom may form a 3-, 4-, 5-, 6 - or 7-membered heterocyclic ring, where the heterocycle may also be substituted, and it may have one, two or three double bonds or more heteroatoms"above.

"n" is an integer in the range from 1 to 8. It is preferable that n was equal to 1-4. Carbon chain to which it relates "n", can be either linear or branched.

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

6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-chloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-toranzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

the hydrochloride of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

the maleate salt of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

the ol D,L-malic acid 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

the oxalate salt of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

the citrate salt of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-chloro-6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-fluoro-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-methyl-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4,8-dimethoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2-ethylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2-chloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,4-dichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,3-dichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

5-chloro-6-(2-N,N-dimethylaminoethyl)-2-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,4,5-trichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2,4-debtorrent[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-fluoro-8-methylbenzo[d]izati the gold[3.2-a]indole-S,S-dioxide;

2,4-debtor-6-(2-N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2,8-dimethoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-[2-(4-methylpiperazin-1-yl)ethyl]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-[2-morpholine-4-ileti]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-pyrrolidin-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-piperidine-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-[2-morpholine-4-ileti]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-pyrrolidin-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-[2-(4-methylpiperazin-1-yl)ethyl]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-diox is d;

6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(pyrrolidin-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(pyrrolidin-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-diethylamino)-2-methylethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-dimethylamino-1-hydroxy-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-(N,N-dimethylamino-1-hydroxy-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-dimethylaminoethyl)-2,4-debtor-8 methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-dimethylamino-2-methylethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-chloro-6-(2-(N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

8-(2-(N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]benzo(g)indole-S,S-dioxide; and

their stereoisomers, their 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 status the status, when 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 use in the treatment and/or prevention of 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 of 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.

It is also expected that compounds of the invention will be applicable in the treatment of certain GI (gastrointestinal) disorders, such as the 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 associated with 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 about what is worn to the way 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 one 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 for receiving the Oia drugs of the present invention together with a conventional pharmaceutical auxiliary substances, carriers and additives.

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

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 a mammal, preferably human, the 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 con is seeking to a method for producing the above compounds, their derivatives, their analogs, 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.

The present invention relates to novel tetracyclic to arylsulfonamides, their derivatives, their analogs, 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 arylsulfonamides General formula (I), their derivatives, their analogs, 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, R and R12may be the same or different and represent, each independently, hydrogen, halogen, oxo, thio, perhalogenated, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl, geterotsiklicheskikh, heteroalkyl, heteroaromatic, heteroaromatic, geterotsiklicheskikh, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, arylamino, diarylamino, aralkylamines, alkoxycarbonyl, aryloxyalkyl, arelaxation, geterotsiklicheskikh, heteroarylboronic, hydroxyalkyl, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, arachidonoylethanolamine, aminocarbonyl, alkylaminocarbonyl, dialkylaminomethyl, alkylamino, alkylguanine, dialkylamino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphoric acid and its derivatives; or neighboring groups, such R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the carbon atoms to which they are attached, may form a 5-, 6 - or 7-membered cycle, which, in addition, may contain one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and combinations of double bond and heteroatoms; or R9and R10or R11and R12together represent a double bond attached to the oxygen or sulfur; or R9and R10or R11and R12together with the carbon atoms to which they are attached, may form a 3-, 4-, 5 - or 6-membered cycle, which, in addition, may contain one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and also includes a combination of one or more double bonds with heteroatoms, the values of which are indicated above.

R13and R14may be the same or different and represent, each independently, hydrogen, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C2-C12)alkanoyl, (C3 7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, aryl, aralkyl, heteroaryl, geterotsiklicheskikh; optional, R13and R14together with the nitrogen atom may form a 3-, 4-, 5-, 6 - or 7-membered heterocyclic ring, where the heterocycle may also be substituted, and it may have one, two or three double bonds or more heteroatoms"above.

"n" is an integer in the range from 1 to 8. It is preferable that n was equal to 1-4. Carbon chain to which it relates "n", can be either linear or branched.

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-C6)alkyl, such as vermeil, deformity, trifluoromethyl, triptorelin, foradil, defloratin and the like; substituted or unsubstituted (C1-C12)alkyl group, linear or branched (C1-C8)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl and the like; substituted or unsubstituted (C2-C12)alkenylphenol group, such as ethylene, n-propylene, Penta is Il, hexenyl, heptenyl, heptadienyl and the like; substituted or unsubstituted (C2-C12)alkylamino group, such as acetylene and the like; cyclo(C3-C7)alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloalkyl group may be substituted; cyclo(C3-C7)alkenylphenol group, such as cyclopentyl, cyclohexenyl, cycloheptenyl, cycloheptadiene, cycloheptatriene etc., cycloalkenyl group may be substituted; and (C1-C12)alkoxy, in particular (C1-C6)alkoxygroup, such as methoxy, ethoxy, propyloxy, bucalossi, isopropoxy, etc. which may be substituted; cyclo(C3-C7)alkoxygroup, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy, cycloheptylamine etc., cycloalkanes may be substituted; aryl group such as phenyl or naphthyl, the aryl group may be substituted; aracelio group, such as benzyl, phenethyl,6H5CH2CH2CH2naphthylmethyl etc., kalkilya group may be substituted, and the substituted kalkilya group represents a group, such as CH3With6H4CH2Hal-C6H4CH2CH3OS6H4CH2CH3OS6H4CH2CH2 and the like; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy etc., urlcategory may be substituted; heterocyclyl group, such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinil etc., heterocyclyl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocycle(C1-C6)alkyl, such as pyrrolidinyloxyl, piperidinyloxy, morpholinylmethyl, thiomorpholine, occasionally etc., heterocycle(C1-C6)alkyl group may be substituted; heteroaryl group, such as furylmethyl, pyridylmethyl, oxazolidinyl, oxazolyl etc., heteroalkyl group may be substituted; heteroaromatic, heteroaromatic, heterocyclics, where heteroaryl, heteroalkyl, heterocytolysine and heterocyclisation part shall have the meanings specified above, and 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, acylamino the group, such as CH3CONH, CH3CH2CONH, C3H7CONH, C6H5CONH, which may be substituted, (C1-C6)monoalkylamines, such as CH3NH, C2H5NH, C3H7NH, C6H13NH, etc. which may be substituted; and (C1-C6)dialkylamino, such as N(CH3)2CH3(C2H5)N and the like, which may be substituted; killingray, such as C6H5NH, CH3(C6H5)N6H4(CH3)NH, NH-C6H4-Hal and the like, which may be substituted; arylalkylamines, such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3and the like, which may be substituted; hydroxy(C1-C6)alkyl which may be substituted, amino(C1-C6)alkyl which may be substituted; mono(C1-C6)alkylamino-(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl group 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; and alkoxyalkyl group, such as6H5CH2Och2With6H5CH2Och2CH2and the like, which may be substituted; and (C1-C6)alkylthio, thio(C1-C6)alkyl which may be substituted; alkoxycarbonyl, such as2H5OCONH, CH3OCONH, etc. which may be substituted; aryloxypropanolamine, such as6H5OCONH, C6H5OCONCH3C6H5OCONC2H5C6H4CH3OCONH, C6H4(OCH3)OCONH, etc. which may be substituted; alcoxycarboxylates, such as6H5CH2OCONH, C6H5CH2CH2OCONH, C6H5CH2OCON(CH3), C6H5CH2OCON(C2H5), C6H4CH3CH2OCONH, C6H4OCH3CH2OCONH, etc. which may be substituted; aminocarbonylmethyl; and (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C6)alkylamino, (C1-C6)alkylguanine - and di(C1-C6)alkylguanine, hydrazino and hydroxylamino; carboxylic acid or its derivatives such as amides, such CONH2alkylaminocarbonyl similar to the CH3NHCO, (CH3)2NCO, C2H5NHCO, C 2H5)2NCO, allumination, such PhNHCO, naphthyl-NHCO etc., aralkylamines, such as PhCH2NHCO, PhCH2CH2NHCO etc., heteroarylboronic and heteroarylboronic group, where the heteroaryl groups have the meanings given above; heterocyclizations where heterocyclyl the group has the values given above, derivatives of carboxylic acids, such as esters, where the ester group are alkoxycarbonyl groups such as substituted or unsubstituted phenoxycarbonyl, naphthalocyanines etc.; alcoxycarbenium group, such as benzyloxycarbonyl, ventilatsioonil, naphthylenediamine etc., heteroarylboronic, heteroarylboronic, where the heteroaryl group has the values stated previously, heterocyclisation, where the heterocycle has the values given above, and these carboxylic acid derivatives may be substituted; 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; phosphoric acid and its derivatives, such as P(O)(OH)2, P(O)(O-(C1-C6 )alkyl)2, P(O)(O-aryl)2etc.

Suitable cyclic structures formed by two adjacent groups, such R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the carbon atoms to which they are attached, may form a five - or six-membered cycle which optionally may contain one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium", or a combination of one or more double bonds and heteroatoms. The cyclic structure may be optionally substituted by phenyl, naphthyl, pyridium, TuranAlem, teinila, pirrallo, imidazolium, pyrimidinium, pyrazinium etc. by Suitable substituents in the cyclic structures formed R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the neighboring carbon atoms to which they are attached, are oxo, hydroxy, halogen atom, such as chlorine, bromine and iodine; nitro, cyano, amino, formyl, (C1-C3)alkyl, (C1-C3)alkoxy, thioalkyl, alkylthio, phenyl or benzyl group.

