1-(aminoalkyl)-3-sulfonylazaindoles as ligands for 5-hydroxytryptamine-6

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) , methods for their synthesis and their using for therapeutic treatment of the nervous system disorders associated with 5-HT-6 receptor. Invention provides synthesis of novel biologically active substances of the formula (I) and pharmaceutical compositions based on thereof used in treatment of the nervous system disorders and controlled by 5-HT-6 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 tbl, 82 ex

 

This invention relates to 1-(aminoalkyl)-3-sulfonylation used as ligands of 5-hydroxytryptamine-6, to methods for their preparation, to methods for therapeutic use and to pharmaceutical compositions containing them.

The level of technology

Serotonin receptors (5-hydroxytryptamine) (5-HT) play a critical role in many physiological and behavioral functions in humans and animals. Such functions mediasource through different receptors, 5-HT, distributed in the body. Currently, there are approximately fifteen different subtypes of receptors 5-HT man who cloned, many of them play a good role in humans. One of the recently identified receptor subtypes 5-HT receptor is a 5-HT, first cloned from tissue of rats in 1993 (Monsma, F.J.; Shen, Y.; Ward, R.P.; Hamblin, M.W. Molecular Pharmacology, 1993, 43, 320-327) and then from human tissues (Cohen, R.; Metcalf, M.A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D.R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is coupled with a G-protein receptor (GPCR), is positively coupled with adenylate cyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical Research Communications 1993, 193, 268-276). The receptor is found almost exclusively in the Central nervous system (CNS), both in rats and in humans. Research in situ hybridization receptor 5-HT Moshe rats using mRNA showed basic localization in the projection of 5-HT, including the striatum, necleus accumbens, olfactory tubercles and hippocampal formation (Ward, R.P.; Hamblin, M.W.; Lachowicz, J.E.; Hoffman, B.J.; Sibley, D.R.; Dorsa, D.M. Neuroscience 1995, 64, 1105-1111).

There are many potential applications for ligands 5-HT in humans, based on direct action and on the testimony of well-known scientific research. These studies include the localization of the receptor, the affinity of ligands with known in vivo activity and various animal studies conducted up to the present time.

One of the potential applications of modulators of receptor function 5-HT is improved cognition and memory in humans for diseases such as Alzheimer's disease. High levels of receptor found in the important structures in the forebrain, including caudate/putamen, hippocampus, necleus accumbens and cortex, suggest the involvement of the receptor in memory and cognitive abilities, as it is known that these areas play a vital role in memory (Garard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M.C.; Verge, D.; Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research, 1997, 746, 207-219). The ability of known ligands of the receptor 5-HT to improve cholinergic transmission also confirms the possibility of applications to improve cognitive abilities (Bentley, J.C.; Boursson, A.; Boess, F.G.; Kone, F.C.; Marsden, C.A.; Petit, N.; Sleight, .J. British Journal of Pharmacology, 1999, 126(7), 1537-1542). During research it was found that the known selective antagonist of 5-HT significantly increases the levels of glutamate and aspartate in the frontal cortex, without increasing the levels of norepinephrine, dopamine or 5-HT. This selective increase neurochemical substances that is known to be involved in memory function and cognitive abilities, clearly indicates the role of ligands 5-HT in cognitive ability (Dawson, L.A.; Nguyen, H.Q.; Li, P. British Journal of Pharmacology, 2000, 120(7), 23-26). Research memory of animals and the study of known selective antagonist of 5-HT showed some positive effect (Rogers, D.C.; Hatcher, P.D.; Hagan, J.J. Society of Neuroscience, Abstracts 2000, 26, 680).

Such potential therapeutic use of ligands 5-HT is the treatment of disorders attention deficit (add, also known as disorder hyperactivity attention deficit or ZGDV) in children and adults. Because, it seems that antagonists of 5-HT improve activity nigrostriatal dopamine pathway and as SGDV associated with abnormalities in caudate (Ernst, M.; Zametkin, A.J.l Matochik, J.H.; Jons, P.A.; Cohen, R. Journal of Neuroscience 1998, 18(15), 5901-5907), antagonists of 5-HT can reduce attention deficit disorder.

In early studies, which studied the affinity of various ligands with known CNS therapeutic use or large with Nocturne similarity to known drugs, was offered the role of ligands 5-HT in the treatment of schizophrenia and depression. For example, clozapine (effective clinical antipsychotic agent) has a high affinity to 5-HT subtype receptor. Also some clinical antidepressants have high affinity to the receptor and act as antagonists at this site (Branchek, T.A.; Blackburn, T.P. Annual Reviews in Pharmacology and Toxicology 2000, 40, 319-334).

Further, recent in vivo studies in rats showed that the modulators of the 5-HT can be useful in the treatment of movement disorders, including epilepsy (Stean, T; Routledge, C.; Upton, N. British Journal of Pharmacology, 1999, 127 Proc. Supplement 131P and Rouledge, C.; Bromidge, S.M.; Moss, S.F.; Price, G.W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarke, S.F.; Brown, A.M. British Journal of Pharmacology, 2000, 130(7), 1606-1612).

Taken together, these studies strongly confirm that compounds that are ligands of 5-HT can be applied in therapeutic indications, including the treatment of diseases associated with deficiency of memory, cognitive ability and learning ability, such as Alzheimer's disease and disorder attention deficit; treatment of personality disorders, such as schizophrenia; treatment of behavioral disorders, such as anxiety, depression, and obsessive-compulsive disorders; treatment of disorders of movement or motor skills, such as Parkinson's disease and epilepsy; treatment of diseases associated what neurodegeneration, such as stroke and head injury; or removing the dependence on drugs, including addiction to nicotine, alcohol, and other substances that are addictive.

Therefore, an object of the present invention are compounds that are useful as therapeutic agents in the treatment of various disorders of the Central nervous system related to or under the influence of the receptor 5-HT.

Another object of the present invention are therapeutic methods and pharmaceutical compositions used in the treatment of disorders of the Central nervous system related to or under the influence of the receptor 5-HT.

A characteristic feature of the present invention is that the compounds in accordance with this invention can also be used for further research and evaluation of the receptor 5-HT.

These and other objects and features of this invention will become clearer from the detailed description presented below.

Brief description of the invention

This invention relates to a derivative of 1-(aminoalkyl)-3-sulfasalazine formula I

where

W is N or CR7;

X is N or CR8;

Y is N or CR9;

Z is N or CR10provided that at least one and not more than the boom of W, X, Y and Z must be N;

n is an integer 2, 3, 4 or 5;

R1is optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, aryl or heteroaryl, or optionally substituted 8 to 13-membered bicyclic or tricyclic system of rings having a N atom at the base of the bridge connection, and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S;

R2is H, halogen or1-C6-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, aryl or heteroaryl, each of which is optionally substituted;

R3and R4each independently is H or optionally substituted C1-C6-alkyl;

R5and R6each independently is H or C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C7-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted, or R5and R6together with the atom to which they are attached, form an optionally substituted 5-8-membered ring, optionally containing an additional heteroatom selected from O, NR11or SOm;

R7, R8, R9and R10independently are H, halogen, CN, OCO2R12, CO2R13, COR 14R15, SOpR16, NR17R18OR19, COR20or1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C7-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted;

R11, R12, R13, R16, R19and R20each independently is H or C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C6-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted;

R14and R15each independently is H or optionally substituted C1-C6-alkyl, or R14and R15together with the atom to which they are attached, may form a 5-7-membered ring, optionally containing another heteroatom selected from O, NR22or S;

R17and R18each independently is H or optionally substituted C1-C4-alkyl, or R17and R18together with the atom to which they are attached, may form a 5-7-membered ring, optionally containing another heteroatom selected from O, NR21or SOx;

R21and R22each independently is H or C1-C6-alkyl, C2-C6-alkenyl,3-the 7-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted; and

m, p and x each independently 0 or an integer 1 or 2; or

its stereoisomer or its pharmaceutically acceptable salt.

This invention also presents methods and compositions used for therapeutic treatment of disorders of the Central nervous system related to or under the influence of the receptor 5-HT.

Detailed description of the invention

Receptor 5-hydroxytryptamine-6 (5-HT) is one of the receptors, recently identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, in combination with interesting distribution in the brain causes a significant interest in new compounds that can interact with or be affected by this receptor. Significant efforts have been made to understand the possible role of the receptor 5-HT in psychiatry, cognitive dysfunction, motor functions and control, memory, mood and the like. To date, compounds that exhibit binding affinity of the receptor 5-HT, are considered to be useful as an aid for studying receptor 5-HT, and as potential is lnyh therapeutic agents in the treatment of disorders of the Central nervous system, for example, see C. Reavill and D.C. Rogers, Current Opinion in Investigational Drugs, 2001, 2(1): 104-109, Pharma Press Ltd.

Unexpectedly, it was found that derivatives of 1-(aminoalkyl)-3-sulfasalazine formula I demonstrate affinity to 5-HT. Mostly such derivatives azaindole can be used as effective therapeutic agents for the treatment of disorders of the Central nervous system (CNS)associated with or under the influence of the receptor 5-HT.

