Muscarinic agonists

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

 

The scope of the invention

The present invention relates to compounds that act on cholinergic receptors, especially muscarinic receptors. The present invention provides compounds that are agonists of cholinergic receptors, including muscarinic receptors, especially the m1 and m4 subtypes of muscarinic receptors. The invention also provides methods of using the proposed compounds for modulation States associated with cholinergic receptors, particularly for the treatment or attenuation of symptoms of painful conditions associated with muscarinic receptors, for example subtypes m1 or m4 receptors.

Background of invention

Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the Central and peripheral nervous systems, gastrointestinal system, heart, glands of internal secretion, lung, and other tissues. Muscarinic receptors play a Central role in the Central nervous system in relation to higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Identified five different subtypes of muscarinic receptors m1-m5. The m1 subtype is the predominant subtype found in the cortex, and suggest that this subtype is involved in regulated is the training of cognitive functions; m2 is the predominant subtype found in the heart, and believe that this subtype is involved in the regulation of heart rate; m3, believed to be involved in the stimulation of the gastrointestinal tract and urinary tract, as well as in sweating and salivation; m4 is present in the brain and can participate in ambulation, and m5 is present in the brain and can participate in some functions of the Central nervous system associated with the dopaminergic system.

Conditions associated with cognitive failure, such as Alzheimer's disease, accompanied by a decrease in (loss) of the level of acetylcholine in the brain. It is believed that this is the result of degeneration of cholinergic neurons in the basal fore brain, which innerviews areas associative areas of the cerebral cortex and the hippocampus, which is involved in higher processes.

Attempts to increase the levels of acetylcholine have been focused on increasing the levels of choline, the precursor for the synthesis of acetylcholine, and blocking acetylcholinesterase (AChE), the enzyme that metabolizes acetylcholine. Introduction choline or phosphatidylcholine was not very successful. The AChE inhibitors have shown some therapeutic efficacy, but could cause cholinergics the e side effects due to stimulation of peripheral acetylcholine, including abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Gastrointestinal side effects were observed in almost one-third of the patients being treated. In addition, some AChE inhibitors, such as taken, as was also found, cause significant hepatotoxicity with increased liver transaminases level observed in approximately 30% of patients. Side effects of AChE inhibitors limit their clinical effectiveness.

Found that the known muscarinic m1 agonists, such as arecoline are weak agonists subtype m2, and m3, and are not very effective in the treatment of cognitive failure, most likely due to DLT (dose limiting side effects.

There is a need for compounds that enhance signal transmission by acetylcholine or act in the brain. Specifically, there is a need in the muscarinic agonists, which are active against different subtypes of muscarinic receptors in the Central and peripheral nervous system. In addition, there is a need for more selective the muscarinic agonists, such as m1 or m4-selective agents, both as pharmacological tools and as therapeutic agents.

Summary SunOS and inventions

The present invention relates to compounds that act on cholinergic, especially muscarinic receptors, which have agonistic activity in subtypes m1 or m4 muscarinic receptors, or both. Compounds of the invention are compounds of General formula (I):

where:

Z1is CR1or N, Z2is CR2or N, Z3is CR3or N and Z4is CR4or N, where not more than two of Z1, Z2, Z3and Z4are N;

W1represents O, S or NR5one of W2and W3is N or CR6and the other of W2and W3is CG; W1is NG, W2is CR5or N and W3is CR6or N; or W1and W3are N and W2is NG;

G represents the formula (II):

Y represents O, S, CHOH, -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -(O)CO-, -NR7-, -CH=N -, or absent;

p is 1, 2, 3, 4 or 5;

Z represents CR8R9or missing;

each t is 1, 2 or 3;

each R1, R2, R3and R4independently, represents H, amino, hydroxyl, halogen or an unbranched or branched C1-6-alkyl, C2-6alkenyl, 2-6-quinil,1-6-heteroalkyl,1-6-halogenated, -CN, -CF3, -OR11, -COR11, -NO2, -SR11, -NHC(O)R11, -C(O)NR12R13, -NR12R13, -NR11C(O)NR12R13, -SO2NR12R13, -OC(O)R11, -O(CH2)qNR12R13or -(CH2)qNR12R13where q is an integer from 2 to 6, or R1and R2together form-NH-N=N - or R3and R4together form-NH-N=N-;

each of R5, R6and R7, independently, is H, C1-6-alkyl; formyl; (C3-6-cycloalkyl; C5-6aryl, optionally substituted with halogen or1-6-alkyl or C5-6-heteroaryl, optionally substituted with halogen or1-6-alkyl;

each of R8and R9, independently, is N or C1-8-alkyl with an unbranched or branched chain;