R13and R14represents hydrogen, substituted or illegal is displaced linear or branched (C 1-C12)alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl and the like; and (C2-C12)alkanoyl, such as acetyl, propanol and the like; aryl group such as phenyl or naphthyl, the aryl group may be substituted; cyclo(C3-C7)alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloalkyl group may be substituted; kalkilya group may be substituted, and the substituted kalkilya group represents a group, such as CH3With6H4CH2Hal-C6H4CH2CH3OS6H4CH2CH3OS6H4CH2CH2and the like; and (C3-C7-zelgeterrolc with heteroatoms, such as "oxygen", "nitrogen", "sulfur" or "selenium", optionally containing one or two multiple bonds, such as double or triple bond. 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 C is displaced; heterocycle(C1-C6)alkyl, such as pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, occasionally etc., heterocycle(C1-C6)alkyl group may be substituted; heteroalkyl group, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl etc., heteroalkyl group may be substituted; heteroaromatic, heteroaromatic, heterocyclics, where heteroaryl, heteroalkyl, heterocytolysine and heterocyclisation groups have the meanings given above, and can also 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 as the source, and then the final connection receive, respectively, as AK is positive 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 of the accession of reasons, and these include salts containing pharmaceutically acceptable cations, such as lithium, sodium, potassium, calciun the e and magnesium salts, salts of 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, water, methanol, ethanol, dimethylformamide, ethyl acetate and similar solvents. You can also get a mixture of these with the of latov. 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; or

3) derivatives that accumulate at the site of action through a selective membrane in relation to Proletarsk is a or a modified form of prodrugs; 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 derivatives, their analogs, 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 a new intermediate compounds of the following formula (II)

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14and "n" have the meanings given above, using as the catalyst derived Pd(0) or Pd(II), for example, tetranitroaniline, (bis-the ri-o-tolylphosphino)palladium and the like; and further, 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 compounds of the following formula (III)

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12and "n" have the meanings specified RA is it with a suitable alkylating agent such as R13X or R14X or XR13R14X, where X is an easily removable group, such as halogen, hydroxyl, etc.

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 values listed previously.

The above interaction is preferably carried out at a temperature of 50° C-150°C. the Formaldehyde can be in the form of an aqueous solution, ie, 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 hydrochloric acid for 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 and the like, or their mixture, 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. the Duration of the reaction may range 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).

New intermediate compounds, their stereoisomers and their salts is below the General formula (II)

where X is a halogen, such as chlorine, bromine or iodine.

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12may be the same or different and represent, each independently, hydrogen, halogen, oxo, thio, perhalogenated, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl, geterotsiklicheskikh, heteroalkyl, heteroaromatic, heteroaromatic, geterotsiklicheskikh, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, arylamino, diarylamino, aralkylamines, alkoxycarbonyl, aryloxyalkyl, arelaxation, geterotsiklicheskikh, heteroarylboronic, hydroxyalkyl, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, arachidonoylethanolamine, aminocarbonyl, alkylaminocarbonyl is ylamino, dialkylaminomethyl, alkylamino, alkylguanine, dialkylamino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphoric acid and its derivatives; or the adjacent groups, such R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the carbon atoms to which they are attached, may form a 5-, 6 - or 7-membered cycle, which, in addition, may contain optionally one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and combinations of double bond and heteroatoms; or R9and R10or R11and R12together represent a double bond attached to the oxygen or sulfur; or R9and R10or R11and R12together with the carbon atoms to which they are attached, may form a 3-, 4-, 5 - or 6-membered cycle, which, in addition, may contain optionally one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and also includes a combination of one or more double bonds with heteroatoms, the values of which are indicated above.

R13and R14may be the same aliasname and present, each independently hydrogen, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C2-C12)alkanoyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, aryl, aralkyl, heteroaryl, geterotsiklicheskikh; optional, R13and R14together with the nitrogen atom may form a 3-, 4-, 5-, 6 - or 7-membered heterocyclic ring, where the heterocycle may also be substituted, and it may have one, two or three double bonds or more heteroatoms"above.

"n" is an integer in the range from 1 to 8. It is preferable that n was equal to 1-4. Carbon chain to which it relates "n", can be either linear or branched.

The present invention also relates to methods of producing a new intermediate compounds represented by the General formula (II).

Path 1. Compounds of General formula (II) can be obtained by the interaction of the compounds of the following formula (VI)

where R1, R2, R3, R4, R9, R10, R11, R12, R13and R14have the meanings indicated in connection with formula (I)with the compound of the formula (VII)

where R5, R67and R8have the meanings indicated in connection with formula (I), and X represents a halogen, preferably chlorine, bromine or iodine.

The interaction can be performed in the presence of solvents such as THF, DMF, DMSO, DME, acetone and the like, and preferably, using or acetone, or DMF. 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, NaH, KH, or a mixture thereof. 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. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours. (Reference: Bio Org. Med. Chem., 2000, 10, 2295-2299).

Preferably, the substituents selected for compounds of formulas (VI) and (VII)are not affected by the reaction conditions, or otherwise protect sensitive groups using suitable groups.

The compounds of formula (VI) are commercially available or can be obtained in the usual ways or modification, using known methods, commercially available compounds of formula (VI). In the PCT patent WO 02/078693 also describes how to obtain again the ranks of the substituted indoles, and tryptamines, and such application is incorporated in this description by reference.

Path 2. Compounds of General formula (II) can be obtained by

where R1, R2, R3, R4, R11, R12, R13, R14and n (=2) are shown in connection with formula (I); R represents either hydrogen, or a group, such as

where X is a halogen, such as chlorine, bromine or iodine; R5, R6, R7and R8have the meanings given above; in the presence of amine hydrochloride and formaldehyde.

The above interaction, 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 a polymeric form of formaldehyde, such as paraformaldehyde or trioxymethylene. When using such polymeric forms, add a molar excess of mineral acid, e.g. hydrochloric acid for regeneration of the polymer of the free aldehyde. The interaction is preferably carried out in an organic solvent, inert under the reaction conditions, such as methanol, ethanol or 3-methylbutanol etc. or their mixture. The inert atmosphere can be maintained by using inert gases such as N2, Ar or Not. Temperature is the RA of the reaction can vary from 20° With up to 150°C, depending on the chosen solvent, and preferably to interact at a temperature in the range from 30°to 100°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.

Path 3. Compounds of General formula (II) can be obtained by recovery other compounds of formula (II), as shown in the diagram

where R1, R2, R3, R4, R11, R12, R13, R14and n (=2) are shown in connection with formula (I); R represents either hydrogen, or a group, such as

where X is a halogen, such as chlorine, bromine or iodine; R5, R6, R7and R8have the meanings given above; using various methods of catalyst (e.g. palladium-on-coal), chemical (e.g., sodium borohydride) or enzymatic recovery.

Path 4. Compounds of General formula (II) can be obtained in the following way:

where R1, R2, R3, R4, R11, R12, R13, R14and n have the meanings indicated in connection with formula (I); R represents either hydrogen, or a group, such as

where X is a halogen, such as x is PR, bromine or iodine; R5, R6, R7and R8have the values listed previously.

The first stage is a well-known reaction of Strecker, followed by conversion of the cyano acid and, finally, acid amide.

The first stage involves adding an aqueous solution of sodium bisulfite in the presence of sodium cyanide in a suitable aqueous solvent. The last two conversions very well described in the literature.

Path 5. Compounds of General formula (II) can be obtained in the following way:

where R1, R2, R3, R4, R11, R12, R13, R14and n have the meanings indicated in connection with formula (I); R represents either hydrogen, or a group, such as

where X is a halogen, such as chlorine, bromine or iodine; R5, R6, R7and R8have the values listed previously.

The first stage is a well-known transformation chlorine, cyano, followed by conversion of the cyano acid and, finally, acid amide.

Path 6. Compounds of General formula (II) can be obtained in the following way:

where R1, R2, R3, R4, R11, R12, R13, R14and n have the meanings indicated in connection with formula (I); R represents either hydrogen, or g is the SCP, such as

where X is a halogen, such as chlorine, bromine or iodine; R5, R6, R7and R8have the values listed previously.

The first stage is a bromination using a suitable agent such as bromine, pyridinium bromide and the like, in a suitable solvent. At the next stage, the bromine is replaced by an amine according to the method.

Path 7. Compounds of General formula (II) can be obtained in the following way:

where R1, R2, R3, R4, R11, R12, R13, R14and n (=2) are shown in connection with formula (I); R0represents a hydrogen or alkyl group. The original substance is an intermediate connection, well known in the chemistry of indoles, which after oxidation leads to the replacement of the type CH2-C(=O)- in the side chain. The subsequent implementation of the sequence of reactions described for path 3 (i.e. recovery carbonyl due to hydroxyl) and on the way 6 (i.e. synthesized), you can get side chains with different substitution.