Therefore, the present invention relates to derivatives of 1-(aminoalkyl)-3-sulfasalazine formula I

where

W is N or CR7;

X is N or CR8;

Y is N or CR9;

Z is N or CR10provided that at least one and not more than two of W, X, Y, and Z must be N;

n is an integer 2, 3, 4 or 5;

R1is optionally substituted C1-C6-alkyl, C3-C7-cycloalkyl, aryl or heteroaryl, or optionally substituted 8 to 13-membered bicyclic or tricyclic system of rings having a N atom at the base of the bridge connection, and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S;

R2is H, halogen or1-C6-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, aryl or het is roario, each of which is optionally substituted;

R3and R4each independently is H or optionally substituted C1-C6-alkyl;

R5and R6each independently is H or C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C7-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted, or R5and R6together with the atom to which they are attached, form an optionally substituted 5-8-membered ring, optionally containing an additional heteroatom selected from O, NR11or SOm;

R7, R8, R9and R10independently are H, halogen, CN, OCO2R12, CO2R13, CONR14R15, SOpR16, NR17R18OR19, COR20or1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C7-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted;

R11, R12, R13, R16, R19and R20each independently is H or C1-C6-alkyl, C2-C6-alkenyl,2-C6-quinil,3-C6-cycloalkyl, cyclogeraniol, aryl or heteroaryl, to each of the categories is optional substituted;

R14and R15each independently is H or optionally substituted C1-C6-alkyl, or R14and R15together with the atom to which they are attached, may form a 5-7-membered ring, optionally containing another heteroatom selected from O, NR22or S;

R17and R18each independently is H or optionally substituted C1-C4-alkyl, or R17and R18together with the atom to which they are attached, may form a 5-7-membered ring, optionally containing another heteroatom selected from O, NR21or SOx;

R21and R22each independently is H or C1-C6-alkyl, C2-C6-alkenyl,3-C7-cycloalkyl, cyclogeraniol, aryl or heteroaryl, each of which is optionally substituted; and

m, p and x each independently 0 or an integer 1 or 2; or

their stereoisomers or their pharmaceutically acceptable salts.

In this description and the claims, the term halogen means F, Cl, Br or I, and the term cyclogeranyl means a 5-7 membered ring system ring containing 1 or 2 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, and optionally contains one double bond. Examples cyclogeraniol system of rings, I is coming in the term, include rings, in which X1is NR, O or S; and R is H or an optional substitute, such as described below:

Used in the description and in the claims the term heteroaryl means a 5-10 membered aromatic system of rings containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl system of rings include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, chinoline, ethenolysis, indolinyl, benzothiazyl, benzofuranyl, benzisoxazole or similar. The term aryl means a carbocyclic aromatic system of rings, for example, having 6-14 carbon atoms, such as phenyl, naphthyl, anthracene and the like. The term halogenated in this description means a group of CnH2n+1having from one to 2n+1 halogen atoms which may be the same or different, and the term halogenoalkane in this description means a group OCnH2n+1having from one to 2n+1 halogen atoms which may be the same or different.

Examples 8 to 13-membered bicyclic or tricyclic systems of rings having a N atom at the base of the bridge connection, and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S, covered used in this description of those who min, include below ring system, in which W2is NR, O or S; and R is H or an optional substitute, such as shown below:

In the description and the claims, where terms such as1-C6-alkyl, C2-C6alkenyl,2-C6-quinil,3-C6-cycloalkyl, cyclogeranyl, aryl or heteroaryl are optionally substituted, a group of substituents, which are optionally present may be one or more, for example, 2 or 3, and represent groups commonly used in the pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial properties. Specific examples of such substituents include halogen atoms, nitro, cyano, hydroxyl, alkyl, halogenated, alkoxy, halogenoalkane, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfonyl, carbarnoyl, alkylamino, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl (such as heteroaryl or cyclogeranyl) or cycloalkyl, preferably, halogen atoms or lower alkyl groups. Typically present from 0 to 3 substituents. If any of these is use substituents represents or contains an alkyl substituent in the form of a group or part of a group, it can be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.

Pharmaceutically acceptable salt may be any acid additive salt formed from the compounds of formula I and pharmaceutically acceptable acid, such as phosphoric, sulfuric, hydrochloric, Hydrobromic, citric, maleic, malonic, almond, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluensulfonate, methanesulfonate acid or the like.

Compounds in accordance with this invention include esters, carbamates, or other common forms of prodrugs, which, in General, are functional derivatives of the compounds in accordance with this invention and which are easily converted into the active group of the present invention in vivo. Accordingly, the method in accordance with this invention includes the treatment of various conditions described above, a compound of formula I or a compound that is not specifically described, but which, when introduced, is transformed into a compound of formula I in vivo. Also includes metabolites of compounds in accordance with this invention, defined as active compounds, obtained by the introduction of these compounds into a biological system.

The connection is possible in accordance with this invention can exist as one or more stereoisomers. Different stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. The person skilled in the art will understand that one stereoisomer may be more active or may have a favorable effect, being enriched with respect to another(them) stereoisomer(s) or when separated from the other(s) stereoisomer(s). In addition, the person skilled in the art knows how to separate, enrich, or to selectively receive said stereoisomers. Therefore, this invention includes compounds of formula I, their stereoisomers and their pharmaceutically acceptable salts. Compounds in accordance with this invention can be in the form of a mixture of stereoisomers, individual stereoisomers or in the form of optically active or enantiomerically pure form.

Preferred compounds in accordance with this invention are the compounds of formula I in which W and Z are N. Also preferred are the compounds of formula I in which n is 2. Another group of preferred compounds of formula I includes compounds in which R1is optionally substituted by phenyl, naphthyl or imidazothiazole.

More preferred compounds in accordance with this invention are the compounds of formula I in which W is CR7; X is CR ; Y is CR9; and Z is N. Another group of preferred compounds includes compounds of formula I in which W is N; X is CR8; Y is CR9; and Z is CR10. More preferred compounds of formula I also include compounds in which n is 2 and R3and R4are N. Also preferred compounds are those compounds of formula I in which W and Z are N; n is 2; R1is optionally substituted by phenyl, naphthyl or imidazothiazole; R2, R3and R4are H; and R5and R6each independently are N or C1-C3-alkyl.

Examples of preferred compounds in accordance with this invention include:

2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethylamine;

2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]ethylamine;

2-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]ethylamine;

2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethylamine;

2-{3-[(4-were)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-[3-(naphthas-1-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethylamine;

2-{3-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-{3-[(2-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-C]pyrid the n-1-yl}ethylamine;

2-{3-[(3-methoxyphenyl)sulfonyl]-1H-pyrrolo[3,2-C]pyridin-1-yl}ethylamine;

2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethylamine;

N,N-dimethyl-N-(2-{3-[(3-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N,N-dimethyl-N-{2-[3-(naphthas-1-ylsulphonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N,N-dimethyl-N-(2-{3-[(6-chloroimidazo[1,2-b][1,3]thiazol-5-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N,N-dimethyl-N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]propan-1-amine;

3-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}propan-1-amine;

2-{6-chloro-3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-{7-chloro-3-[(2-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-C]pyridin-1-yl}ethylamine;

4-{3-[(3-methoxyphenyl)sulfonyl]-1H-pyrrolo[3,2-C]pyridin-1-yl}butane-1-amine;

4-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}butane-1-amine;

N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]ethyl}amine;

N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]ethyl}amine;

N,N-dimethyl-N-{2-[3-(Thian-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N,N-dimethyl-N-{2-[3-(naphthas-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N,N-dimethyl-N-(2-{3-[(4-shall terphenyl)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(3-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-{2-[3-(naphthas-1-ylsulphonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N-methyl-N-(2-{3-[(6-chloroimidazo[1,2-b][1,3]thiazol-5-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(2-chlorophenyl)sulfonyl]-1H-pyrrolo[3,2-C]pyridin-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(3-methoxyphenyl)sulfonyl]-1H-pyrrolo[2,3-C]pyridin-1-yl}ethyl)amine;

N-benzyl-N-(2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethyl)amine;

N,N-dibenzyl-3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]propan-1-amine;

their stereoisomers and pharmaceutically acceptable salts.

This invention also presents methods for obtaining compounds of formula I, such as defined above, or stereoisomers or pharmaceutically acceptable salts, where the methods include one of the following:

a) interaction of the compounds of formula II

where W, X, Y, Z, R1and R2such as described above, with halogenosilanes formula III

where Hal is Cl, Br or I and R3, R4, R5, R6and n such as OPI is ANO above, in the presence of a base to obtain the compounds of formula I;

or

b) interaction of the compounds of formula (V)

where W, X, Y, Z, R1, R3, R4and n such as described above, and Hal is halogen, with a compound of the formula

HNR5R6,

where R5and R6such as described above, to obtain compounds of formula I;

or

(C) sulfonylamine the compounds of formula XVI:

where W, X, Y, Z, R3, R4, R5, R6and n such as described above, with the compound of the formula:

ClSO2R1,

where R1such as defined above, to obtain compounds of formula I;

or

d) recovering the compound of formula XX:

where W, X, Y, Z, R1, R3, R4and n such as described above, to obtain the corresponding compounds of formula I in which R5and R6both are hydrogen;

or

(e) the interaction of the compounds of formula

where W, X, Y, Z, R1, R2, R3, R4n and m such as described above, with hydrazine to obtain the corresponding compounds of formula I in which R5and R6both are hydrogen;

or

f) transforming the compound of formula I in the pharmaceutical and food & the automatic acceptable salt or Vice versa.