R10represents an unbranched or branched C1-8-alkyl, C2-8alkenyl,2-8-quinil,1-8-alkyliden,1-8-alkoxy, C1-8-heteroalkyl,1-8-aminoalkyl,1-8-halogenated,1-8-alkoxycarbonyl,1-8-hydroxyalkoxy,1-8-hydroxyalkyl, -SH, C1-8-alkylthio, -O-CH2-C5-6-aryl, -C(O)-C5-6aryl (substituted C1-3-alkyl or halogen), C5-6-aryl, C5-6-cyclea the keel, With5-6-heteroaryl,5-6-heteroseksualci, -NR12R13, -C(O)NR12R13, -NR11C(O)NR12R13, -CR11R12R13, -OC(O)R11, -(O)(CH2)sNR12R13or -(CH2)sNR12R13and s is an integer from 2 to 8;

R'10is H, unbranched or branched C1-8-alkyl, C2-8alkenyl,2-8-quinil,1-8-alkyliden,1-8-alkoxy, C1-8-heteroalkyl,1-8-aminoalkyl,1-8-halogenated,1-8-alkoxycarbonyl,1-8-hydroxyalkoxy,1-8-hydroxyalkyl or1-8-alkylthio;

each R11, independently, is H, unbranched or branched C1-8-alkyl, C2-8alkenyl,2-8-quinil,2-8-heteroalkyl,2-8-aminoalkyl,2-8-halogenated,1-8-alkoxycarbonyl,2-8-hydroxyalkyl, -C(O)-C5-6aryl (substituted C1-3-alkyl or halogen), C5-6-aryl, C5-6-heteroaryl,5-6-cycloalkyl,5-6-heteroseksualci, -C(O)NR12R13, -CR5R12R13, -(CH2)tNR12R13and t is an integer from 2 to 8; and

each R12and R13, independently, is H, C1-6-alkyl; C3-6-cycloalkyl; C5-6aryl, optionally substituted galogenami 1-6-alkyl or C5-6-heteroaryl, optionally substituted with halogen or1-6-alkyl, or R12and R13together form a cyclic structure;

or their pharmaceutically acceptable salts, esters and prodrugs.

The present invention further relates to pharmaceutical compositions comprising an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salts, esters or prodrugs.

The invention relates also to methods for increasing the activity of the cholinergic receptor, comprising contacting cholinergic receptor or a system containing cholinergic receptor with an effective amount of the compounds of formula (I), as well as sets for implementing the method. Receptor, preferably, is a muscarinic receptor subtype m1 or m4. The receptor may be located in the Central nervous system, peripheral nervous system, gastrointestinal system, heart, glands of internal secretion or lungs, and the receptor may be truncated, mutated or modified cholinergic receptor.

In addition, the present invention relates to a method of activation of the cholinergic receptor, comprising contacting cholinergic receptor or a system containing cholinergic receptor with an effective amount of the Ohm, at least one of the compounds of formula (I), as well as to kits for carrying out the method. In a preferred implementation, the compound is selective in relation subtype m1 or m4 muscarinic receptor or for both subtypes. In another preferred implementation, the compound has a weak action, or renders it on the activity of m2 or m3.

Another aspect of the present invention relates to a method of treatment of a pathological state associated with cholinergic receptor comprising the administration to a subject in need of such treatment, an effective amount of at least one of the compounds of the invention. The invention relates also to a kit for carrying out the method. Painful conditions that are treated include, but are not limited to, the state of dysfunction cognitive abilities, forgetfulness, confusion, memory loss, attention deficit, deficits in visual perception, depression, pain, sleep disorders and psychosis. Painful conditions include, but are not limited to, Alzheimer's disease, Parkinson's disease, horey Huntington, ataxia of Frederica syndrome Gilles de La Tourette's, down's syndrome, the disease Peak, dementia pugilistica, clinical depression, age-related variance in cognitive abilities, a disorder associated with deficiency of attention to the Oia, and the syndrome of sudden death of a seemingly healthy infant.

The invention further relates to methods of treating symptoms of a disease or condition associated with reduced levels of acetylcholine, including the introduction of an effective amount of at least one compound of the invention.

In another embodiment the present invention relates to a method of treatment of Alzheimer's disease. The method comprises the administration to a subject in need of such treatment, an effective amount of at least one compound of the invention.

In another embodiment the present invention relates to a method for the treatment of glaucoma. The method includes introducing an effective amount of at least one compound of the invention.

Another aspect of the present invention is a method for identifying a predisposition to a genetic polymorphism of the subject that is susceptible to the compound of the invention. The method includes introducing to the subject a therapeutically effective amount of the compound; measuring a response of the specified entity on connection (whereby identify sensitive subject that has weakened (not clinically evident) a painful condition associated with cholinergic receptor), and identification of genetic polymorphism in susceptible subject, where specified emeticeski polymorphism leads to a predisposition of the subject to susceptibility to the compound.

The present invention relates also to a method of identifying a subject suitable for treatment with the compound of the invention, and kits for such identification. The method includes detecting the presence of the polymorphism in the subject, where the polymorphism leads to a predisposition specified subject to the susceptibility of the connection and where the presence of the polymorphism indicates that the subject is suitable for treatment of a connection.

Detailed description of the invention

Definition

For the purposes of the present description, the following definitions in their entirety will be used to define technical terms and to determine the amount of chemical compounds whose protection defined in the claims.