New intermediate compounds is below the General formula (III)

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R1 , R11and R12may be the same or different and represent, each independently, hydrogen, halogen, oxo, thio, perhalogenated, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl, geterotsiklicheskikh, heteroalkyl, heteroaromatic, heteroaromatic, geterotsiklicheskikh, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, arylamino, diarylamino, aralkylamines, alkoxycarbonyl, aryloxyalkyl, arelaxation, geterotsiklicheskikh, heteroarylboronic, hydroxyalkyl, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, arachidonoylethanolamine, aminocarbonyl, alkylaminocarbonyl, dialkylaminomethyl, alkylamino, alkylguanine, dialkylamino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphorus is th acid and its derivatives; or neighboring groups, such R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the carbon atoms to which they are attached, may form a 5-, 6 - or 7-membered cycle, which, in addition, may contain optionally one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and combinations of double bond and heteroatoms; or R9and R10or R11and R12together represent a double bond attached to the oxygen or sulfur; or R9and R10or R11and R12together with the carbon atoms to which they are attached, may form a 3-, 4-, 5 - or 6-membered cycle, which, in addition, may contain optionally one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and also includes a combination of one or more double bonds with heteroatoms, the values of which are indicated above.

"n" is an integer in the range from 1 to 8. It is preferable that n was equal to 1-4. Carbon chain to which it relates "n", can be either linear or branched.

The present invention also relates to a method of obtaining a new intermediate compounds represented by the General formula (III).

The compound of formula (III) ← a Compound of formula (II)

Substituted indoles can be alkilirovanii 1-dimethylamino-2-nitroethylene in the presence triperoxonane acid and then you can restore with lithium aluminum hydride to obtain the substituted tryptamines. All the stages described in J. Med. Chem., 1993, 36, 4069, and in J. Med. Chem., 2000, 43, 1011-1018.

The compounds of formula (II) can be metilirovanie by reductive alkylation using formaldehyde and cyanoborohydride sodium in acetonitrile under stirring at room temperature to obtain compounds of formula (I).

New intermediate compound is of the following formula (IV)

where R1, R2, R3, R4, R5, R6, R7and R8may be the same or different and represent, each independently, hydrogen, halogen, oxo, thio, perhalogenated, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups such as linear or branched (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, Alcoxy, GE is eroticly, heteroaryl, geterotsiklicheskikh, heteroalkyl, heteroaromatic, heteroaromatic, geterotsiklicheskikh, acyl, acyloxy, acylamino, monoalkylamines, dialkylamines, arylamino, diarylamino, aralkylamines, alkoxycarbonyl, aryloxyalkyl, arelaxation, geterotsiklicheskikh, heteroarylboronic, hydroxyalkyl, aminoalkyl, monoalkylamines, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, arachidonoylethanolamine, aminocarbonyl, alkylaminocarbonyl, dialkylaminomethyl, alkylamino, alkylguanine, dialkylamino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphoric acid and its derivatives; or the adjacent groups, such R1and R2or R2and R3or R3and R4or R5and R6or R6and R7or R7and R8together with the carbon atoms to which they are attached, may form a 5-, 6 - or 7-membered cycle, which, in addition, may contain optionally one or more double bonds and/or one or more heteroatoms, such as a group of "oxygen", "nitrogen", "sulfur" or "selenium"and combinations of double bond and heteroatoms; and R9and R10in this case represent the keys of the double bond, attached to the "oxygen".

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 values specified above; 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 therefore is at they can also exist as stereoisomers. The stereoisomers of the compounds of the present invention can be obtained in one or more ways below.

i) you Can use 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, preferably, 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, which may be a tartaric acid, almond acid, lactic acid, camphorsulfonic acid, amino acids and other Chiral bases that can be used, can be a Hinn 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, is kasna acid, benzoic acid, succinic acid, palmitic acid, oxalic acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and the like, 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 containing ka is este active ingredient at least one representative compounds of General formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their geometric forms, 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 (for example, abuse corn starch, polyvinylpyrrolidone or hypromellose), fillers (e.g. 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 clearancesale administration by injection, including the known methods of catheterization or infusion. Compositions for injection can be presented in a standard dosage form, e.g., 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 can 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, such as 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 with p the power of the installed valve to deliver a metered amount. 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, preferably, be such that each measured dose or "unbounded" of aerosol contains from 20 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 evaluated using the conventional analysis of the binding of 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

M is materials 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)

The end is the concentration of 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.

Literary reference:

- 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).

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 of test connection is the link 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.

v)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.

Literary links;

- 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 Radoligand Binding. Mol. Pharmacol. 33:303 (1988).

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

vi)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).

vii)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

p> Positive control: 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.

viii)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 l the specific interaction of the test(s) connection(s) with the binding site cloned serotonin NT 6.

Literary reference:

- 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).

ix)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 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). Chromatographia 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'-brompheniramine)tryptamine (D1)

A suspension of potassium hydride (9.0 mmol, 1.2 g (30% suspension in mineral oil, washed with THF before use)) in THF is stirred and cooled to 0-5°C. To obtained which the cooled solution gradually, within 15 min, keeping the temperature below 10°C, add a solution of N,N-dimethyltryptamine (6.0 mmol) in THF. Upon completion of the addition the mixture is heated to 25-30°and incubated for 30-45 min Then the reaction mixture is cooled to 0-5°and to the mixture with good stirring, a solution of 2-bromobenzaldehyde in THF (6.0 mmol, 1.7 g, 7 ml of THF), maintaining the reaction temperature below 10° (exothermic reaction). The reaction mixture was kept at 20-25aboutEven within 2-4 hours. Upon completion of reaction (TLC) the excess THF is distilled off and the concentrate is diluted with a mixture of ice water 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'-brompheniramine)tryptamine, which identify the analyses by IR, NMR and mass spectrometry.

Description 2-55 (D2-D55)

Various intermediate indoles are arylsulfonamides with the use of substituted 2-bromobenzylamine according to the procedure described in step 1. The compounds identified analysis and by IR, NMR and mass spectrometry. Among such compounds include the compounds listed below.

437
List 1
DescriptionMass ions (M+N)+
D12-[1-(2-Brompheniramine)indol-3-yl]ethyl-N,N-dimethylamine407
D22-[1-(2-Brompheniramine)-5-bromoindole-3-yl]ethyl-N,N-dimethylamine485
D32-[1-(2-Brompheniramine)-5-Clorinda-3-yl]ethyl-N,N-dimethylamine441
D42-[1-(2-Brompheniramine)-5-Florinda-3-yl]ethyl-N,N-dimethylamine425
D52-[1-(2-Brompheniramine)-5-methylindol-3-yl]ethyl-N,N-dimethylamine421
D62-[1-(2-Brompheniramine)-5-methoxyindol-3-yl]ethyl-N,N-dimethylamine437
D72-[1-(2-Bromo-4-methoxybenzenesulfonyl)indol-3-yl]ethyl-N,N-dimethylamine437
D82-[1-(2-Bromo-4-methoxybenzenesulfonyl)-5-bromoindole-3-yl]ethyl-N,N-dimethylamine515
D92-[1-(2-Bromo-4-methoxybenzenesulfonyl)-5-Clorinda-3-yl]ethyl-N,N-dimethylamine471
D102-[1-2-Bromo-4-methoxybenzenesulfonyl)-5-Florinda-3-yl]ethyl-N,N-dimethylamine 455
D112-[1-(2-Bromo-4-methoxybenzenesulfonyl)-5-methylindol-3-yl]ethyl-N,N-dimethylamine451
D122-[1-(2-Bromo-4-methoxybenzenesulfonyl)-5-methoxyindol-3-yl]ethyl-N,N-dimethylamine467
D132-[1-(2-Brompheniramine)-7-ethylindole-3-yl]ethyl-N,N-dimethylamine435
D142-[1-(2-Brompheniramine)-7-Clorinda-3-yl]ethyl-N,N-dimethylamine441
D152-[1-(2-Brompheniramine)-5,7-dichloride-3-yl]ethyl-N,N-dimethylamine475
D162-[1-(2-Brompheniramine)-6,7-dichloride-3-yl]ethyl-N,N-dimethylamine475
D172-[1-(2-Brompheniramine)-4-chloro-7-methylindol-3-yl]ethyl-N,N-dimethylamine455
D182-[1-(2-Brompheniramine)-4-chloro-7-methoxyindol-3-yl]ethyl-N,N-dimethylamine471
D192-[1-(2-Brompheniramine)-4,6,7-trichloride-3-yl]ethyl-N,N-dimethylamine509
D202-[1-(2-Brompheniramine)-5,7-differental-3-yl]ethyl-N,N-dimethylamine443
D212-[1-(2-Bromo-4-methylphenylsulfonyl)-5,7-differental-3-yl]ethyl-N,N-dimethylamine457
2-[1-(2-Bromo-4-methylphenylsulfonyl)-5-Florinda-3-yl]ethyl-N,N-dimethylamine439
D232-[1-(2-Brompheniramine)-7-methoxyindol-3-yl]ethyl-N,N-dimethylamine421
D242-[1-(2-Bromo-4-methoxybenzenesulfonyl)-7-methoxyindol-3-yl]ethyl-N,N-dimethylamine467
D252-[1-(2-Bromo-4-methylphenylsulfonyl)indol-3-yl]ethyl-N,N-dimethylamine421
D261-[1-(2-Brabanthallen)-5-bromo-1H-indol-3-yl]-3-dimethylaminopropan-1-ol515
D271-[1-(2-Bromo-4-methoxybenzenesulfonyl)-1H-indol-3-yl]-3-dimethylaminopropan-1-ol467
D281-[1-(2-Bromo-4-methylbenzenesulfonyl)-1H-indol-3-yl]-3-dimethylaminopropan-1-ol451
D291-[1-(2-Bromo-4-methoxybenzenesulfonyl)-5-bromo-1H-indol-3-yl]-3-dimethylaminopropan-1-ol545
D301-(2-Brabanthallen)-3-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indole462
D311-(2-Brabanthallen)-3-[2-(morpholine-1-yl)ethyl]-1H-indole449
D321-(2-Brabanthallen)-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole433
D331-(2-Brombenzene hanil)-3-[2-(piperidine-1-yl)ethyl]-1H-indole 447
D341-(2-Brabanthallen)-5-bromo-3-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indole540
D351-(2-Brabanthallen)-5-bromo-3-[2-(morpholine-1-yl)ethyl]-1H-indole527
D361-(2-Brabanthallen)-5-bromo-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole511
D371-[1-(2-Brabanthallen)-1H-indol-3-yl]-3-(piperidine-1-yl)propan-1-ol477
D381-[1-(2-Bromo-4-methoxybenzenesulfonyl)-1H-indol-3-yl]-3-(piperidine-1-yl)propan-1-ol507
D391-[1-(2-Brabanthallen)-5-bromo-1H-indol-3-yl]-3-(piperidine-1-yl)propan-1-ol555
D401-[1-(2-Bromo-4-methoxybenzenesulfonyl)-5-bromo-1H-indol-3-yl]-3-(piperidine-1-yl)propan-1-ol587
D411-[1-(2-Brabanthallen)-1H-indol-3-yl]-3-(pyrrolidin-1-yl)propan-1-ol463
D421-[1-(2-Bromo-4-methoxybenzenesulfonyl)-1H-indol-3-yl]-3-(pyrrolidin-1-yl)propan-1-ol493
D43{2-[1-(2-Brabanthallen)-1H-indol-3-yl]-1-methylethyl}-N,N-dimethylamine421
D441-[1-(2-Brabanthallen)-1H-indol-3-yl]-2-dimethylaminopropan-1-ol