Compounds in accordance with this invention are usually obtained by the methods illustrated in the following schemes, in which Hal is Cl, Br or I.

Scheme I

Bases suitable for use in the method in accordance with this invention, include strong bases such as NaH, KOt-Bu, NaOH, or any suitable base capable of removing a proton from the basic nitrogen atom of azaindole.

Solvents suitable for use in the method in accordance with this invention include polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran or the like. If you apply two immiscible solvent may be present interphase catalyst. Preferably, to obtain compounds of the formula I, in which R5and R6are H, the compound of formula II may be subjected to interaction with the bottom, as described above, in the presence of a phase transfer catalyst such as tetrabutylammonium hydrosulfate, to give the desired compounds of formula I in which R5and R6are N.

Alternatively, the compounds of formula I in which R5and R6are N (Ia)can be obtained by the coupling of compounds of formula II with a compound of dihalogenoalkane formula IV to obtain 1-(Gal shall penalcol)azaindole formula V; the interaction of azaindole formula V with phthalimide potassium with obtaining the intermediate compounds of formula VI, and the interaction of the specified intermediate compound with hydrazine to give the desired compounds of formula Ia. The sequence of reactions shown in scheme II, where Hal is Cl, Br or I.

Scheme II

The compounds of formula V can also be subjected directly to the interaction with the amine, HNR5R6with obtaining the compounds of formula I. the compounds of formula II can be obtained by conventional methods of synthesis and, if necessary, the standard division and separation. For example, the connection of nitropyridine formula VII may be subject to interaction with the connection chloromethanesulfonyl formula VIII in the presence of a strong base to obtain the intermediate compounds of formula IX; specified intermediate compound of formula IX can then be processed regenerating agent such as Fe, Zn or Sn in the presence of acid to obtain an amine of formula X; then the specified amine can be allerban corresponding complex orthoevra formula XI with obtaining the compounds of formula XII; and the specified connection can be cyclosiloxane in the presence of base to give the desired 3-sulfasalazine formula II. General method of synthesis described by W Wojciechowski and M. Makosza, Synthesis, 1986, 651-653. The sequence of reactions shown in scheme III.

Scheme III

The compounds of formula II can also be obtained directly from a compound of azaindole, for example, azaindole formula XIII may be subjected to interaction with iodine, optionally in the presence of KI, to obtain the corresponding 3-itasaidia formula XIV, and the specified 3-yogasana can be combined with an appropriate thiol of formula XV with 3-toaseinal formula XVI. The specified connection formula XVI can then be oxidized using conventional oxidizing agents, such as H2About2m-chloroperbenzoic acid or the like to obtain the intermediate compounds of formula II. The reaction is shown in scheme IV.

Scheme IV

Alternatively, the intermediate compound 3-toaseinal formula XVI can be obtained in one stage of azaindole formula XIII by the interaction of the compounds of formula XIII with a thiol of formula XV in the presence of iodine, preferably in a polar solvent such as aqueous alcohol. Thus obtained compounds of formula II can then be converted into the desired compounds of formula I by alkylation of the nitrogen atom of the main azaindole, as shown in schemes I and II above.

The compounds of formula XIII is e can be converted into the desired compounds of formula I, in which R5and R6different from N (Ia), interaction of azaindole formula XIII with an amine of the formula IIIa, in which R5and R6other than N, to obtain N-alkylated compounds of formula XVII; the interaction of the compounds of formula XVII with sulphonylchloride formula XVIII, optionally in the presence of reagent such as Ag(OSO2CF3) or Bi(OSO2CF3)3, to give the desired compounds of formula Ia. Also the compounds of formula I in which R5and R6are N (Ib)can be obtained directly from the intermediate compounds of formula XIII interaction specified intermediate compounds of formula XIII with a nitrile of formula XIX to obtain the corresponding alkylated compounds of formula XX; sulfonation of the compounds of formula XX with obtaining the compounds of formula XXI and restoration of the compounds of formula XXI with conventional reducing agents such as borane in tetrahydrofuran (THF) to give the desired compounds of formula Ib. The reaction shown in scheme V, where Hal is Cl, Br or I.

Scheme V

Primarily, the compounds of formula I in accordance with this invention used for the treatment of CNS disorders associated with or under the influence of the receptor 5-HT, including motility disorders, the crust is oene, personality, behavioral, psychiatric, cognitive, neurodegenerative, or the like, for example, Alzheimer's disease, Parkinson's disease, a disorder attention deficit, anxiety, epilepsy, depression, obsessive-compulsive disorder, sleep disorders, neurodegenerative disorders (such as trauma or stroke), eating disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with the cancellation of drugs or nicotine addiction, or the like, or certain gastrointestinal disorders such as irritable bowel syndrome. Therefore, this invention is a method of treating disorders of the Central nervous system, associated or under the influence of the receptor 5-HT in a patient in need of such treatment, which includes the introduction of the indicated patient a therapeutically effective amount of the compounds of formula I, such as described above. The compounds can be administered orally or parenterally or by any conventional means, which provides an effective introduction of a therapeutic agent to a patient in need of it.

The term "introduction", in this context, in terms of introducing compounds or substances in accordance with this invention, means either the introduction of directly such connection Il the matter, or administration of the prodrug, derivative or analogue, which gives the equivalent amount of the compounds or substances in the body.

Therapeutically effective amount used for the treatment of certain Central nervous system disorders can vary depending on certain conditions treat the condition, size, age and response of the patient, the severity of the disorder, the testimony of the attending physician and the like. In General, effective amounts for daily oral administration comprise from about 0.01 to 1000 mg/kg, preferably from about 0.5 to 500 mg/kg, and an effective amount for parenteral administration is from about 0.1 to 100 mg/kg, preferably from 0.5 to 50 mg/kg

In practice, the compounds in accordance with this invention give by introducing the compound or its precursor in solid or liquid form, either in pure form or in combination with one or more conventional pharmaceutical carriers or excipients. Therefore, this invention is a pharmaceutical composition that contains a pharmaceutically acceptable carrier and an effective amount of the compounds of formula I, such as described above.

Solid carriers which are suitable for use in compositions in accordance with this invention include one or more substances which may also act the AMB as flavoring agents, lubricants, soljubilizatory, suspendresume agents, fillers, glidant, support for pressing agents, binding agents, agents for disintegration of tablets or encapsulating materials. In powders, the carrier can be a finely ground solid substance in a mixture with finely ground compound of formula I. In tablets, the compound of formula I may be mixed with carrier having the necessary properties for pressing, in suitable proportions, and to have a desired shape and size. These powders and tablets can contain up to 99 wt.% the compounds of formula I. Solid carriers suitable for use in compositions in accordance with this invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, waxes with low melting temperature and ion-exchange resins.

In the compositions in accordance with this invention can be any pharmaceutically acceptable liquid carriers suitable for obtaining solutions, suspensions, emulsions, syrups and elixirs. The compounds of formula I can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a pharmaceutically acceptable oil is whether fat, or mixtures thereof. These liquid compositions may contain other pharmaceutically acceptable additives such as solubilization, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspendresume agents, thickeners, dyes, viscosity regulators, stabilizers, osmotic regulators or similar. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives such as above, e.g. cellulose derivatives, preferably, a solution of sodium carboxymethyl cellulose), alcohols (including monohydroxy alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and peanut butter). For parenteral administration, the carrier can also be a complex ester of fatty acids, such as etiloleat or isopropylmyristate.

Compositions in accordance with this invention, which are sterile solutions or suspensions used for intramuscular, intraperitoneal or subcutaneous doing. Sterile solutions can also be administered intravenously. Compositions in accordance with this invention suitable for oral administration may be in liquid or solid form.

For a clearer understanding and to illustrate this image is the shadow below are specific examples. The examples below are illustrative only and should not be construed as limiting the scope and underlying principles of the present invention in any way.

The term H-NMR means proton nuclear magnetic resonance. The terms of CH2Cl2and mean DMF methylene chloride and dimethylformamide, respectively. Chromatography is carried out with the use of SiO2as a substrate.

Example 1

Obtaining 3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine

The solution methylphenylsulfonyl (8,33 g, to 59.4 mmol) in CH2Cl2cooled to a temperature of -78°C and treated dropwise triperoxonane anhydride (4,1 ml, 5.3 mmol). After stirring for 30 minutes at a temperature of -78°add a solution of 7-azaindole (5,2 g, to 44.0 mmol) in CH2Cl2. After 30 minutes at a temperature of -78°With add triethylamine (74 ml, 534 mmol)and the reaction mixture is heated to ambient temperature. After stirring for 3.5 days, the reaction mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3and extracted with CH2Cl2. The organic extracts are combined and concentrated in vacuo. The resulting residue is crystallized from methanol/N2O and recrystallized from CH2Cl2/hexane to obtain specified in zag is lowke connection in the form of a whitish solid, 1.26 g, TPL 188-189°With, characterized by mass spectral analysis and analysis H-NMR.