The term "receptor" includes any molecule present inside or on the surface of cells, which can affect cell physiology when it inhibit or stimulate ligand. In a typical case, the receptor comprises the extracellular domain with a ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and cytoplasmic domain, which generates cellular signal in response to the binding of the ligand ("signal transduction"). The receptor also includes any molecule having a characteristic structure of the receptor, but without identifiable Li gang is and. In addition, the receptor includes a truncated, modified, mutated receptor, or any molecule that includes part or all of the sequence of the receptor.

"Ligand" means any substance that interacts with the receptor.

"Agonist" is defined as a compound that increases the activity of the receptor upon interaction with the receptor.

"The m1 receptor" is defined as the receptor with activity corresponding to the activity subtype m1 muscarinic receptor, characterized by molecular cloning and pharmacology.

"Selective" or "selectivity" is defined as the ability of a joint to cause the desired response of a particular type, subtype, class, or subclass of the receptor with less or little reaction from other types of receptor. "Selective" or "selectivity" compounds, which are muscarinic receptor m1 or m4, means the ability of a compound to increase the activity of the muscarinic receptor m1 or m4, respectively, causing minor activity or not causing the activity of the other subtypes, including subtype m3 and m5, preferably, the m2 subtype. Compounds of the present invention can also show selectivity to the receptor as m1 and m4, i.e. to increase the activity of muscarinic receptors as m1 and m4, with slightly the activity or no activity on other subtypes, including subtypes m3 and m5, preferably, the m2 subtype.

The term "subject" refers to an animal, preferably a mammal or to a person who is the object of treatment, observation or experiment.

Used herein, the term "co-administration" pharmacologically active compounds refers to the delivery of two or more separate chemical agents, regardless introduce them in vitro or in vivo. Joint introduction means simultaneous delivery of individual agents, simultaneous delivery of a mixture of agents; as well as delivery of one agent after delivery of the second agent or additional agents. The agents that are administered jointly, are intended in a typical case for action in combination with each other.

The term "effective amount", as used here, means the amount of active compound or pharmaceutical agent that causes the biological or medical response in a tissue, system, animal or human body, which is determined by the researcher, veterinarian, medical doctor or other Clinician, which includes alleviation or lessening symptoms of the disease being treated.

"Alkyl" means a group of alkane with an unbranched or branched chain with 1-6 carbon atoms in the chain, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyle etc. The term "heteroalkyl" is intended to denote the alkane group containing 1 or 2 heteroatoms selected from O, S or N.

"Alkenyl" means an alkene group with unbranched or branched chain with 2 to 6 carbon atoms in the chain, the term "quinil" is intended to denote a group of the alkyne with an unbranched or branched chain with 2 to 6 carbon atoms in the chain.

The terms "aryl" and "cycloalkyl", preferably, relates to the structures of the mono - or bicyclic ring comprising 5 to 12 carbon atoms, more preferably monocyclic ring comprising 5 or 6 carbon atoms. When such rings include one or more heteroatoms selected from N, S and O (i.e. heterocyclic or heteroaryl rings, such rings include from 5 to 12 atoms, more preferably 5 or 6 atoms. Heterocyclic rings include, but are not limited to, furyl, pyrrolyl, pyrazolyl, thienyl, imidazolyl, indolyl, benzofuranyl, benzothiophene, indazole, benzoimidazole, benzothiazole, isoxazolyl, oxazolyl, thiazolyl, isothiazolin, pyridyl, piperidinyl, piperazinil, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolidinyl and the like. The ring may be substituted by one or more groups listed in the above definition of R2Ponyatno, that alternates With1-6-alkyl, C2-6alkenyl,2-6-quinil,1-6-alkoxy, C1-6-heteroalkyl,1-6-aminoalkyl,1-6-halogenated or1-6-alkoxycarbonyl, if present, can be substituted by one or more hydroxyl,1-4-alkoxy, halogen, cyano, amino or nitro.

Used herein, the term "halogen" includes chlorine, fluorine, are preferred, and iodine and bromine.

The present invention relates to compounds which are agonists of cholinergic receptors, including muscarinic receptors. The present invention especially relates to compounds that are selective for subtypes m1 or m4 muscarinic receptor or for both types. The connection proposed by the present invention have a therapeutic effect and can be used for the treatment of painful conditions associated with cholinergic receptors, for example, lack of cognitive ability in Alzheimer's disease, glaucoma, pain, or schizophrenia.