Description 45. 2-(Benzo[d]isothiazole[3.2-a]-1H-indol-3-yl-S,S-dioxide)ethylamine (D45)

In a 100-ml 3-necked round-bottom flask is charged with 2-[1-(2-brabanthallen)-1H-indol-3-yl]ethylamine (0,286 mmol) with N,N-dimethylacetamide (40 ml), potassium acetate (0,343 mol, of 0.337 g) and dichloro-bis(tri-o-tolylphosphino)palladium (0,0143 mmol, 0,0112 g). The reaction mixture was kept under nitrogen atmosphere and warm at 140-160°With stirring for 2-5 hours. Upon completion of reaction (TLC), the reaction mass is filtered through hyflow, washed with ethyl acetate, and the combined filtrate is diluted with cold water. The aqueous layer was extracted with ethyl acetate (3 × 50 ml). United an ethyl acetate layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure at a temperature below 50°C.

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.

MS (m/z): 299 (M+N)+.

Example 1. 6-(2-N,N-Dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

In a 100-ml 3-necked round-bottom flask is charged with 1-(2'-brompheniramine)-N,N-dimethyltryptamine (0,286 mol) with N,N-dimethylacetamide (40 ml), potassium acetate (0,286 mol, 0,281 g) and di is the ENT-bis(tri-o-tolylphosphino)palladium (0,0143 mol, 0,0126 g). The reaction mixture was kept under nitrogen atmosphere and warm 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. Interval TPL (°C): 128-131; IR spectrum (cm-1): 2946, 1601, 1461, 1443; MS (m/z): 327 (M+N)+;1H-NMR (δ, ppm): 2,39 (6H, s), 2,58-of 2.66 (2H, m), 3,11-3,19 (2H, m), 7,22-7,86 (8H, m).

Example 2. 4-Bromo-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 162 to 165; IR spectrum (cm-1): 2969, 2770, 1344, 1176; MS (m/z): 405 (M+H)+407 (M+3)+;1H-NMR (δ ppm): 2,40 (6H, s), 2,58-of 2.66 (2H, m), is 3.08-and 3.16 (2H, m), 7,46-7,89 (7H, m).

Example 3. 4-Chloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes recip who have derived above. Interval TPL (°C): 156-158; IR spectrum (cm-1): 2941, 2768, 1440, 1344; MS (m/z): 361 (M+H)+,1H-NMR (δ ppm): of 2.51 (6H, s), 2,72 is 2.80 (2H, m), 3,16-of 3.25 (2H, m), 7,32-of 7.95 (7H, m).

Example 4. 6-(2-N,N-Dimethylaminoethyl)-4-toranzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 136-140; IR spectrum (cm-1): 2966, 1463, 1327; MS (m/z): 345 (M+H)+;1H-NMR (δ ppm): of 2.38 (6H, s), 2,55-of 2.64 (2H, s), 3,05-3,14 (2H, m), 7,06-7,86 (7H, m).

Example 5. 6-(2-N,N-Dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 138-142; IR spectrum (cm-1): 2941, 1607, 1332, 1177; MS (m/z): 341 (M+H)+1H-NMR (δ ppm): 2,40 (6H, s), a 2.45 (3H, s), 2,58-of 2.66 (2H, s), is 3.08-and 3.16 (2H, m), 7,20-7,80 (7H, m).

Example 6. The hydrochloride of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Compound of example No. 5 (19,8 mg) dissolved in 3 ml of ether. To the resulting clear solution was added a mixture of isopropyl alcohol - hydrochloric acid (1 ml). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (°) >250 (decomp).

Example 7. Salt is alienboy acid 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Compound of example No. 5 (to 19.4 mg) dissolved in 3 ml of ether. To the resulting clear solution was added a solution of maleic acid (7,3 mg, dissolved in a mixture of 3 ml of ether:0.5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 192-194 (decomp).

Example 8. Salt D,L-malic acid 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Compound of example No. 5 (19,8 mg) dissolved in 3 ml of ether. To the resulting clear solution was added a solution of D,L-malic acid (8,4 mg, dissolved in a mixture of 3 ml of ether:0.5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 202-204 (decomp).

Example 9. The oxalate salt of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Compound of example No. 5 (19.7 mg) dissolved in 3 ml of ether. To the resulting clear solution was added a solution of oxalic acid (8.1 mg, dissolved in a mixture of 3 ml of ether:0.5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 226-228 (decomp).

Example 10. The citrate salt of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Compound of example No. 5 (20.2 mg) dissolved in 3 ml of ether. To the resulting clear solution add auth solution of citric acid (12.0 mg, dissolved in a mixture of 3 ml of ether:0.5 ml methanol). Immediately separated white precipitate, which is filtered off, washed with ether and dried. Interval TPL (° (C) 184-186 (decomp).

Example 11. 6-(2-N,N-Dimethylaminoethyl)-4-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 148-150; IR spectrum (cm-1): 2936, 1613, 1463, 1327; MS (m/z): 357 (M+H)+;1H-NMR (δ ppm): 2,39 (6H, s), 2,56-of 2.64 (2H, m), 3,06-3,14 (2H, m), 3,86 (3H, s), 6,98-7,84 (7H, m).

Example 12. 6-(2-N,N-Dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

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): 2933, 1603, 1438, 1325; MS (m/z): 357 (M+H)+;1H-NMR (δ ppm): 2,40 (6H, s), 2,58-of 2.66 (2H, m), 3,09-3,18 (2H, m), of 3.94 (3H, s), 6,93-to 7.77 (7H, m).

Example 13. 4-Bromo-6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C):158-160; IR spectrum (cm-1): 2964, 2759, 1434, 1174; MS (m/z): 435 (M+H)+, 437 (M+3)+;1H-NMR (δ ppm): 2,40 (6H, s), a 2.5 to 2.65 (2H, m), 3,05-3,13 (2H, m), of 3.94 (3H, s), of 6.96 for 7.78 (6H, m).

Example 14. 4-Chloro-6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 172-174; IR spectrum (cm-1): 2970, 2762, 1590, 1324; MS (m/z): 391 (M+H)+;1H-NMR (δ ppm): 2,39 (6H, s), 2,56-to 2.65 (2H, m), 3,09-3,13 (2H, m), of 3.94 (3H, s), of 6.96 for 7.78 (6H, m).

Example 15. 6-(2-N,N-Dimethylaminoethyl)-4-fluoro-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 148-156; IR spectrum (cm-1): 2943, 1600, 1472, 1438; MS (m/z): 375 (M+H)+;1H-NMR (δ ppm): of 2.38 (6H, s), 2,56-of 2.64 (2H, m), 3.00 and-of 3.12 (2H, m), of 3.94 (3H, s), 6,95-to 7.77 (6H, m).

Example 16. 6-(2-N,N-Dimethylaminoethyl)-4-methyl-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 126-130; IR spectrum (cm-1): 2963, 1590, 1324, 1174; MS (m/z): 371 (M+H)+;1H-NMR (δ ppm): 2,40 (6H, s)to 2.46 (3H, s), 2.57 m)-2,66 (2H, s), 3,11-3,15 (2H, m), of 3.94 (3H, s), 6,92-of 7.60 (6H, m).