Example 2

Obtaining 3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

A solution of 3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.44 mmol) in tert-butyl alcohol process MnSO4·H2O (4 mg, at 0.020 mmol) and cooled to a temperature of 0°C. a Mixture of 30% aqueous hydrogen peroxide (500 mg, to 4.41 mmol) and 0.2 N. aqueous NaHCO3(7.5 ml) is added dropwise. The reaction mixture is stirred for 23 hours at a temperature of 20°C, diluted with saturated aqueous NaHCO3and extracted with ethyl acetate. The combined extracts dried over MgSO4and concentrated in vacuo. Chromatography (1:50 methanol/CH2Cl2) the obtained residue gives a solid product, which is recrystallized from CH2Cl2/hexane to obtain specified in the title compound as a pinkish-white solid, 50 mg, TPL >250°With, characterized by mass spectral analysis and analysis H-NMR.

Example 3

Obtain 1-(2-chloroethyl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

A solution of 3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4,30 g of 16.6 mmol) in 1,2-dichloroethane (33 ml, 420 mmol) is treated with Aliquat® (chloride of tricaprylate is the Aldrich, Milwaukee, WI) (6,9 g) and 50% aqueous NaOH (1.6 g, 20 mmol). The reaction mixture is stirred for 6 hours at a temperature of 45°C. the Cooled solution was diluted with N2O (200 ml) and extracted with CH2Cl2(3×250 ml). The combined extracts CH2Cl2dried over MgSO4and concentrated in vacuo to a brown resin. This resin is subjected to chromatography (1:4 ethyl acetate/hexane) and then crystallized from ethyl acetate/hexane to obtain specified in the title compounds as white solids, of 3.84 g, TPL 117-119°With, characterized by mass spectral analysis and analysis H-NMR.

Example 4

Getting 2-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione

A solution of 1-(2-chloroethyl)-3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3,84 g, 12,0 mmol) in DMF is treated with potassium phthalate (2,78 g, 15.0 mmol), heated at a temperature of 115°C for 16 hours, cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. The resulting residue is crystallized from CH2Cl2/hexane to obtain specified in the title compounds as white solids, of 4.54 g, characterized by the analysis of the H-NMR.

Use the 5

Getting dihydrochloride of 2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethylamine

A solution of 2-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione (4,54 g, 10.5 mmol) in dioxane is treated with anhydrous hydrazine (8,3 ml, 265 mmol), heated at a temperature of 50°C for 3 hours, concentrated in vacuo, diluted with water and extracted with CH2Cl2. The combined extracts dried over MgSO4and concentrated in vacuo to obtain a transparent resinous residue. Chromatography (1:9 methanol/CH2Cl2the remainder gives the free amine indicated in the title compound in the form of a transparent resin. The free amine was dissolved in ethanol, acidified with 2 N. aqueous HCl and concentrated in vacuo. Crystallization of the resulting residue from ethanol/simple broadcast network specified in the title compound as a white solid, 3,20 g, TPL 195-197°With, characterized by mass spectral analysis and analysis H-NMR.

Example 6

Obtain hydrochloride of N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine

A solution of 3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.55 mmol) in dry DMF cooled to a temperature of 0°C, treated with sodium hydride (60% in oil, 97 mg, 2,43 mmol), peremeci is up for 3 hours at a temperature of 20° C, cooled to a temperature of -20°With handle hydrochloride 2-(dimethylamino)f (336 mg, of 2.33 mmol), stirred at a temperature of 60°C for 16 hours, cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic extracts are combined, washed with saturated salt solution, dried over MgSO4and concentrated in vacuo to obtain the free amine indicated in the title compound as a yellowish resin. The resin is dissolved in ethanol, treated with 1 N. aqueous HCl and concentrated in vacuo. Crystallization of the resulting residue from ethanol/simple broadcast network specified in the title compound as a light tan solid, 111 mg, TPL 214-217°With, characterized by mass spectral analysis and analysis H-NMR.

Example 7

Getting dihydrochloride 2-{3-[(4-were)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine

According to the method of examples 1 to 6 and using 7-azaindole and methyl p-cellsurface as starting materials, get mentioned in the title compound as a white solid, TPL 215-217°With, characterized by mass spectral analysis and analysis H-NMR.

Example 8

Obtaining 3-iodine-1H-pyrrolo[2,3-b]pyridine

A solution of 7-is sandala (20,0 g, 169 mmol) in ethanol is treated with iodine (57,9 g, 228 mmol), potassium iodide (37,8 g, 228 mmol) and 1 N. aqueous NaOH (204 ml, 204 mmol). After stirring for 4 hours at a temperature of 20°the reaction mixture is diluted with water and extracted with ethyl acetate. The organic extracts are combined and concentrated in vacuo. The resulting residue is crystallized from methanol/water to obtain specified in the title compound as a pinkish-white solid, 35.4 g, TPL 201-204°With, characterized by mass spectral analysis and analysis H-NMR.

Example 9

Obtain 3-[(4-forfinal)thio]-1H-pyrrolo[2,3-b]pyridine

A solution of 3-iodine-1H-pyrrolo[2,3-b]pyridine (4.0 g, 16.4 mmol) in DMF is treated with 4-fermentation (2,09 ml of 19.7 mmol), potassium carbonate (3,40 g, 24.6 mmol) and copper iodide (4,21 g, 22,1 mmol). The reaction mixture is heated at a temperature of 65°C for 4 hours, cooled, diluted with conc. water NH4OH and extracted with ethyl acetate. The extracts are combined, washed with saturated salt solution, dried over MgSO4and concentrated in vacuo. Chromatography (1:50 methanol/CH2Cl2the remainder followed by crystallization from methanol/N2About network specified in the title compound in the form of a whitish solid, of 3.56 g, TPL 183-184°With, characterized by mass spectral is the analysis and analysis H-NMR.

Example 10

Obtain 3-[(4-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine

A solution of 3-[(4-forfinal)thio]-1H-pyrrolo[2,3-b]pyridine (3,36 g of 13.8 mmol) in acetone is treated with a solution of NaHCO3(2,90 g of 35.4 mmol) in water. The reaction mixture was treated with Oxone® (2KHSO5×KHSO4×K2SO4production DuPont, Wilmington, DE.) (25,5 g, 41,4 mmol), stirred for 3 hours at a temperature of 20°C, diluted with water, cooled in a bath of ice-water and filtered. The filter cake is washed with water and dried in vacuum to obtain specified in the title compounds as white solids, 1.73 g, TPL 212-213°With, characterized by mass spectral analysis and analysis H-NMR.

Example 11

Obtain hydrochloride of 2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethylamine

According to the method of examples 3-5, using 3-[(4-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine as a substrate, get mentioned in the title compound as a white solid, TPL 193-197°With, characterized by mass spectral analysis and analysis H-NMR.

Example 12

Getting dihydrochloride 2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine

On these enter the methods and with the use of 3-iodine-1H-pyrrolo[2,3-b]pyridine and 3-chlorobenzoyl as starting materials get mentioned in the title compound as a white solid, TPL 203-206°With, characterized by mass spectral analysis and analysis H-NMR.

Examples 13-30

Obtain hydrochloride of N,N-dimethyl-N-(2-{3-[(substituted phenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine

According to the methods indicated in examples 4, 5, or 6, or by applying the method described in J. Alvarez-Builla, et al., Synthetic Communications, (1991) 21(4) 535-544, and applying the corresponding 3-(substituted sulfonyl)-1H-pyrrolo[2,3-b]pyridine and the desired halogenosilanes, receive the products shown in table 1, and identify their mass spectral analysis and analysis H-NMR.

Table I
Example No.R1R2R5R6TPL, °
134-F-C6H4HCH3CH3189-192a
143-Cl-C6H4HCH3CH3182=186and
151-naphthylHCH3CH3203-206
161-naphthylH HH148-170
173-F-C6H4HHH202-204
18C6H5CH3HH>250and
193-CF3-C6H4HCH3CH3108-112
202-CF3-C6H4HCH3CH3196-198
212-CF3-C6H4HHH182-185and
223-CF3-C6H4HHH179-183
232-thienylHHH202-204and
243,5-Cl-C6H3HHH136-140
252-thienylHCH3CH3212-216and
263,5-Cl-C6H3HCH3CH3 227-232and
273-Cl-C6H4HCH2-CH2-CH2-CH2183-185and
283-F-C6H4HCH2-CH2-CH2-CH2198-200and
293-F-C6H4HCH2-CH2-CH2-CH2-CH2197-199and
303-F-C6H4HCH2-CH2-O-CH2-CH2127-129
andthe dihydrochloride

Example 31

Obtaining N,N-dimethyl-N-[2-(1H-pyrrolo[2,3-b]pyridine-1-yl)ethyl]amine

Mix a solution of 1H-pyrrolo[2,3-b]pyridine (5,00 g of 42.3 mmol) in DMF at ambient temperature is treated with 95% sodium hydride in oil (of 3.78 g, 150 mmol). After the gas evolution, the reaction mixture is treated with the hydrochloride of 2-(dimethylamino)ethylchloride (6,40 g, 44.4 mmol), stirred for 16 hours and concentrated in vacuo. The resulting residue partitioned between EtOAc and water. The organic phase is separated, dried over MgSO4and conc is t in vacuum to obtain specified in the connection header in the form of oil, 6.50 g (yield 81%)identified by mass spectral analysis and analysis H-NMR.