In accordance with one embodiment, the present invention relates to compounds of the formula I:

where:

Z1is CR1or N, Z2is CR2or N, Z3is CR3or N and Z4PR is dstanley CR 4or N, but not more than two of Z1, Z2, Z3and Z4are N;

W1represents O, S or NR5one of W2and W3is N or CR6and the other of W2and W3is CG; W1is NG, W2is CR5or N and W3is CR6or N; or W1represents N, W2are NG and W3is N;

G represents the formula (II):

Y represents O, S, CHOH, -NHC(O)-, -C(O)NH-, -C(O)-, -OC(O)-, -(O)CO-, -NR7-, -CH=N -, or absent;

p is 1, 2, 3, 4 or 5;

Z represents CR8R9or missing;

each t is 1, 2 or 3;

each R1, R2, R3and R4independently, represents H, amino, hydroxyl, halogen or an unbranched or branched C1-6-alkyl, C2-6alkenyl,2-6-quinil,1-6-heteroalkyl,1-6-halogenated, -CN, -CF3, -OR11, COR11, -NO2, -SR11, -NHC(O)R11, -C(O)NR12R13, -NR12R13, -NR11C(O)NR12R13, -SO2NR12R13, -OC(O)R11, -O(CH2)qNR12R13or -(CH2)qNR12R13where q is an integer from 2 to 6, or R1and R2together form-NH-N=N - or R3and R4together form-NH-N=N-;

each of R5 , R6and R7, independently, is H, C1-6-alkyl; formyl; (C3-6-cycloalkyl; C5-6aryl, optionally substituted with halogen or1-6-alkyl or C5-6-heteroaryl, optionally substituted with halogen or1-6-alkyl;

each of R8and R9, independently, is N or C1-8-alkyl with an unbranched or branched chain;

R10represents an unbranched or branched C1-8-alkyl, C2-8alkenyl,2-8-quinil,1-8-alkyliden,1-8-alkoxy, C1-8-heteroalkyl,1-8-aminoalkyl,1-8-halogenated,1-8-alkoxycarbonyl,1-8-hydroxyalkoxy,1-8-hydroxyalkyl, -SH, C1-8-alkylthio, -O-CH2-C5-6-aryl, -C(O)-C5-6aryl (substituted C1-3-alkyl or halogen), C5-6-aryl, C5-6-cycloalkyl,5-6-heteroaryl,5-6-heteroseksualci, -NR12R13, -C(O)NR12R13, -NR11C(O)NR12R13, -CR11R12R13, -OC(O)R11, -(O)(CH2)sNR12R13or -(CH2)sNR12R13and s is an integer from 2 to 8;

R'10is H, unbranched or branched C1-8-alkyl, C2-8alkenyl,2-8-quinil,1-8-alkyliden,1-8-alkoxy, C1-8-heteroalkyl 1-8-aminoalkyl,1-8-halogenated,1-8-alkoxycarbonyl,1-8-hydroxyalkoxy,1-8-hydroxyalkyl or1-8-alkylthio;

each R11, independently, is H, unbranched or branched C1-8-alkyl, C2-8alkenyl,2-8-quinil,2-8-heteroalkyl,2-8-aminoalkyl,2-8-halogenated,1-8-alkoxycarbonyl,2-8-hydroxyalkyl, -C(O)-C5-6aryl (substituted C1-3-alkyl or halogen), C5-6-aryl, C5-6-heteroaryl,5-6-cycloalkyl,5-6-heteroseksualci, -C(O)NR12R13, -CR5R12R13, (CH2)tNR12R13and t is an integer from 2 to 8; and

each R12and R13, independently, is H, C1-6-alkyl; C3-6-cycloalkyl; C5-6aryl, optionally substituted with halogen or1-6-alkyl or C5-6-heteroaryl, optionally substituted with halogen or1-6-alkyl, or R12and R13together form a cyclic structure;

or their pharmaceutically acceptable salts, esters and prodrugs.

In accordance with the preferred embodiment, t is 2 and R'10is N.

In accordance with the preferred number of embodiments, Y is-C(O)-, -NHC(O)-, S, O, -OC(O) -, or absent. In another R10the submitted is alkyl and Z 1is CR1or N, Z2is CR2, Z3is CR3or N and Z4is CR4. In one embodiment p is 2. In another R5represents N or C1-6-alkyl.

In one preferred embodiment, each of R1, R2, R3and R4independently, represents H, halogen, -NO2or unbranched or branched C1-6-alkyl, or R1and R2together form-NH-N=N - or R3and R4together form-NH-N=N-.

Specific compounds of the invention include:

3-[3-(4-methoxypiperidine)-1-ylpropyl]-1H-indole;

3-[3-(4-ethoxypyridine)-1-ylpropyl]-1H-indole;

3-[3-(4-propoxyphene)-1-ylpropyl]-1H-indole;

3-[3-(4-butoxyphenyl)-1-ylpropyl]-1H-indole;

3-[3-(4-methoxypiperidine)-1-ylpropyl]-1H-indole;

3-[3-(4-ethoxymethylene)-1-ylpropyl]-1H-indole;

3-[3-(4-proximitybased)-1-ylpropyl]-1H-indole;

3-[3-(4-methylpiperidin)-1-ylpropyl]-1H-indole;

3-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-indole;

3-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-indole;

3-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-indole;

3-[2-(4-methoxypiperidine)-1-ileti]-1H-indole;

3-[2-(4-ethoxypyridine)-1-ileti]-1H-indole;

3-[2-(4-propoxyphene)-1-ileti]-1H-indole;

3-[2-(4-butoxyphenyl)-1-ileti]-1H-indole;

3-[2-(4-methoxypiperidine)-1-ileti]-1H-indole;