Example 17. 6-(2-N,N-Dimethylaminoethyl)-4,8-dimethoxybenzo[d]isothiazole[3.2-a]indole-S,S-is ioxid

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 160-164; IR spectrum (cm-1): 2963, 2760, 1591, 1478, 1321, 1171; MS (m/z): 387 (M+H)+;1H-NMR (δ ppm): 2,40 (6H, s), 2.57 m-to 2.65 (2H, m), 3,05-3,14 (2H, m), a 3.87 (3H, s), 3,93 (3H, s), 6.90 to to 7.75 (6H, m).

Example 18. 6-(2-N,N-Dimethylaminoethyl)-2-ethylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

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 19. 2-Chloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 166-170; IR spectrum (cm-1): 2966, 2770, 1440, 1345; MS (m/z): 361 (M+H)+;1H-NMR (δ ppm): of 2.38 (6H, s), 2,55-2,62 (2H, m), 3,10-3,19 (2H, m), 7,16-7,89 (7H, m).

Example 20. 2,4-Dichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): wing 112-116; IR spectrum (cm-1): 2964, 1614, 1559, 1342; 1179, 823, 796; MS (m/z): 395 (M+H)+;1H-NMR (δ ppm): to 2.42 (6H, s), 2,63-2,67 (2, m), 3,10-3,18 (2H, m), 7,34-7,89 (6H, m).

Example 21. 5-Chloro-6-(2-N,N-dimethylaminoethyl)-2-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 153-154; MS (m/z): 375 (M+H)+;1H-NMR (δ ppm): to 2.42 (6H, s), 2,65-by 2.73 (2H, m), and 2.79 (3H, s), 3,42-3,51 (2H, m), 7,02-7,93 (6H, m).

Example 22. 2,4,5-Trichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 447 (M+18)+, 449 (M+18)+;1H-NMR (δ ppm): is 2.37 (6H, s), 2,67 is 2.75 (2H, m), 3,09-3,17 (2H, m), 7,15-with 8.05 (5H, m).

Example 23. 6-(2-N,N-Dimethylaminoethyl)-2,4-debtorrent[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 180-182; IR spectrum (cm-1): 2963, 2789, 1593, 1347, 1184, 919, 796, 586; MS (m/z): 363 (M+H)+;1H-NMR (δ ppm): is 2.37 (6H, s), of 2.54 2.63 in (2H, s), is 3.08-3,13 (2H, m), 6,93-of 7.90 (6H, m).

Example 24. 6-(2-N,N-Dimethylaminoethyl)-4-fluoro-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some non-critical changes shall receive the above derivative. Interval TPL (°C): 158-160; MS (m/z): 359 (M+H)+;1H-NMR (δ ppm): to 2.41 (6H, s), of 2.51 (3H, s), 2,59-to 2.67 (2H, m), 3,05-and 3.16 (2H, m), 7,05-7,74 (7H, m).

Example 25. 2,4-Debtor-6-(2-N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 182-184; MS (m/z): 377 (M+N)+;1H-NMR (δ ppm): to 2.42 (6H, s), of 2.53 (3H, s), 2,60 of 2.68 (2H, m), 3,09-3,17 (2H, m), 6.87 in-to 7.77 (5H, m).

Example 26. 6-(2-N,N-Dimethylaminoethyl)-2-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2935, 2781, 1342, 1184; MS (m/z): 357 (M+H)+;1H-NMR (δ ppm): of 2.38 (6H, s), 2,56-of 2.64 (2H, m), 3,09-3,17 (2H, m), 4,08 (3H, s), 6,84-7,86 (7H, m).

Example 27. 6-(2-N,N-Dimethylaminoethyl)-2,8-dimethoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 387 (M+H)+;1H-NMR (δ ppm): 2,47 (6H, s), 2,68-2,77 (2H, m), 3.15 and is 3.23 (2H, m), of 3.94 (3H, s)4,07 (3H, s), 6,80-7,76 (7H, m).

Example 28. 6-(2-N,N-Dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the total p is ocedure, described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 156-158; MS (m/z): 341 (M+H)+;1H-NMR (δ ppm): 2,40 (6H, s)of 2.50 (3H, s), 2,58-of 2.66 (2H, m), 3,11-3,19 (2H, m), 7,22-7,74 (7H, m).

Example 29. 6-(3-N,N-Dimethylamino-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 144-146; IR spectrum (cm-1): 3307, 2826, 1602, 1331, 1182; MS (m/z): 357 (M+H)+.

Example 30. 4-Bromo-6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and making non-critical changes, get the above derivative. IR spectrum (cm-1): 3430, 2924, 2854, 1332; MS (m/z): 435 (M+H)+, 437 (M+H)+.

Example 31. 6-(3-N,N-Dimethylamino-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and making non-critical changes, get the above derivative. IR spectrum (cm-1): 3405, 2927, 1587, 1447, 1365, 1174; MS (m/z): 387 (M+H)+.

Example 32. 6-(3-N,N-Dimethylamino-1-hydroxyprop-1-yl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially General the procedures described in example 1, and making non-critical changes, get the above derivative. Interval TPL (°C): 116-119; IR spectrum (cm-1); 3307, 3059, 2828, 1601, 1325, 1177; MS (m/z): 371 (M+H)+.

Example 33. 4-Bromo-6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 37, and making non-critical changes, get the above derivative. Interval TPL (°C): 128 depression -133; MS (m/z): 465 (M+H)+, 467 (M+N)+.

Example 34. 6-[2-(4-Methylpiperazin-1-yl)ethyl]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2938, 2806, 1652, 1372, 1174; MS (m/z): 382 (M+H)+;1H-NMR (δ ppm): 2,30 (3H, s), 2,53-3,0 (12H, m), 7,00-8,00 (8H, m).

Example 35. 6-[2-Morpholine-4-ileti]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 155-158; IR spectrum (cm-1): 2958, 1604, 1443, 1331, 1177; MS (m/z): 369 (M+H)+;1H-NMR (δ ppm): 2,58-2,63 (4H, m), 2,68-by 2.73 (2H, m), 3,14-3,18 (2H, m), 3.75 to with 3.79 (4H, m), 7,26-7,87 (8H, m).

Example 36. 6-(2-Pyrrolidin-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxy the

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2951, 1604, 1444, 1323, 1180; MS (m/z): 353 (M+H)+; 1H-NMR (δ ppm): 1,85-to 1.87 (4H, USS), 2,64 of 2.68 (4H, USS), 2,75-and 2.83 (2H, m), 3,17-3,26 (2H, m), 7,30-7,80 (8H, m).

Example 37. 6-(2-piperidine-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2931, 1604, 1442, 1330, 1181; MS (m/z): 367 (M+H)+;1H-NMR (δ ppm): 1,60 was 1.69 (10H, m), 2.57 m-to 2.67 (2H, m), 3,16-3,20 (2H, m), 7,20-7,80 (8H, m).

Example 38. 4-Bromo-6-[2-morpholine-4-ileti]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 220-224; IR spectrum (cm-1): 2929, 2794, 1438, 1338, 1184, 769, 590; MS (m/z): 447 (M+H)+, 449 (M+3)+;1H-NMR (δ ppm): 2.57 m-2,62 (4H, m), 2,62-2,70 (2H, m), is 3.08-and 3.16 (2H, m), 3,74-of 3.78 (4H, m), 7,45-7,87 (7H, m).

Example 39. 4-Bromo-6-(2-pyrrolidin-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 140-144; IR spectrum cm -1): 2957, 2792, 1346, 1175, 764, 579; MS (m/z): 431 (M+H)+, 433 (M+3)+;1H-NMR (δ ppm): 1.85 to 1.89 respectively (4H, USS), 2,69-by 2.73 (4H, USS), 2.77-to and 2.79 (2H, m), 3,13-is 3.21 (2H, m), 7,44-7,88 (7H, m).

Example 40. 4-Bromo-6-[2-(4-methylpiperazin-1-yl)ethyl]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 180-182; IR spectrum (cm-1): 2962, 2784, 1457, 1333, 1175, 797, 590; MS (m/z): 460 (M+N)+, 462 (M+3)+;1H-NMR (δ ppm): 2,32-of 2.38 (3H, s), 2,43-2,73 (10H, m), 3,07-3,18 (3H, m), 7,44-7,87 (7H, m).

Example 41. 6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 3175, 2939, 1598, 1343, 1177; MS (m/z): 397 (M+N)+.

Example 42. 6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (° (C): 177-180; MS (m/z): 427 (M+N)+.

Example 43. 4-Bromo-6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in the example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 2932, 1593, 1338, 1181, 800, 728; MS (m/z): 475 (M+H)+.

Example 44. 4-Bromo-6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 192-196; IR spectrum (cm-1): 2927, 1594, 1326, 1172, 798; MS (m/z): 507 (M+H)+, 509 (M+H)+.

Example 45. 6-(3-(Pyrrolidin-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 128-130; IR spectrum (cm-1): 3321, 2962, 1598, 1336, 1180; MS (m/z): 383 (M+H)+.

Example 46. 6-(3-(Pyrrolidin-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. IR spectrum (cm-1): 3306, 2965, 1602, 1374, 1177; MS (m/z): 413 (M+N)+.

Example 47. 6-(2-(N,N-Diethylamino)-2-methylethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

MS (m/z): 369 (M+N)+.