Example 32

Getting the dihydrochloride of N,N-dimethyl-N-(2-{3-[(3-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine

Mix a solution of N,N-dimethyl-N-[2-(1H-pyrrolo[2,3-b]pyridine-1-yl)ethyl]amine (1.66 g, 8,8 mmol) in nitrobenzene is treated with 3-fortuneloungecasino (1.88 g, 9.7 mmol) in nitrogen atmosphere, followed by processing triftormetilfullerenov silver (2,94 g of 11.4 mmol), heated to a temperature of 100°C for 22 hours, cooled and filtered through a cotton filter. The filtrate is treated with water and saturated aqueous NaHCO3and extracted with CH2Cl2. The extracts are combined, dried over MgSO4and concentrated in vacuo. The resulting residue is subjected to chromatography elwira 2:98 concentrated NH4OH/ethanol, to obtain the free amine indicated in the title compound as a viscous oil, which solidified (1,25 g, 41%). The free amine was dissolved in warm ethanol, treated with 4 M HCl in dioxane and filtered. The filtrate is dried with obtaining specified in the title compounds as a pale yellow solid, 1.07 g (29% yield), TPL 191-192°With, characterized by mass spectral analysis and analysis H-NMR.

Examples 33-56

Obtaining production is s N-{[2-(3-arylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine

According to the methods mentioned above, and applying the corresponding N1-substituted 1H-pyrrolo[2,3-b]pyridine and the desired arylsulfonate, receive the products shown in table II, and identify their mass spectral analysis and analysis H-NMR.

Table II
Example No.R1R2R9R5R6TPL, °
335-Cl-Tien-2-ylHHCH3CH3169-171a
346-Cl-imidazo[2,1-b][1,3]thiazol-5-ylHHCH3CH3180-182a
353-Cl-C6H4HHC2H5C2H574-76
363-CH3-5-Cl-benzothieno-2-ylHHCH3CH3212-215
372,6-Cl-C6H3HHCH3C 3220-222
382,5-Cl-C6H3HHCH3CH3230-232a
396-Cl-imidazo[2,1-b][1,3]thiazol-5-ylHHbenzilbenzil140-145b
403-CH3-C6H4HHCH3CH3195-197
41C6H5HBrCH3CH3182-184
42C6H5HOCH3CH3CH3217-119
43C6H5HClCH3CH3193-195
443-CN-C6H4HHCH3CH3148-150
452-naphthylCH3HCH3CH3238-240
463-CN-C6H4CH3 HCH3CH3158-160
473,5-Cl-C6H3CH3HCH3CH3250-252
483-CF3-C6H4CH3HCH3CH3195-197
492-thienylCH3HCH3CH3213-216
506-Cl-imidazo[2,1-b][1,3]thiazol-5-ylCH3HCH3CH3195-199
513-F-C6H4CH3HCH3CH3185-190
521-naphthylCH3HCH3CH3135-139
532,5-Cl-C6H3CH3HCH3CH3222-224
543-CH3-5-Cl-benzothieno-2-ylCH3HCH3CH 3193-197
553-Cl-C6H4CH3HCH3CH3210-213
565-Cl-Tien-2-ylCH3HCH3CH3208-211
andthe dihydrochloride

bfoam

Example 57

Obtain hydrochloride of N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)-N-methylamine

Mix in a nitrogen atmosphere a solution of N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)-N,N-dimethylamine (0,540 g, 1,49 mmol) in 1,2-dichloroethane is treated with 1-chloritisation (and 0.40 ml, 3.7 mmol), heated to the boiling temperature under reflux for 2 hours, cooled and concentrated in vacuo. The resulting residue is treated with ethanol, heated at boiling temperature under reflux for 2 hours and concentrated in vacuo. The resulting residue is subjected to chromatography using 2:98 of concentrated NH4OH/ethanol as eluent, to obtain the free amine indicated in the title compound in the form of semi-solid substances (311 mg, 60%). The free amine was dissolved in ethanol, treatment is with 4 M HCl in dioxane and filtered. The filtrate is dried with obtaining specified in the title compounds as a pale yellow solid, 274 mg (48% yield), TPL 263-265°C (decomp.), characterized by mass spectral analysis and analysis H-NMR.

Examples 58-62

Preparation of derivatives of N-{[2-(3-arylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine

According to the methods mentioned above, and applying the appropriate N-(N,N-disubstituted aminoalkyl)-1H-pyrrolo[2,3-b]pyridine, receive the products shown in table III, and identify their mass spectral analysis and analysis H-NMR.

Table III
Example No.R1R6TPL, °
586-Cl-imidazo[2,1b][1,3]thiazol-5-ylCH3182-186

(foam)
593-F-C6H4CH3225-260
603-Cl-C6H4C2H5231-233
616-Cl-imidazo[2,1-b][1,3]thiazol-5-ylCH2C6H5173-175
623-CH3-C6H4 CH3244-246

Example 63

Obtaining 1-(1H-pyrrolo[2,3-b]pyridine-1-yl)acetonitrile

Mix a solution of 1H-pyrrolo[2,3-b]pyridine (of 5.06 g, 42.8 mmol) in DMF at ambient temperature portions handle 95% sodium hydride (1.10 g, to 43.5 mmol). After completion of gas evolution, the reaction mixture is treated with bromoacetonitrile (3,00 ml, to 43.1 mmol), stirred for 16 hours and concentrated in vacuo. The resulting residue partitioned between EtOAc and water. The organic phase is separated, dried over MgSO4and concentrated in vacuo. The residue is subjected to chromatography elwira 1:3 EtOAc/hexane to obtain specified in the title compound as a waxy solid, TPL 77-79°With, characterized by mass spectral analysis and analysis H-NMR.

Example 64

Obtaining 1-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]acetonitrile

Mix a solution of 1-(1H-pyrrolo[2,3-b]pyridine-1-yl)acetonitrile (0.68 g, to 4.33 mmol) in nitrobenzene is treated with benzosulphochloride (or 0.57 ml, 4.4 mmol) and triftoratsetata silver (1.50 g, 5.8 mmol), heated at a temperature of 125°C for 16 hours, cooled and divided between saturated aqueous NaHCO3and CH2Cl2. The organic phase from the shat over MgSO 4and concentrated in vacuo. The resulting residue is subjected to chromatography elwira first 1:4 EtOAc/hexane, then 1:2 EtOAc/hexane to obtain specified in the connection header in the form of a reddish-brown solid, 0,70 g (54% yield), TPL 140-142°With, characterized by mass spectral analysis and analysis H-NMR.

Example 65

Getting 2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethylamine

Part 1-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]acetonitrile (0,30 g, 1.00 mmol) is treated with 1.0 M borane in tetrahydrofuran (THF) (4.0 ml, 4.0 mmol) in portions of 0.5 ml at ambient temperature, stirred for 16 hours, treated with 2.0 M HCl (15 ml), heated at a temperature of 100°C for 2 hours, cooled in an ice bath, treated with 2.5 M aqueous NaOH and extracted with simple ether. The extracts are combined, dried over MgSO4and concentrated in vacuo to obtain specified in the connection header in the form of oil, 0,180 g (60% yield), characterized by mass spectral analysis and analysis H-NMR.

Examples 66-68

Obtaining derivatives [3-(arylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]alkylamine

According to the methods described in examples 64 and 65, and applying the corresponding 3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridin-acetonitrile, get connection, shown in table IV, and identify their mass spectral analysis and analysis H-NMR.

Table IV
Example No.R1R2R3TPL, °
663-F-C6H4CH3H239-241a
672-naphthylHH233-238a
68C6H5HCH3180-185a
andhydrochloride

Example 69

Getting 4-nitro-3-[(phenylsulfonyl)methyl]pyridine-N-oxide

Using adapted methods Makosza, et al., Liebigs Ann. Chem., 1984, 8-14, stir a mixture of 4-nitropyridine-N-oxide (1.40 g, 10.0 mmol) and chloromethanesulfonyl (1.92 g, 10.0 mmol) in DMSO (25 ml) cold water bath, treated with a solution of KOH (4.0 g, 71 mmol) in DMSO, stirred for 45 minutes, poured into 1.0 M hydrochloric acid and water and extracted with CH2Cl2. The aqueous phase is filtered and the filter cake is dried in HAC the mind with obtaining specified in the connection header, 1.20 g (yield 41%). The organic extracts are combined, dried over MgSO4and concentrated in vacuo. The obtained wet solid is heated in boiling ethanol/water (4:1) and filtered. The filtrate is cooled, concentrated and filtered. The obtained filter cake is dried in vacuum to obtain additional portion specified in the connection header, 0,967 g (total yield 74%), TPL 219-220°With, characterized by mass spectral analysis and analysis H-NMR.