3-2-(4-ethoxymethylene)-1-ileti]-1H-indole;

3-[2-(4-proximitybased)-1-ileti]-1H-indole;

3-[2-(4-methylpiperidin)-1-ileti]-1H-indole;

3-[2-(4-ethylpiperazin)-1-ileti]-1H-indole;

3-[2-(4-n-propylpiperidine)-1-ileti]-1H-indole;

3-[2-(4-n-butylpiperazine)-1-ileti]-1H-indole;

3-[2-(4-methoxypiperidine)-1-ileti]benzo[d]isoxazol;

3-[2-(4-butoxyphenyl)-1-ileti]benzo[d]isoxazol;

3-[2-(4-methoxypiperidine)-1-ylpropyl]benzo[d]isoxazol;

3-[3-(4-butoxyphenyl)-1-ylpropyl]benzo[d]isoxazol;

3-[4-(4-methoxypiperidine)-1-libutil]benzo[d]isoxazol;

3-[4-(4-butoxyphenyl)-1-libutil]benzo[d]isoxazol;

1-[3-(4-methoxypiperidine)-1-ylpropyl]-1H-indole;

1-[3-(4-ethoxypyridine)-1-ylpropyl]-1H-indole;

1-[3-(4-propoxyphene)-1-ylpropyl]-1H-indole;

1-[3-(4-butoxyphenyl)-1-ylpropyl]-1H-indole;

1-[3-(4-methoxypiperidine)-1-ylpropyl]-1H-indole;

1-[3-(4-ethoxymethylene)-1-ylpropyl]-1H-indole;

1-[3-(4-proximitybased)-1-ylpropyl]-1H-indole;

1-[3-(4-methylpiperidin)-1-ylpropyl]-1H-indole;

1-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-indole;

1-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-indole;

1-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-indole;

1-[2-(4-methoxypiperidine)-1-ileti]-1H-indole;

1-[2-(4-ethoxypyridine)-1-ileti]-1H-indole;

1-[2-(4-propoxyphene)-1-ileti]-1H-indole;

1-[2-(4-butoxyphenyl)-1-ileti]-1H-indole;

1-[2-(4-methoxypiperidine)-1-ileti]-1H-indole;

1-[2-(4-ethoxymethylene)-1-ileti]-1H-indole;

1-[2-(4-proximitybased)-1-ileti]-1H-indole;

1-[2-(4-methylpiperidin)-1-ileti]-1H-indole;

1-[2-(4-ethylpiperazin)-1-ileti]-1H-indole;

1-[2-(4-n-propylpiperidine)-1-ileti]-1H-indole;

1-[2-(4-n-butylpiperazine)-1-ileti]-1H-indole;

1-[3-(4-methoxypiperidine)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-ethoxypyridine)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-propoxyphene)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-butoxyphenyl)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-methoxypiperidine)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-ethoxymethylene)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-proximitybased)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-methylpiperidin)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-benzotriazol;

1-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-benzotriazol;

1-[2-(4-methoxypiperidine)-1-ileti]-1H-benzotriazol;

1-[2-(4-ethoxypyridine)-1-ileti]-1H-benzotriazol;

1-[2-(4-propoxyphene)-1-ileti]-1H-benzotriazol;

1-[2-(4-butoxyphenyl)-1-ileti]-1H-benzotriazol;

1-[2-(4-methoxypiperidine)-1-ileti]-1H-benzotriazol;

1-[2-(4-ethoxymethylene)-1-ileti]-1H-benzotriazol;

1-[2-(4-proximitybased)-1-ileti]-1H-benzotriazol;

1-[2-(4-methylpiperidin)-1-ileti]-1H-benzotri the azole;

1-[2-(4-ethylpiperazin)-1-ileti]-1H-benzotriazol;

1-[2-(4-n-propylpiperidine)-1-ileti]-1H-benzotriazol;

1-[2-(4-n-butylpiperazine)-1-ileti]-1H-benzotriazol;

1-[4-(4-methoxypiperidine)-1-libutil]-1H-benzotriazol;

1-[4-(4-ethoxypyridine)-1-libutil]-1H-benzotriazol;

1-[4-(4-propoxyphene)-1-libutil]-1H-benzotriazol;

1-[4-(4-butoxyphenyl)-1-libutil]-1H-benzotriazol;

1-[4-(4-methoxypiperidine)-1-libutil]-1H-benzotriazol;

1-[4-(4-ethoxymethylene)-1-libutil]-1H-benzotriazol;

1-[4-(4-proximitybased)-1-libutil]-1H-benzotriazol;

1-[4-(4-methylpiperidin)-1-libutil]-1H-benzotriazol;

1-[4-(4-ethylpiperazin)-1-libutil]-1H-benzotriazol;

1-[4-(4-n-propylpiperidine)-1-libutil]-1H-benzotriazol;

1-[4-(4-n-butylpiperazine)-1-libutil]-1H-benzotriazol;

2-[4-(4-methylpiperidin)-1-libutil]-1H-benzotriazol;

2-[4-(4-ethylpiperazin)-1-libutil]-1H-benzotriazol;