Example 48. 6-(2-(N,N-Dimethylamino-1-hydroxy-1-yl)benzo[d]isothiazole[3.2-a]S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 343 (M+N)+.

Example 49. 4-Bromo-6-(2-(N,N-dimethylamino-1-hydroxy-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (aboutS): 148-152; (m/z): 421 (M+N)+, 423 (M+N)+.

Example 50. 6-(2-(N,N-Dimethylaminoethyl)-2,4-debtor-8 methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. Interval TPL (°C): 140-142; IR spectrum (cm-1): 2937, 1602, 1332, 1177, 795, 587; MS (m/z): 393 (M+H)+;1H-NMR (δ ppm): 2,43 (6H, s), 2,62-2,70 (2H, m), 3,09-3,17 (2H, m), of 3.96 (3H, s), 6.87 in-7,80 (5H, m).

Example 51. 6-(2-(N,N-Dimethylamino-2-methylethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some minor changes to get the above derivative. MS (m/z): 341 (M+N)+.

Example 52. 6-(2-(N,N-Dimethylaminoethyl)-4-chloro-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1 and some C is intitially changes receive the above derivative. Interval TPL (° (C): above 250; MS (m/z): 375 (M+N)+;1H-NMR (δ ppm): 2.63 in (3H, s), 2,90 (6N, (C), 3,24 (2H, m), 3,61 (2H, m), 7,32-7,74 (6N, m).

Example 53. 8-(2-(N,N-Dimethylaminoethyl)benzo[d]isothiazole[3.2-a]benzo(g)indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derivative. MS (m/z): 377 (M+N)+.

Example 54: 6-(2-N,N-dimethylamino-2-methylethyl)-4-methoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derivative. IR spectrum (cm-1): 2933, 1461, 1438, 1323, 1174, 582;

The range of melting temperature (° (C): 202,4-205,3;

1H-NMR (ppm): 1,00-1,02 (D., 3H, J=6,44 Hz), 2,44 (C, 6N), 2,81-2,87 (DD., J=13,44, 6,56, 1H), 2,93-3,10 (m, 1H), 3,18-3,23 (DD., 1H, J=13,44, 3,20 Hz), a 3.87 (s, 3H), 6,99-7,02 (m, 2H), 7,45-to 7.59 (m, 1H), 7,58 to 7.62 (m, 1H), of 7.64-of 7.69 (m, 1H), 7,79-a 7.85 (m, 2H);

Mass spectrum (m/z): 371,2 (M+N)+.

Example 55: (-) 6-(2-N,N-dimethylamino-2-methylethyl)-4-methoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2933, 1461, 1438, 1323, 1174, 582;

The range of melting temperature (° (C): 202,4-205,3;

1H-NMR (ppm): 1,00-1,02 (D., 3H, J=6,44 Hz), 2,44 C., 6N), 2,81-2,87 (DD., J=13,44, 6,56, 1H), 2,93-3,10 (m, 1H), 3,18 - 3,23 (DD., 1H, J=13,44, 3,20 Hz), a 3.87 (s, 3H), 6,99-7,02 (m, 2H), 7,45-to 7.59 (m, 1H), 7,58-7, 62 (m, 1H), of 7.64-of 7.69 (m, 1H), 7,79-a 7.85 (m, 2H);

Mass spectrum (m/z): 371,2 (M+N)+.

Example 56: (+) 6-(2-N,N-dimethylamino-2-methylethyl)-4-methoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2933, 1461, 1438, 1323, 1174, 582;

The range of melting temperature(° (C): 202,4-205,3;

1H-NMR (ppm): 1,00-1,02 (D., 3H, J=6,44 Hz), 2,44 (s, 611), 2,81-2,87 (DD., J-13,44, 6,56, 1H), 2,93-3,10 (m, 1H), 3,18-3,23 (DD., 1H, J=13,44, 3,20 Hz), a 3.87 (s, 3H), 6,99-7,02 (m, 2H), 7,45-to 7.59 (m, 1H), 7,58-7, 62 (m, 1H), of 7.64-of 7.69 (m, 1H), 7,79-a 7.85 (m, 2H);

Mass spectrum (m/z): 371,2 (M+N)+.

Example 57: 6-(2-N,N-dimethylamino-2-methylethyl)-4-ethoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2968, 2782, 1461, 1324, 1177, 1044, 755, 585;

The range of melting temperature (° (C): 162,4-164,7;

1H-NMR (ppm): 1,00-1,01 (D., 3H, J=6.4 Hz), USD 1.43 to 1.47 (t, 3H), 2,44 (C, 6N), 2,8-2,87 (DD., J=13,4, a 10.6 Hz), 2,92-3,1 (m, 1H), 3,17-up 3.22 (DD., 1H, J=13,44, 3,32 Hz), 4,05-4,10 (K., J=7,0, 2H), 6,98-7, 03 (m, 2H), 7,45-7,49 (m, 1H), EUR 7.57-to 7.59 (D., 1H, J=8,88 Hz), 7,63-to 7.68 (m, 1H), 7,79-to 7.84 (m, 2H);

Mass spectrum (m/z): 385,3 (M+N)+.

Por the measures 58: (-) 6-(2-N,N-dimethylamino-2-methylethyl)-4-ethoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2968, 2782, 1461, 1324, 1177, 1044, 755, 585;

The range of melting temperature (° (C): 162,4-164,7;

1H-NMR (ppm): 1,00-1,01 (D., 3H, J=6.4 Hz), USD 1.43 to 1.47 (t, 3H), 2,44 (C, 6N), 2,8-2,87 (DD., J=13,4, a 10.6 Hz), 2,92-3,1 (m, 1H), 3,17-up 3.22 (DD., 1H, J=13,44, 3,32 Hz), 4,05-4,10 (K., J=7,0, 2H), 6,98-7,03 (m, 2H), 7,45-7,49 (m, 1H), EUR 7.57-7, 59 (D., 1H, J=8,88 Hz), 7,63-to 7.68 (m, 1H), 7,79-to 7.84 (m, 2H);

Mass spectrum (m/z): 385,3 (M+N)+.

Example 59: (+) 6-(2-N,N-dimethylamino-2-methylethyl)-4-ethoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2968, 2,782, 1461, 1324, 1177, 1044, 755, 585;

The range of melting temperature (° (C): 162,4-164,7;

1H-NMR (ppm): 1,00-1,01 (D., 3H, J=6.4 Hz), USD 1.43 to 1.47 (t, 3H), 2,44 (C, 6N), 2,8-2,87 (DD., J=13,4, a 10.6 Hz), 2,92-3,1 (m, 1H), 3,17-up 3.22 (DD., 1H, J=13,44, 3,32 Hz), 4,05-4,10 (K., J=7,0, 2H), 6,98-7,03 (m, 2H), 7,45-7,49 (m, 1H), EUR 7.57-to 7.59 (D., 1H, J=8,88 Hz), 7,63-to 7.68 (m, 1H), 7,79-to 7.84 (m, 2H);

Mass spectrum (m/z): 385,3 (M+N)+.

Example 60: 6-(2-N,N-dimethylamino-2-metalsteel)-4-methyldibenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above manufacturing the same.

IR spectrum (cm-1): 2920, 1609, 1455, 1334, 1179, 1044, 758, 600;

The range of melting temperature (° (C): 164, 8mm-167,0;

1H-NMR (ppm): 1,00-a 1.01 (3H, d, J=6.4 Hz), 2,43 (6N, C)to 2.54 (3H, c.), 2,81-2,87 (1H, m), 2,94 are 2.98 (1H, m),

3,1 is 3.23 (1H, m), 7,33 and 7.36 (1H, DD), J=8,48, 1,72 Hz), 7,49-7,52 (2H, m), to 7.61-7,63 (1H, d, J=8,48 Hz), 7,65-of 7.69 (1H, m), 7,81-to 7.84 (2H, m);

Mass spectrum (m/z): 387,3 (M+N)+.

Example 61: 6-(2-N,N-dimethylaminoethyl)-4-phenylbenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2441, 1602, 1325, 1174, 756;

The range of melting temperature (° (C):of 174.4;

1H-NMR (ppm): 2,42 (C, 6N), 2,66-a 2.71 (m, 2H), 3,20-3,24 (m, 2H), was 7.36-7,40 (m, 1H), 7,46-rate of 7.54 (m, 3H), to 7.61-7,66 (m, 3H), 7.68 per-7,73 (dt., 1H), 7,75 for 7.78 (m, 2H), 7,84-7,88 (m, 2H);

Mass spectrum (m/z): 403,3 (M+N)+.

Example 62: 6-(2-N,N-dimethylamino-2-atility)-4-methoxybenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2961, 1463, 1321, 1175, 764, 582;

The range of melting temperature (° (C): 222,5;

1H-NMR (ppm): 0,83-0,87 (t, 3H, J=to 7.32 Hz), 1,39 is 1.58 (m, 2H), 2,46 (C, 6N), 2,71-of 2.81 (m, 2H), 3,13-is 3.21 (m, 1H), a 3.87 (s, 3H), 6, 99-7,03 (m, 2H), 7,45 is 7.50 (m, 1H), 7,45 is 7.50 (m, 1H), 7,58-7,60 (D., 1H, J=8,8 Hz), of 7.64-of 7.69 (m, 1H), 7,79-to 7.84 (m, 2H);

Mass spectrum (m/z): 385,1 (M+N)+.