Example 70

Obtaining 3-phenylsulfonyl-1H-pyrrolo[3,2-c]pyridine

A mixture of 4-nitro-3-[(phenylsulfonyl)methyl]pyridine-N-oxide (1,43 g of 4.90 mmol) in methanol is heated with ammonium formate (1.54 g, 24.5 mmol) and 10% palladium on coal (0.50 g) at a temperature of 50°within 24 hours, treated with additional ammonium formate (0,63 g, 10 mmol), heated at boiling temperature under reflux for 30 hours, cooled and filtered. The filtrate was concentrated in vacuo. The resulting residue is suspended in ethanol/water and filtered to remove residual catalyst. The filtrate is concentrated, cooled and filtered. The filter cake is dried to obtain a reddish brown solid (0,60 g). This solid (0.55 g) is mixed with triethylorthoformate (1,84 ml, 11.1 mmol), monohydrate paratoluenesulfonyl (pTsOH) (42 mg, 0.22 mmol) and 1,2-dichloroethane is heated at the boiling point under reflux for 7 hours and concentrated in vacuo. The obtained residue was dispersed in tetrahydrofuran, treated with 1.0 M KO-t-Bu in tetrahydrofuran (3.1 ml, 3.1 mmol), stirred for 2 hours, treated with saturated aqueous NH4Cl and water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4and concentrated in vacuo. The obtained orange solid is subjected to chromatography elwira first with EtOAc, then 10:90 ethanol/EtOAc to obtain specified in the connection header in the form of a whitish solid, 330 mg (58% yield), TPL 261-263°With, characterized by mass spectral analysis and analysis H-NMR.

Example 71

Getting the dihydrochloride of N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]ethyl}amine

According to the method of example 6 using 3-phenylsulfonyl-1H-pyrrolo[3,2-c]pyridine, at ambient temperature as the reaction temperature and the reaction time is 24 hours, get mentioned in the title compound in the form of a whitish solid, TPL 255-257°With, characterized by mass spectral analysis and analysis H-NMR.

Example 72

Getting 6-methoxy-3-nitro-2-[(phenylsulfonyl)methyl]-pyridine

1 M KOt-Bu solution in tetrahydrofuran (50 ml, 50 mmol) is cooled to a temperature of -40°, portions are treated with a solution of chloromethanesulfonyl (4,39 g, 23,0 mmol) and then a solution of 2-methoxy-5-nitropyridine (3.55 g, 23,0 mmol) in tetrahydrofuran, stirred for 45 minutes at a temperature of -40°C, treated with glacial acetic acid (3.0 g, 50 mmol) and filtered. The filter cake is dried in air to obtain specified in the connection header in the form of a reddish-brown solid, 5,70 g (80% yield), TPL 147-149°With, characterized by mass spectral analysis and analysis H-NMR.

Example 73

Obtain 3-amino-6-methoxy-2-[(phenylsulfonyl)methyl]pyridine

To a stirred mixture of 6-methoxy-3-nitro-2-[(phenylsulfonyl)methyl]pyridine (6,17 g, 20.0 mmol) in methanol and conc. HCl (50 ml) add thin strips of tin foil (10.0 g, 84,2 mmol), heated at a temperature of 60°C for 20 hours and filtered hot. The filtrate is poured on ice and 2.5 N. aqueous NaOH, stirred for 0.5 hour and filtered. The filter cake is dried in air to obtain specified in the title compound as a white solid, yield of 5.26 g (94%), characterized by mass spectral analysis and analysis H-NMR.

Example 74

Complex ethyl ester of N-{6-the methods of the si-[2-(phenylsulfonyl)methyl]pyridine-3-yl}formamide acid

Stir a mixture of 3-amino-6-methoxy-2-[(phenylsulfonyl)methyl]pyridine (2,40 g, to 8.62 mmol) in triethylorthoformate (20 ml) and the monohydrate of p-toluenesulfonic acid (pTsOH) (0.15 g, 0,788 mmol) is heated at a temperature of 155°C for 48 hours and concentrated in vacuo. The obtained residue was diluted with hexane and filtered to obtain specified in the connection header in the form of a reddish-brown substance, of 2.54 g (88% yield), characterized by mass spectral analysis and analysis H-NMR.

Example 75

Getting 5-methoxy-3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine

Mix a solution of complex ethyl ester N-{6-methoxy-[2-(phenylsulfonyl)methyl]pyridine-3-yl}formamide acid (2,54 g, 7,60 mmol) in DMSO is treated with powdered KOt-Bu (4.59 g, 38,0 mmol), stirred at ambient temperature for 4 hours, treated with 10% aqueous NH4Cl and extracted with EtOAc. The extracts are combined, dried over MgSO4and concentrated in vacuo. The obtained residue is recrystallized from EtOAc to obtain specified in the connection header in the form of a reddish-brown substance, 0,42 g (19% yield), TPL 223-225°With, characterized by mass spectral analysis and analysis H-NMR.

Example 76

Getting the dihydrochloride of N,N-dimethyl-N-{2-[3-(anysurfer)-1H-pyrrolo[3,2-b]pyridine-1-yl]ethyl}amine

Stir a solution of 5-methoxy-3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine (in 0.288 g, 1.00 mmol) in dry dimethylformamide is treated with 95% NaH (0.075 g, of 2.97 mmol), stirred at ambient temperature until gas evolution stops, handle hydrochloride 2-(dimethylamino)ethylchloride (0,200 g of 1.39 mmol), stirred for 16 hours at a temperature of 80°C, concentrated in vacuo and partitioned between water and EtOAc. The organic phase is dried over MgSO4and concentrated in vacuo. The resulting residue is subjected to chromatography elwira EtOAc, then 1:9 CH3OH/EtOAc to obtain semi-solid substances (0,216 g, 60% yield free amine). Semi-solid substance is dissolved in ethanol and treated with 4 N. HCl in dioxane and filtered. The filter cake is dried and triturated with simple ether to obtain specified in the title compounds as white solids, 0,19 g, TPL 212-214°With, characterized by mass spectral analysis and analysis H-NMR.

Example 77

Getting the dihydrochloride of N,N-dimethyl-N-(2-{3-[(3-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethyl)amine

According to the method of examples 6, 8, 9 and 10, using 1H-pyrrolo[3,2-b]pyridine as the starting material, get mentioned in the title compound as a white solid in the society, TPL 163-165°With, characterized by mass spectral analysis and analysis H-NMR.

Examples 78-81

Preparation of derivatives of N-{2-[3-(arylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-1-yl]ethyl}amine

According to the method of examples 72-76, using the appropriate substituted nitrobenzene as source material and arylsulfonate and chloroethylamine obtain compounds shown in table V, characterized by mass spectral analysis and analysis H-NMR.

Table V
Example No.R1R8R5R6TPL, °
784-Br-C6H4OCH3CH3CH3225-226
793-F-C6H4OCH3CH3CH3208-212
801-naphthylOCH3CH3CH3233-235
81C6H5ClCH3CH3244-246

Example 82

Comparative evaluation of the affinity of binding of the test compounds for 5-HT

The affinity of test compounds for the serotonin receptor 5-HT evaluated as follows. Cultured Hela cells expressing human cloned receptors 5-HT, harvested and centrifuged at low speed (1000×g) for 10 minutes to remove the cultural environment. The collected cells are suspended in a half volume of fresh saline solution with phosphate buffer and re-centrifuged at the same speed. The operation is repeated. The collected cells are then homogenized in ten volumes of 50 mm Tris·HCl (pH 7.4) and 0.5 mm etc. The homogenate was centrifuged at 40,000×g for 30 minutes and the precipitate collected. The precipitate after centrifugation, re-suspended in 10 volumes of Tris·HCl buffer and re-centrifuged at the same speed. The final precipitate after centrifugation suspended in a small volume of Tris·HCl buffer and the protein content in the tissue is determined in the aliquot volume of 10-25 μl. Bovine serum albumin used as a standard for determination of protein according to the method described by Lowry et al., J. Biol. Chem., 193:265 (1951). The amount of suspended membranes of cells adjusted to obtain the protein concentration in the tissue of 1.0 mg/ml suspension. The resulting suspension of membranes (koncentrira is nnow 10 times) aliquoting in volumes of 1.0 ml and stored at -70° To use in subsequent experiments on the binding.

Experiments on the binding is carried out in 96-cell title microplate total volume of 200 μl. In each cell, add the following mixture: 80,0 ál of incubation buffer obtained in 50 mm Tris·HCl buffer (pH 7.4)containing 10.0 mm MgCl2and 0.5 mm etc and 20 μl of [3H]-LSD (S.A., 86,0 CI/mmol, Amersham Life Science), 3,0 nm. The dissociation constant, Kd [3H]-LSD for the human serotonin receptor 5-HT is 2.9 nm, which is determined by saturation binding with increasing concentrations of [3H]-LSD. The reaction starts by adding a 100.0 μl of the suspension fabric. Nonspecific binding was measured in the presence of 10.0 μm methiothepin. The test compound added in a volume of 20.0 μl.

The reaction is carried out in the dark for 120 minutes at room temperature, during which the associated complex ligand-receptor sucked in 96-cell unifilter with a Packard harvester Filtermate® 196. The associated complex captured on the filter disk, air-dried and the radioactivity was measured on a Packard TopCount®equipped with six sensors photomultiplier, after addition of 40.0 ál of scintillant Microscint®-20 to each flat cell. Tablet unifilter seal when heated and read on a Packard TopCount® efficiency of tritium was 31.0%.

The special is specific binding to receptors of the 5-HT is defined as the total bound radioactivity minus binding in the presence of 10.0 μm unlabeled methiothepin. Binding in the presence of various concentrations of the test compounds is expressed as the percent specific binding compared to the absence of the test compound. The results are applied in the form of logarithm of % binding in relation to the logarithm of the concentration of the tested compounds. Nonlinear regression analysis of the data is performed using the software Prism® obtaining values of the IC50and Kithe tested compounds with 95% reliability. Build linear regression of data from which to determine the value of the IC50and the value of Kidetermined using the following equation:

Ki= IC50/(1 + L/KD),

where L is the concentration of the applied radioactive ligand and KDis the dissociation constant of the ligand for a receptor expressed in nm.