2-[4-(4-n-propylpiperidine)-1-libutil]-1H-benzotriazol;

2-[4-(4-n-butylpiperazine)-1-libutil]-1H-benzotriazol;

2-[3-(4-methylpiperidin)-1-ylpropyl]-1H-benzoimidazol;

2-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-benzoimidazol;

2-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-benzoimidazol;

2-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-benzoimidazol;

2-[2-(4-methylpiperidin)-1-ileti]-1H-benzoimidazol;

2-[2-(4-ethylpiperazin)-1-ileti]-1H-benzoimidazol;

2-[2-(4-n-propylpiperidine)-1-Latin]-1H-benzoimidazol;

2-[2-(4-n-butylpiperazine)-1-ileti]-1H-benzoimidazol;

1-(1H-benzoimidazol-2-yl)-4-(4-methylpiperidin)butanone;

1-(1H-benzoimidazol-2-yl)-4-(4-ethylpiperazin)butanone;

1-(1H-benzoimidazol-2-yl)-4-(4-n-propylpiperidine)butanone;

1-(1H-benzoimidazol-2-yl)-4-(4-n-butylpiperazine)butanone;

1-(1H-benzoimidazol-2-yl)-3-(4-methylpiperidino)propanone;

1-(1H-benzoimidazol-2-yl)-3-(4-ethylpiperazin)propanone;

1-(1H-benzoimidazol-2-yl)-3-(4-n-propylpiperidine)propanone;

1-(1H-benzoimidazol-2-yl)-3-(4-n-butylpiperazine)propanone;

3-[3-(4-methylpiperidin)-1-ylpropyl]-1H-indazol;

3-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-indazol;

3-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-indazol;

3-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-indazol;

1-(3-benzofuran-3-ylpropyl)-4-methylpiperidin;

1-(3-benzofuran-3-ylpropyl)-4-ethylpiperidine;

1-(3-benzofuran-3-ylpropyl)-4-n-propylpiperidine;

1-(3-benzofuran-3-ylpropyl)-4-n-butylpiperazine;

3-(3-(4-methylpiperidin)-1-ylpropyl)benzo[d]isothiazol;

3-(3-(4-ethylpiperazin)-1-ylpropyl)benzo[d]isothiazol;

3-(3-(4-n-propylpiperidine)-1-ylpropyl)benzo[d]isothiazol;

3-(3-(4-n-butylpiperazine)-1-ylpropyl)benzo[d]isothiazol;

1-[3-(4-methylpiperidin)-1-ylpropyl]-1H-benzoimidazol;

1-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-benzoimidazol;

1-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-benzoimidazol;

1-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-benzoyl Gasol;

1-[2-(4-methylpiperidin)-1-ileti]-1H-benzoimidazol;

1-[2-(4-ethylpiperazin)-1-ileti]-1H-benzoimidazol;

1-[2-(4-n-propylpiperidine)-1-ileti]-1H-benzoimidazol;

1-[2-(4-n-butylpiperazine)-1-ileti]-1H-benzoimidazol;

1-[3-(4-methylpiperidin)-1-ylpropyl]-1H-benzoimidazol;

1-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-indazol;

1-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-indazol;

1-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-indazol;

2-[4-(4-methylpiperidin)-1-libutil]-1H-benzothiazole;

2-[4-(4-ethylpiperazin)-1-libutil]-1H-benzothiazole;

2-[4-(4-n-propylpiperidine)-1-libutil]-1H-benzothiazole;

2-[4-(4-n-butylpiperazine)-1-libutil]-1H-benzothiazole;

2-[3-(4-methylpiperidin)-1-ylpropyl]-1H-benzothiazole;

2-[3-(4-ethylpiperazin)-1-ylpropyl]-1H-benzothiazole;

2-[3-(4-n-propylpiperidine)-1-ylpropyl]-1H-benzothiazole;

2-[3-(4-n-butylpiperazine)-1-ylpropyl]-1H-benzothiazole;

2-[2-(4-methylpiperidin)-1-ileti]-1H-benzothiazole;

2-[2-(4-ethylpiperazin)-1-ileti]-1H-benzothiazole;

2-[2-(4-n-propylpiperidine)-1-ileti]-1H-benzothiazole;

2-[2-(4-n-butylpiperazine)-1-ileti]-1H-benzothiazole;

2-[3-(4-methylpiperidin)-1-ylpropyl]benzoxazol;

2-[3-(4-ethylpiperazin)-1-ylpropyl]benzoxazol;

2-[3-(4-n-propylpiperidine)-1-ylpropyl]benzoxazol;

2-[3-(4-n-butylpiperazine)-1-ylpropyl]benzoxazol;

2-[2-(4-methylpiperidin)-1-ileti]benzoxazol;

2-[2-(4-ethylpiperazin)-1-ileti]benzoxazol;

2-[2-(4-n-propylpiperidine)-1-ileti]benzoxazol;

2-[2-(4-n-butylpiperazine)-1-ileti]benzoxazol;

2-[4-(4-methylpiperidin)-1-libutil]benzoxazol;