Example 63: 6-(2-N,N-dimethylamino-2-methylethyl)-4-bromobenzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2963, 1440, 1328, 1177, 761, 592;

1H-NMR (ppm): 1,00-1,01 (D., 3H, J=6.4 Hz), 2,43 (C, 6N), 2,81-2,89 (DD., 1H, J=13,44, 10,36 Hz), 2,92-3,1 (m, 1H), 2,99-up 3.22 (DD., 1H, J=13,44, to 3.36 Hz), 7,46-7,49 (DD., 1H, J=charged 8.52, to 1.76 Hz), 7,50-rate of 7.54 (m, 1H), 7,56-7,58 (D., 1H, J=8,56 Hz), 7.68 per-7,73 (m, 2H), 7,83-7,86 (m, 2H);

Mass spectrum (m/z): 419,4 (M+N)+.

Example 64: 6-(2-N,N-dimethylamino-2-methylethyl)-benzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2934, 1601, 1462, 1440, 1330, 1178, 739, 582;

The range of melting temperature (° (C): 96,4-110,8 (Razlog.);

1H-NMR (ppm): 0,99-1,01 (D., 3H, J=6,36 Hz), 2,43 (C, 6N), 2,83-2,89 (DD., 1H, J=13,44, a 10.6 Hz), 2,93-to 3.02 (m, 1H), 3,20-3,25 (DD., 1H, J=13,24, 3,20 Hz), 7.24 to 7,28 (m, 1H), was 7.36-7,41 (m, 1H), 7,45 is 7.50 (m, 1H), EUR 7.57-7,60

(doctor, 1H, J=a 7.92 Hz), of 7.64-of 7.69 (m, 1H), 7,69-7,71 (D., 1H, J=8,2 Hz), 7,81-7,83 (m, 2H);

Mass spectrum (m/z): 341,2 (M+N)+.

Example 65: 6-(2-N,N-dimethylamino-2-methylethyl)-4-benzyloxybenzyl[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and h which are unimportant changes receive the above derived.

IR spectrum (cm-1): 2969, 1613, 1459, 1324, 1228, 1174, 1015, 733, 596;

The range of melting temperature (° (C): 154,0-155,6;

1H-NMR (ppm): 1,00-1,01 (D., 3H, J=6,32 Hz), 2,41 (C, 6N), 2,78 2,84 (DD., 1H, J=13,24, 10,56 Hz), 2,88-2,96 (m, 1H), 3,15-3,19 (DD., 1H, J=13,32, 3,2 Hz)to 5.13 (s, 2H), 7,06-7,11 (m, 2H), 7,31-7,5 (m, 6N), 7,58-7, 68 (m, 2H), 7,78-a 7.85 (m, 2H);

Mass spectrum (m/z): 447,4 (M+N)+.

Example 66: 6-(2-N,N-dimethylamino-2-methylethyl)-toranzo[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2936, 1578, 1462, 1328, 1177, 911, 761, 579;

The range of melting temperature (° (C): 158,2-to 163.1;

1H-NMR (ppm): 1,02 was 1.04 (3H, d, J=6,44 Hz), 2,46 (6N, (C), 2,83-2,89 (1 H, DD., J=13,48 Hz), 2,98-of 3.00 (1H, m),

3,25 of 3.28 (1H, sm. J=to 12.52 Hz), 7,09-7,16 (1H, TD., J=2.4 Hz), 7,25-7,27 (1H, m), 7,50-of 7.55 (1H, T., J=of 7.48 Hz), 7,62-7, 66 (1H, DD), J=4,2 Hz), 7.68 per-7,73 (1H, T., J=7.8 Hz), 7,84-7,9 (2H, m);

Mass spectrum (m/z): 359,1 (M+N)+.

Example 67: 6-(2-N,N-dimethylamino-2-methylethyl)-isopropoxybenzoic[d]isothiazole[3,2-a]indole-S,S-dioxide

Using essentially the General procedure described in example 1, and some unimportant changes receive the above derived.

IR spectrum (cm-1): 2975, 1613, 1460, 1333, 1179, 963, 794, 580;

1H-NMR (ppm): 1,09-1,10 (D., 3H, J=6,56 Hz), of 1.35 to 1.37 (D., 6N), 2,58 (c. 6N), 2,93-2,96 (DD., 1H, J=13,52, 11,36 Hz), 3,16-3,26 (m, 1H), 3,38-3, 46 (m, 1H), 4,59-to 4.62 (m, 1H, 6,99-7,01 (DD., 1H, J=8,8, 2,32 Hz), 7,10 (D., 1H, J=2.4 Hz), 7,47-7,51 (m, 1H), EUR 7.57-7,60 (D., 1H, J=8,8 Hz), 7,66-7,72 (m, 1H), 7,82-7,84 (D., 1H, J=7.8 Hz), 7,94-of 7.96 (D., 1H, J=a 7.92 Hz);

Mass spectrum (m/z): 399,3 (M+N)+.

1. The compound of General formula (I)

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12may be the same or different and represent, each independently, hydrogen, halogen, hydroxy, unsubstituted (C1-C6)alkyl, (C1-C6)alkoxy, or adjacent groups R2and R3together with the carbon atoms to which they are attached, may form a benzene ring;

R13and R14may be the same or different and represent, each independently, hydrogen, unsubstituted (C1-C6)alkyl, optionally, R13and R14together with the nitrogen atom can form a 5-, 6-membered heterocyclic ring, where the heterocycle may also be substituted (C1-C6)alkyl, and he may have additional heteroatoms selected from O, N; and

"n" is an integer in the range from 1 to 4, and the carbon chain to which it belongs, is linear;

its pharmaceutically acceptable salt.

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

6-(2-N,N-dimethylamino the l)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-chloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-toranzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

hydrochloride of 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

salt maleate 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

salt D,L-malic acid 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

salt oxalate 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole [3.2-a]indole-S,S-dioxide;

salt citrate 6-(2-N,N-dimethylaminoethyl)-4-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-chloro-6-(2-N,N-dimethylaminoethyl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-fluoro-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-methyl-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioc the IDA;

6-(2-N,N-dimethylaminoethyl)-4,8-dimethoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2-ethylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2-chloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,4-dichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,3-dichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

5-chloro-6-(2-N,N-dimethylaminoethyl)-2-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,4,5-trichloro-6-(2-N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2,4-debtorrent[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-4-fluoro-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

2,4-debtor-6-(2-N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-2,8-dimethoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-is ethoxybenzo[e]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-N,N-dimethylamino-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-[2-(4-methylpiperazin-1-yl)ethyl]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-[2-morpholine-4-ileti]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-pyrrolidin-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-piperidine-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-[2-morpholine-4-ileti]benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-pyrrolidin-1-retil)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-[2-(4-methylpiperazin-1-yl)ethyl]benzo [d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(3-(piperidine-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(pyrrolidin-1-yl)-1-hydroxyprop-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(3-(pyrrolidin-1-yl)-1-hydroxyprop-1-yl)-8-methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-is ethylamino)-2-methylethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-dimethylamino-1-hydroxy-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-bromo-6-(2-(N,N-dimethylamino-1-hydroxy-1-yl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-dimethylaminoethyl)-2,4-debtor-8 methoxybenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

6-(2-(N,N-dimethylamino-2-methylethyl)benzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

4-chloro-6-(2-(N,N-dimethylaminoethyl)-8-methylbenzo[d]isothiazole[3.2-a]indole-S,S-dioxide;

8-(2-(N,N-dimethylaminoethyl)benzo[d]isothiazole[3.2-a]benzo(g)indole-S,S-dioxide; and pharmaceutically acceptable salts.

3. Pharmaceutical composition having the properties of modulators of the activity of 5-HT containing any of the pharmaceutically acceptable carrier, diluent(s), excipient(s) together with a therapeutically effective amount of a compound according to claim 1, or 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 for use in disposable or reusable injection.

5. The use of compounds of General formula (I) according to claim 1 to obtain drugs for 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 for treatment, when gellately is and modulation of the activity of 5-HT.

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

8. The use of the pharmaceutical composition according to claim 3 for the treatment when the desired modulation of the activity of 5-HT.

9. The use of compounds according to claim 1 for obtaining a medicinal product for the treatment and/or prevention of conditions under which shows the impact on the receptors 5-HT.

10. 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 disorders, migraine, cognitive memory disorders, ADHD (attention deficit/hyperactivity disorder), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophrenic disorders forms, panic attacks, sleep disorders.

11. The use of compounds according to claim 1, radiolabelled, as a diagnostic tool to modulate the function of the receptors 5-HT.

12. The use of compounds according to claim 1 in combination with an inhibitor of the reuptake of 5-HT and/or its pharmaceutically acceptable salt.

13. The compound of General formula (I) according to claim 1 and its pharmaceutically acceptable salt for a medicinal product having the properties of modulators of the activity of 5-HT.

14. The method of obtaining compounds of General forms of the crystals (I) according to claim 1, involving the cyclization of compounds of the following formula (II)

where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14and "n" have the meanings specified in claim 1, in the presence of a catalyst comprising a derivative of Pd(0) or Pd(II), followed, if necessary, (i) removing the protective group, and/or (ii) receipt of pharmaceutically acceptable compounds of formula (I).