In this study, determine the values of Kiand compare them with the values obtained for the comparative compounds, the known binding with the receptor 5-HT. The data shown in table VI below.

tr> td align="center"> 48
Table VI
The test compound (example no.) Kibinding of 5-HT (nm)
56
623
79
1122
1220
1350
142
151
162
176
185
195
2011
212
222
239
243
2515
264
2745
2888
29158
30403
325
334
342
3520
36102
379
3812
39212
4010
4141
4239
4327
4463
4510
4610
477
2
4914
501
513
523
5311
5494
554
562
570,3
581
591
603
619
621
656
662
6724
6814
7656
77200
784
7911
802
81214
Comparative examplesKibinding of 5-HT (nm)
Clozapine6,0
Loxapine41,4
Parlodel23,0
Methiothepin8,3
Mianserin44,2
Olanzapine19,5

As you can see above financial p the tats, compounds in accordance with this invention demonstrate a significant affinity to the receptor 5-HT.

1. The compound of formula (I)

where W is N or CR7;

X is N or CR8;

Y is N or CR9;

Z is N or CR10provided that at least one and not more than two of W, X, Y, and Z must be N;

n is an integer 2, 3, 4 or 5;

R1is optionally substituted aryl or heteroaryl, or optionally substituted 8 to 13-membered bicyclic or tricyclic system of rings having 1, 2 or 3 additional heteroatoms selected from N, O or S;

R2is H, halogen, unsubstituted or substituted C1-C6-alkyl, C1-C6-alkoxy or C3-C7-cycloalkyl;

R3and R4each independently is H or optionally substituted C1-C6-alkyl;

R5and R6each independently is H or C1-C6-alkyl, C3-C7-cycloalkyl, or R5and R6together with the nitrogen atom to which they are attached, form an optionally substituted 5-8-membered ring, optionally containing an additional atom Of;

R7, R8, R9and R10independently researched the mo are H, halogen, OR19, COR20C1-C6-alkyl or C3-C7-cycloalkyl;

R19and R20each independently is C1-C6-alkyl or C3-C6-cycloalkyl, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which W or Z is N.

3. The compound according to claim 1 or 2, in which n is 2.

4. The compound according to claim 3 in which R1is optionally substituted by phenyl, naphthyl or imidazothiazole.

5. The compound according to claim 4, in which R1is phenyl, optionally substituted with halogen or 1-naphthyl or 6-chloroimidazo[1,2-b][1,3]thiazol-5-yl.

6. The compound according to claim 3, in which W is CR7; X is CR8; Y is CR9.

7. The compound according to claim 3, in which X is CR8; Y is CR9; and Z is CR10.

8. The connection according to claim 6, in which R5and R6each independently is H or C1-C3-alkyl.

9. The connection of claim 8, in which R3and R4are N.

10. The connection according to claim 9, in which R2is N.

11. The compound according to claim 1, selected from the group including

2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethylamine;

2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]ethylamine;

2-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]ethylamine;

2-{3-[(-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethylamine;

2-{3-[(4-were)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-[3-(naphthas-1-yl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethylamine;

2-{3-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-{3-[(2-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-C]pyridin-1-yl}ethylamine;

2-{3-[(3-methoxyphenyl)sulfonyl]-1H-pyrrolo[3,2-C]pyridin-1-yl}ethylamine;

2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethylamine;

N,N-dimethyl-N-(2-{3-[(3-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N,N-dimethyl-N-{2-[3-(naphthas-1-ylsulphonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N,N-dimethyl-N-(2-{3-[(6-chloroimidazo[1,2-b][1,3]thiazol-5-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N,N-dimethyl-N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]propan-1-amine;

3-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}propan-1-amine;

2-{6-chloro-3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethylamine;

2-{7-chloro-3-[(2-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-C]pyridin-1-yl} - atrami is;

4-{3-[(3-methoxyphenyl)sulfonyl]-1H-pyrrolo[3,2-C]pyridin-1-yl}butane-1-amine;

4-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}butane-1-amine;

N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]ethyl}amine;

N,N-dimethyl-N-{2-[3-(phenylsulfonyl)-1H-pyrrolo[3,2-C]pyridin-1-yl]ethyl}amine;

N,N-dimethyl-N-{2-[3-(Thian-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N,N-dimethyl-N-{2-[3-(naphthas-1-yl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N,N-dimethyl-N-(2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(3-chlorophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(3-forfinal)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-{2-[3-(naphthas-1-ylsulphonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]ethyl}amine;

N-methyl-N-(2-{3-[(6-chloroimidazo[1,2-b][1,3]thiazol-5-yl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(2-chlorophenyl)sulfonyl]-1H-pyrrolo[3,2-C]pyridin-1-yl}ethyl)amine;

N-methyl-N-(2-{3-[(3-methoxyphenyl)sulfonyl]-1H-pyrrolo[2,3-C]pyridin-1-yl}ethyl)amine;

N-benzyl-N-(2-{3-[(4-forfinal)sulfonyl]-1H-pyrrolo[3,2-b]pyridine-1-yl}ethyl)amine;

N,N-dibenzyl-3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-C]pyridin-1-yl]propan-1-amine;

3-[3-(phenylsulfonyl)-1H-pyrrolo[32-C]pyridin-1-yl]propan-1-amine;

and their pharmaceutically acceptable salts.

12. A method of treating disorders of the Central nervous system, associated or under the influence of the receptor 5-HT, in a patient in need thereof, which includes the introduction of the indicated patient a therapeutically effective amount of the compounds of formula I according to any one of claims 1 to 11, or its pharmaceutically acceptable salt.

13. The method according to item 12, in which the specified disorder is a disorder of motor skills, anxiety, or cognitive disorder.

14. The method according to item 12, in which the specified disorder is a neurodegenerative disorder.

15. The method according to item 13, in which the specified disorder is attention deficit disorder or obsessive-compulsive disorder.

16. The method according to 14, in which the specified disorder is a stroke or a head injury.

17. Pharmaceutical composition having activity against receptor 5-hydroxytryptamine-6, which contains a compound of formula I or its pharmaceutically acceptable salt according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

18. The method of obtaining the compounds of formula I according to claim 1, or its pharmaceutically acceptable salts, which comprises the interaction of the compounds of formula II

where W, X, Y, Z, R1and R2matter, the decree is given in claim 1, with halogenosilanes formula III

where Hal is Cl, Br or I, and R3, R4, R5, R6and n have the meanings indicated in claim 1, in the presence of a base to obtain the compounds of formula I; and, if necessary, the transformation of the basic compounds of formula I in a pharmaceutically acceptable salt, or Vice versa.

19. The method of obtaining the compounds of formula I according to claim 1, or its pharmaceutically acceptable salts, which comprises the interaction of the compounds of formula (V)

where W, X, Y, Z, R1, R2, R3, R4and n have the meanings indicated in claim 1 and Hal is halogen, with a compound of the formula

HNR5R6

where R5and R6have the meanings indicated in claim 1, to obtain the compounds of formula I; and, if necessary, the transformation of the basic compounds of formula I in a pharmaceutically acceptable salt, or Vice versa.

20. The method of obtaining the compounds of formula I according to claim 1, or its pharmaceutically acceptable salts, which includes sulfonylamine the compounds of formula XVI

where W, X, Y, Z, R2, R3, R4, R5, R6and n have the meanings indicated in claim 1, the compound of the formula

ClSO2R1,

where R1matter specified in claim 1,to obtain the compounds of formula I; and, if necessary, the transformation of the basic compounds of formula I in a pharmaceutically acceptable salt or Vice versa.

21. The method of obtaining the compounds of formula I according to claim 1, where W, X, Y, Z, R1, R2, R3, R4and n have the meanings indicated in claim 1, R5and R6represent hydrogen; or pharmaceutically acceptable salts, which includes the recovery of the compounds of formula XX

where W, X, Y, Z, R1, R2, R3, R4and n have the meanings mentioned above, and, if necessary, the transformation of the basic compounds of formula I in a pharmaceutically acceptable salt, or Vice versa.

22. The method of obtaining the compounds of formula I according to claim 1,

where W, X, Y, Z, R1, R2, R3, R4and n have the meanings indicated in claim 1, R5and R6represent hydrogen, or its pharmaceutically acceptable salts which involves reacting the compounds of formula

where W, X, Y, Z, R1, R2, R3, R4and n have the meanings stated above, with hydrazine, and, if necessary, the transformation of the basic compounds of formula I in a pharmaceutically acceptable salt or Vice versa.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I) wherein radical values are given in the invention claim that are novel histamine receptors antagonist. Preferable compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo]2,1-b][3]benazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-α]benzimidazole-4(10H)-one or its salts, isomers and N-oxides. Proposed compounds are useful in prophylaxis and treatment of increased intracranial pressure and/or secondary ischemia caused by craniocerebral trauma.

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

13 cl, 13 tbl, 5 dwg, 14 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

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25 cl, 3 tbl, 135 ex

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EFFECT: improved method for treatment and prophylaxis, valuable medicinal properties of derivatives.