2-[4-(4-ethylpiperazin)-1-libutil]benzoxazol;

2-[4-(4-n-propylpiperidine)-1-libutil]benzoxazol;

2-[4-(4-n-butylpiperazine)-1-libutil]benzoxazol;

4,5-debtor-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

6-fluoro-5-nitro-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

5-tert-butyl-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

5-chloro-6-methyl-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

4,6-debtor-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-imidazo[4,5-c]pyridine;

8-(3-(4-n-butylpiperazine)-1-ylpropyl)-N-purine;

7-(3-(4-n-butylpiperazine)-1-ylpropyl)-3,8-dihydroimidazo[4',5':3,4]benzo[1,2-d][1,2,3]triazole;

2-(3-(4-n-butylpiperazine-1-yl)propyl)-3A,4,5,6,7,7a-hexahydro-1H-benzoimidazol;

3-methyl-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

5-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

3-formyl-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

3-(3-(4-n-butylpiperazine)-1-ylpropyl)benzo[d]isoxazol;

4-nitro-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

5-nitro-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

4-hydroxy-2-(3-(4-n-butylbiphenyl the n)-1-ylpropyl)-1H-benzoimidazol;

4-methyl-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

3-(2-(4-n-butylpiperazine)ethoxy)-7-methylbenzo[d]isoxazol;

1-(3-(4-methylpiperidin)-1-ylpropyl)-1H-indazol;

1-(3-(4-pentylpyridine)-1-ylpropyl)-1H-indazol;

1-(3-(4-propylpiperidine)-1-ylpropyl)-1H-;

1-(3-(4-(3-methylbutyl)piperidine)-1-ylpropyl)-1H-indazol;

1-(3-(4-interidentified)-1-ylpropyl)-1H-indazol;

1-(3-(4-propylenpipeline)-1-ylpropyl)-1H-indazol;

1-benzo[b]thiophene-2-yl-4-(4-butylpiperazine-1-yl)butane-1-it;

4-(4-butylpiperazine-1-yl)-1-(3-methylbenzofuran-2-yl)butane-1-it;

4-(4-butylpiperazine-1-yl)-1-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)butane-1-it;

1-benzofuran-2-yl-4-(4-butylpiperazine-1-yl)butane-1-it;

1-(3-bromobenzo[b]thiophene-2-yl)-4-(4-butylpiperazine-1-yl)butane-1-it;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-butylpiperazine;

1-(3-benzofuran-2-ylpropyl)-4-butylpiperazine;

4-butyl-1-[3-(3-methylbenzofuran-2-yl)propyl]piperidine;

4-butyl-1-[3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)propyl] piperidine;

2-(3-improper)benzo[b]thiophene;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-methylpiperidin;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-benzylpiperidine;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-(2-methoxyphenyl)piperidine;

2-(3-bromopropyl)-2H-benzotriazole;

2-[3-(4-butylpiperazine-1-yl)propyl]-2H-benzotriazole;

1-(3-bromopropyl)-1H-benzotriazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-1H-benzotriazol;

1-[3-(-butylpiperazine-1-yl)propyl]-1H-indole-3-carbaldehyde;

{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-yl}methanol;

1-[3-(4-butylpiperazine-1-yl)propyl]-2-phenyl-1H-benzoimidazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-3-chloro-1H-indazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-6-nitro-1H-indazol;

Benzo[d]isoxazol-3-ol;

3-(2-chloroethoxy)benzo[d]isoxazol;

3-[2-(4-Butylpiperazine-1-yl)ethoxy]benzo[d]isoxazol;

3-(1H-indol-3-yl)propan-1-ol;

hydrochloride 3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indole;

methyl ester of 4-(4-butylpiperazine-1-yl)butyric acid;

2-[3-(4-butylpiperazine-1-yl)propyl]-1-methyl-1H-benzimidazole;

(2-(4-butylpiperazine)-1-retil)amide 1H-indazol-3-carboxylic acid;

1-[3-(4-butylpiperazine-1-yl)propyl]-5-nitro-1H-indazol;

2-[3-(4-butylpiperazine-1-yl)propyl]-5-nitro-2H-indazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-2-methyl-1H-indole;

1-{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-yl}Etalon;

{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-yl}acetonitrile;

1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-carbonitrile;

1-[3-(4-butylpiperazine-1-yl)propyl]-5,6-dimethyl-1H-benzoimidazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-5(6)-dimethyl-1H-benzoimidazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-5-methoxy-1H-benzoimidazol;

{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-benzoimidazol-2-yl} methanol;

1-[3-(4-butylpiperazine-1-yl)propyl]-2-trifluoromethyl-1H-benzoimidazol;

tert-butyl ether (2-Tr is methylstyrene)carbamino acid;

tert-butyl ether [2-(4-chlorobutyryl)phenyl]carbamino acids;

tert-butyl ether {2-[4-(4-butylpiperazine-1-yl)butyryl] phenyl}carbamino acids;

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol, HCl;

3-[3-(4-butylpiperazine-1-yl)propyl]-5-nitro-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-5,7-dinitro-1H-indazol;

4-(4-butylpiperazine-1-yl)-1-(2-methylsulfinylphenyl)butane-1-it;

3-[3-(4-butylpiperazine-1-yl)propyl]benzo[d]isothiazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-5-methoxy-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-4-methoxy-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-6-methoxy-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol-4-ol (53MF51);

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol-6-ol (53MF52) and

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol-5-ol.