15. The method according to 14, including the implementation of one or more of the following stages: i) removing any protective group; and (ii) obtaining the pharmaceutically acceptable salts of the compounds of formula (I).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention was targeted at obtaining crystals of acetonitrile solvate of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (compound B), which is an intermediate compound in obtaining crystals of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of III type (compound A). Compound B crystals are mostly precipitated by regulation of super-saturation during crystallisation involving acetonitrile as a solvent. Then compound A crystals of III type are obtained crystal desolvation.

EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to cyclic sulphonamide derivatives of general formula I where bonds indicated with wavy lines represent mutually cis- in relation to cyclohexane ring; R3 represents H or hydrocarbon group having up to 10 carbon atoms; Ar1 and Ar2 independently represent phenyl which carries 0-3 substitutes independently selected from halogen, CF3, CHF2; or its pharmaceutically acceptable salt. Besides, invention refers to technology of compounds of general formula I and to pharmaceutical composition based on compounds of general formula I and applied as gamma-secretase inhibitor.

EFFECT: new derivatives of cyclic sulphonamide, activating gamma-secretase inhibition and suitable for treatment and prevention of Alzheimer's disease.

9 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

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: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

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

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: chemistry.

SUBSTANCE: in general formula I

R1 is phenyl or 5-6-member heterocycle, containing one N atom and/or one O atom; R2 is imidazole or annelated imidazole, selected from group, including a), b), c), d) and e); and R3 stands for hydrogen, phenyl, 2,3-dihydrobenzo[1,4]dioxin-6-yl, benzo[b]thiophen-3-yl, 3-methylbenzo[b] thiophen-2-yl, thiophen-2-yl or thiophen-2-ylmethyl, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, halogen, morpholinyl, -NR'R", piperydinyl, optionally substituted with hydroxy-group, or is pyrrolidin-1-yl; R6 is hydrogen or -(CH2)nO-lower alkyl, R7 is hydrogen, -C(O)O-lower alkyl, -C(O)-C6H4-halogen, -C(O)-C6H4-lower alkyl, -C(O)-lower alkyl, -C(O)-cycloalkyl, -C(O)-NR'R", -C(O)-(CH2)nO-lower alkyl, -S(O)2-lower alkyl, -(CH2)nO-lower alkyl, -C(O)-pyridin-4-yl, whose ring can contain as substituents lower alkyl, halogen-lower alkyl or pyrrolidin-1-ylmethyl or is -(CH2)n-C(O)-NR'R"; R'/R" independently on each other stand for hydrogen, lower alkyl or -(CH2)n-tetrahydropyran-4-yl, X is -CH2-, -NR'''- or -O-; R''' is hydrogen, -C(O)-lower alkyl, -C(O)O-lower alkyl, -C(O)-C6H4CH3 or benzyl; n is 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

14 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula I R1 is -(CH2)n-CO-NR5R6; -(CH2)n-COOR7; -(CH2)n- NR5R6; -(CH2)n-CN; -(CH2)n-OR8 or phenyl, which is unsubstituted or substituted with from one to three substituents, selected from halogen; R2 is hydrogen; R3 is hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl or benzyl; R4 is halogen; R5 and R6 are hydrogen; R7 is hydrogen or C1-C6-alkyl; R8 is C1-C6-alkyl; m is 1, 2 or 3; and n is 0, 1 or 2.

EFFECT: increase of composition and treatment method efficiency.

5 cl, 2 dwg, 27 ex

FIELD: chemistry.

SUBSTANCE: in novel derivatives of 4-(4-alkoxy-3-hydroxyphenyl)-2-pyrrolidone of formula I , X represents O, R1 represents C1-C8alkyl, C3-C8cycloalkyl, C8-C16arylalkyl, C8-C16arylalkenyl, in which alkenyl fragment contains up to 5 carbon atoms, C4-C16cycloalkylalkyl, R2 represents C1-C4alkyl, unsubstituted or substituted with one or more halogens, R3 represents C3-C8cycloalkyl, C7-C16arylalkyl, substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, cyano or CF3, C3-C8alkoxyalkyl, -C(O)R4 or -CH2CONHR5; R4 represents C6-C14aryl, substituted with one or more substituents from halogen line, C1-C8alkoxy or nitro; R5 represents C6-C14aryl, unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, nitro or amino, heterocyclic group, saturated, partially saturated or fully unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, or additionally second atom is represented with heteroatom, selected from N, O and S, heterocyclic group is unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, or their combinations; or heterocyclylC1-C5alkyl, saturated, partially saturated or unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, O or S, and which is unsubstituted or substituted in heterocyclic fragment with C1-C8alkyl or C1-C8alkoxy group, and their physiologically acceptable salts, in each case compound can be in form of enantiomer mixture, such as racemate, or mixture of diastereomers, or can be in form of one enantiomer or one diastereomer; on condition that if R1 represents cyclopentyl and R2 represents methyl, R3 does not represent benzyl, 4-bromobenzyl, 3,4-dimethoxybenzyl or 4-cyanobenzyl. Compounds I inhibit activity of PDE-4 enzyme, which allows using them in pharmaceutical compositions.

EFFECT: increase of composition and treatment method efficiency.

38 cl, 11 ex

FIELD: medicine.

SUBSTANCE: suitable for transdermal introduction of rotigotine [(-)-5,6,7,8-tetrahydro-6[propyl[2(2-thienyl)ethyl]amino]-1naphthol] in an organism, the polymeric matrix contains polymer forming it which is supersaturated with rotigotine in the form of the free base, thus not dissolved in a polymer forming a matrix the part of rotigotine is dispersed in it in the form of amorphous particles with average diameter of 30 microns maximum, and hydrotropic solubilisers, inhibitors of crystallisation and dispersants are absent in the matrix. The device of the flat form for transdermal introduction of rotigotine in an organism, containing specified above a rotigotine supersaturated polymeric matrix is described also, it is preferable on a silicon basis, and an impenetrable for rotigotine back layer.

EFFECT: matrix allows to provide therapeutically comprehensible rate of penetration of rotigotine from it through a skin.

14 cl, 7 dwg, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: minitablets have a kernel and an external cover which makes 2-15% of gross weight of minitablets, the kernel of the specified minitablets, includes a venlafaxine hydrochloride, microcrystallic cellulose and a polyvinylpyrolidone, and the specified cover includes polymer, insoluble in water, and a polymer, soluble in water.

EFFECT: provision of levels of concentration in a blood plasma above the minimum therapeutic concentration during the long period of time.

10 cl, 1 dwg, 1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) HetAr represents pyrimidinyl or thiadiasolyl; R1 and R2 represent H; A represents C1-C2-alkyl; B represents aryl(CH2)0-3-O-C(O)-or arylcyclopropyl-C(O)-, in which aryl can be substituted with 1-5 substituents, each substituent represents C1-C4-alkyl. Invention also relates to pharmaceutical composition and to application of compounds of item 1. Obtaining novel compounds, as well as pharmaceutical composition possessing NMDA/NR2B antagonist activity.

EFFECT: increase of composition efficiency.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: in arylpiperazinyl compounds of general formula , where R1 is unsubstituted alkyl or cycloalkyl; R2 and R3 independently hydrogen; lower alkyl; cycloalkyl; or -NR4R5, where R4 and R5 independently represent H, O, R6 or COR6, where R6 can represent lower alkyl or sulfonamidoalkyl; on condition that R2 and R3 both are not hydrogen; -atoms designated as bound with dotted line, taken together with atoms, to which they are joined, can form six-member ring; - Z represents N or C; - m equals 0, 1 or 2; - n equals 1, 2, 3, 4, 5 or 6; - p equals 0, 1, 2, 3 or 4. Compounds can be used for treatment of diseases, mediated directly or indirectly by 5-HT receptors. Such diseases are disorders of central nervous system.

EFFECT: increase of composition and method of treatment efficiency.

50 cl, 12 dwg, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: compounds of formula (I) can be efficient with respect to diseases, in which phosphorylation of Tau protein takes place. , R3 stands for CONR1R2, where R1 and R2 can be substituted with heterocycle; R5, R6, R7 independently on each other are selected from halogen and phenyl; R1, R2 independently on each other stand for hydrogen, (C1-C6)alkyl or together with nitrogen of group CONR1R can form heterocycle.

EFFECT: obtaining novel biologically active compounds.

4 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: obtained is acceptable for pharmaceutical purposes oxalate of N,N-dimethyl-2-N,N-dimethylaminomethylpyridyl-3-carbamate, possessing anti-cholinesterase and anti-amnestic activity, which, in contrast to other salts of this structure, is not a hydroscopic compound.

EFFECT: increased anti-cholinesterase activity.

1 cl, 1 ex, 8 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: applying of 2-amino-7-bromo-4-acetylthiazolo-[5,4-b]indole hydrobromide for increase of working capability is proposed. Previously the substance was used for liver anti-toxic protection. It was shown that 2-amino-7-bromo-4-acetylthiazolo-[5,4-b]indole hydrobromide can two times increase working capability, just as the matched drug, phenamine, does; after 24 hours the capability can be increased 5.9 times, well above than phenamine and bemitile.

EFFECT: providing of long-lasting actoprotector activity.

2 tbl

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