22 cl, 2 tbl, 73 ex

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EFFECT: improved preparing method.

1 tbl, 2 dwg, 1 ex

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EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

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< / BR>
where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

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EFFECT: improved method of synthesis.

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EFFECT: improved method of synthesis.

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 tbl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel 4-oxo-1-(3-substituted phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamides of the general formula (I): or their pharmaceutically acceptable salts wherein Ar means phenyl or thienyl; Y means -COOH, (C1-C6)-alkyl, (C1-C4-alkyl)n-COOH, (C3-C4)-cycloalkyl-COOH wherein (C1-C6)-alkyl and (C3-C4)-cycloalkyl are optionally substituted with halogen atom, hydroxy-group, -CN, and (C1-C4)-alkyl-substitutes are bound optionally to form (C3-C4)-cycloalkyl and wherein n = 0, 1, 2, 3 or 4; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, (C1-C6)-alkyl optionally substituted with halogen atom; (C3-C6)-cycloalkyl optionally substituted with halogen atom, (C1-C6)-alkyl, -OH, -CN or phenyl; (C1-C6-alkyl)-SOp-(C1-C6)-alkyl wherein p = 0, 1 or 2; or 1,3,4-thiadiazolyl substituted with halogen-(C1-C6)-alkyl; or R1 means methyl substituted with cyclopropyl; R2 means H, halogen atom or (C1-C6)-alkyl; R3 means H or halogen atom, and pharmaceutical compositions based on thereof. Compounds possess inhibitory activity and can be used in treatment of asthma and inflammatory diseases.

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

22 cl, 4 tbl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or its pharmaceutically acceptable salts that possess properties of CB2 receptors agonist and can be used in preparing drugs exerting analgesic effect, in particular, for pain treatment. In compound of the formula (I) R1 is chosen from group consisting of (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C2-C6)-alkenyl, R42N-(C1-C6)-alkyl, R42NC(=O)-(C1-C6)-alkyl, R4O-(C1-C6)-alkyl, R4OC(=O)-(C1-C6)-alkyl, R4C(=O)-(C1-C6)-alkyl, R4C(=O)-NR4-(C1-C6)-alkyl, R42NSO2-(C1-C6)-alkyl, R42NC(=O)-NR4-(C1-C6)-alkyl, radicals phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocycloalkyl-(C1-C6)-alkyl, bicyclic heteroaryl-(C1-C6)-alkyl; Ar represents phenyl or pyridyl; R2 represents (C1-C6)-alkyl that is unsubstituted or substituted at 1-6 carbon atoms with one or more fluorine atom substitute or (C3-C6)-cycloalkyl; R3 is chosen from the following group consisting of: (a) , (b) , (c) , (d) , (e) , (f) , (g) , (h) , (i) , (j) and (k) ; R4 represents group chosen independently from group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl; groups R5 are chosen independently from group consisting of H, (C2-C6)-alkenyl; groups R6 are chosen independently from group consisting of H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, heterocyclyl, radical (C1-C3)-alkyl, phenyl, radical phenyl-(C1-C3)-alkyl, heteroaryl, radicals heteroaryl-(C1-C3)-alkyl, bicyclic heteroaryl and bicyclic heteroaryl-(C1-C3)-alkyl; R5 and R6 can be combined to form 5-7-membered heterocycle; X is chosen from group consisting of -C(R5)2-, -NR5-, C(=O)-, -CH2-CH2-, CH=CH- and -C(R)(R') wherein R and R' represent (C1-C6)-alkyl, -OR'' or H and R'' represents H; Y represents -CH or nitrogen atom and wherein heterocyclyl or heterocycloalkyl represent 5-6-membered ring comprising from 1 to 2 heteroatoms chosen from nitrogen (N) and oxygen (O) atoms that is unsubstituted or substituted with (C1-C6)-alkyl; heteroaryl represents heteroaromatic 5-6-membered ring comprising from 1 to 2 heteroatoms chosen from N, S and sulfur atom (S) that is unsubstituted or substituted with group chosen from group consisting of (C1-C6)-alkyl, nitro-group, halogen atom and acetoxymethyl; bicyclic heteroaryl represents 5-6-membered nitrogen-containing ring condensed with benzene ring. Also, invention relates to a pharmaceutical composition and a method for paintreatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 15 sch, 3 tbl, 130 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I) wherein radical values are given in the invention claim that are novel histamine receptors antagonist. Preferable compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo]2,1-b][3]benazepin-6-yl)-2-(phenylmethyl)-1-piperidinyl]ethyl]-2,10-dimethylpyrimido[1,2-α]benzimidazole-4(10H)-one or its salts, isomers and N-oxides. Proposed compounds are useful in prophylaxis and treatment of increased intracranial pressure and/or secondary ischemia caused by craniocerebral trauma.

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

13 cl, 13 tbl, 5 dwg, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of diazabicyclic alkanes of the formula (1) and their pharmaceutically acceptable salts and stereoisomers wherein R1 means phenyl, 3-indolyl or benzo[b]thiophene-3-yl and wherein indicated phenyl group can be substituted with halogen atom; R2 and R3 represent independently halogen atom, -CH3 or -CF3; R4 represents hydrogen atom (H), hydroxyl group (-OH), -CH2OH, -NH2, dialkyl-(C1-C3)-N, pyrrolidine-1-yl, piperidine-1-yl, morpholine-4-yl or morpholine-4-yl substituted with one or two methyl or methoxymethyl groups, morpholine-4-ylamino-group, morpholine-4-ylmethyl, imidazole-1-yl, thiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl or 3-oxa-8-azabicyclo[3.2.1]oct-8-yl; R5 means hydrogen atom; R4 and R5 can represent in common keto-group, 1,3-dioxane-2-yl or 1,3-dioxalane-2-yl; R6 represents H, morpholine-4-yl substituted with methyl group or -CH2OH wherein indicated group -CH2OH can form ester with organic acid; X represents oxygen atom (O); n = 1 or 2. Proposed compounds possess antagonistic activity with respect to NK1-receptors. Also, invention describes intermediate compounds used in synthesis of compounds of the formula (I), pharmaceutical composition and using compounds in preparing drugs in treatment, for example, such diseases as chronic pains, inflammatory diseases and disorders of the central nervous system.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

7 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I) involving their pharmaceutically acceptable salts or solvates wherein R means phenyl or pyridinyl, and each of them can be substituted with 1-4 groups chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, nitro-group, -NR6R7, cyano-group and R8 group; R1 means hydrogen atom or (C1-C6)-alkyl; R2 and R3 in common with nitrogen atom (N) form group of the formula: ; R4 means hydrogen atom; R6 means hydrogen atom or (C1-C6)-alkyl; R7 means hydrogen atom or (C1-C6)-alkyl; R8 represents 5-6-membered saturated or aromatic heterocycle comprising 1-2 heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms. Also, invention describes methods for synthesis of these compounds, pharmaceutical compositions containing these compounds, using in treatment of states mediated by corticotropin-releasing factor, and a method for treatment of mammals using these compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

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

22 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of high purity from ethyl-(2,6-dichloro-5-fluoropyridine-3-yl)-3-oxopropanate and using a single solvent in one reaction vessel. Effective synthesis of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylc acid by this method is very significant in economical producing antibiotics based on fluoroquinolones used in treatment of microbial infections.

EFFECT: improved method of synthesis.

10 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of pyridazino[1,6-b]isoquinolones of the general formula (4a-f): that can be used potential biologically active substances wherein (1a): R1 means hydrogen atom (H); R2 means H; (1b): R1 means chlorine atom (Cl); R2 means H; (1c): R1 means bromine atom (Br); R2 means H; (1d): R1 means iodine atom (J); R2 means H; (1e): R1 means H; R2 means Cl; (1f): R1 means H; R2 means Br. Synthesis is carried out by two variants. The first variant involves carrying out a sequence of three chemical reactions: (A) alkylation reaction of derivatives of 2-di-(5-methyl-2-furyl)methylbenzoic acid with methyl iodide to form corresponding esters; (b) hydrazinolysis reaction of esters to form corresponding hydrazides, and (c) acid-catalyzed recyclization of hydrazides to derivatives of pyridazino[1,6-b]isoquinolone (4a-f). The second variant involves chemical conversion of derivatives of 4-(5-methyl-2-furyl)-3-oxobutylisochromem-1-one to derivatives of pyridazino[1,6-b]isoquinolone (4a-f) by addition of hydrazine hydrate to solution of the corresponding derivative of 4-(5-methyl-2-furyl)-3-oxobutylisochromen-1-one in ethylene glycol medium at room temperature followed by boiling the prepared reaction mixture.

EFFECT: improved method of synthesis.

2 cl, 1 tbl, 2 ex

FIELD: pharmaceutical industry and technology, pharmacy, medicine, phytotherapy.

SUBSTANCE: method involves three-times extraction of milled coriander herb with 40% ethyl alcohol taken in the ratio raw : extractant = 1:5 for 1 h in each extraction step. Extracts are combined, filtered, ethyl alcohol is removed and prepared aqueous residue is kept at temperature +10°C, not above, for 5 h, not less. Deposit is separated, aqueous extract is dried and the end product is prepared. Invention provides realizing the indicated designation.

EFFECT: improved preparing method.

5 tbl, 2 dwg, 1 ex

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