The present invention also relates to pharmaceutical compositions comprising an effective amount of at least one compound of the invention, including all connections in the range of the formula (I).

In General, the compounds of the present invention are active against cholinergic, especially muscarinic receptors. Preferred compounds have the General property of acting as agonists subtype m1 or m4 muscarinic receptors, or both. In the preferred implementation of the compounds of this image is to be placed are selective with respect to m1, m4 or both subtypes of muscarinic receptors of the m1 and m4, i.e. compounds have weak or do not have a substantive effect on other types of muscarinic receptors. In a typical case, selective for m1 and/or m4 compounds of the invention have no effect on other related receptors, including G-protein-coupled receptors, such as serotonin, histamine, dopamine, or adrenergic receptors. The invention relates to compounds that are selective as agonists subtypes either m1 or m4, as well as compounds that are agonists of receptor subtypes as m1 and m4. In one embodiment of the compounds of the present invention have a smaller or have no effect on subtypes of muscarinic receptors m2 and m3. In another embodiment of the compounds of the present invention have a smaller or have no effect on subtypes of muscarinic receptors m2, m3, m4 and m5.

Compounds of the present invention typically have a therapeutic action, they can be used to cure or ameliorate symptoms of painful conditions associated with cholinergic receptors, such as lack of cognitive ability, forgetfulness, confusion, memory loss, attention deficit, deficits in visual perception, depression, pain, sleep disorders, psychosis, hallucinate is, aggressiveness, paranoia, and increased intraocular pressure. Painful condition may be the result of dysfunction, increased activity, modification, mutation, truncation or loss of cholinergic receptors, especially muscarinic receptors, as well as reduced levels of acetylcholine.

Compounds of the present invention can also be used to treat diseases such as age-related decline in cognitive abilities, Alzheimer's disease, Parkinson's disease, Horai Huntington, ataxia of Frederica syndrome Gilles de La Tourette's, down syndrome, disease Peak, dementia, clinical depression, disorders associated with attention deficit syndrome of sudden death of seemingly healthy baby and glaucoma.

Compounds of the present invention have the ability to increase the activity of cholinergic receptor or activate cholinergic receptors. The activity of cholinergic receptors includes activity in the signal transmission, or any other activity that directly or indirectly relates to cholinergic signaling or activation. Cholinergic receptors include muscarinic receptors, especially the subtype m1 or m4 muscarinic receptors. Muscarinic receptor can be, for example, in the Central nervous system, peripheral nervous system, gelado the but-intestinal system, heart, glands of internal system or lungs. Muscarinic receptor can be muscarinic receptor wild-type, truncated, mutated or modified cholinergic receptor. Kits comprising the compounds of the present invention to increase the activity of the cholinergic receptors or activation of cholinergic receptors are also addressed by the present invention.

System containing cholinergic receptor may be, for example, a subject such as a mammal, non-human Primate or human. The system can be experimental model in vivo or in vitro, such as a model system in cell culture that expresses cholinergic receptor that does not contain cells of its extract, which contains cholinergic receptor or purified receptor. Non-limiting examples of such systems are tissue culture cells expressing the receptor, or their extracts or lysates. Cells that can be used in the present method include any cells that can mediate signal transduction through cholinergic receptors, especially muscarinic m1 receptor, either by endogenous expression of this receptor (some line types of neural cells, for example, natively Express the receptor m1) or, for example, after introduction the exogenous gene in the cell, for example, transfection of cells with plasmids containing the gene of the receptor. These cells typically are mammalian cells (or other eukaryotic cells such as insect cells or Xenopus oocytes), because the cells of the lower forms of life is usually no way suitable signal transduction for this purpose. Examples of suitable cells include mouse fibroblast cell line (NIH 3T3 (ATCC CRL (1658), which responds to transfetsirovannyh receptors m1 enhanced growth; cells RAT 1 (Pace et al., Proc. Natl. Acad. Sci. USA 88:7031-35 (1991)) and cells of the pituitary gland (Vallar et al., Nature 330:556-58 (1987)). Other suitable mammalian cells for the present method include, but are not limited to, cells HEK 293 cells, Cho cells and COS.

Compounds of the present invention also possess the ability to lower intraocular pressure and, therefore, they can be used in the treatment of diseases such as glaucoma. Glaucoma is a disease in which the anomaly observed in the mechanism of regulation of the circulation of aqueous humor that fills the anterior chamber of the eyeball, i.e. the space formed between the cornea and the crystalline lens. This leads to an increase of intraocular fluid and increased intraocular pressure, subsequently resulting in impaired field of vision or even loss TREN is I due to the compression and reduction of the papilla of the optic nerve.

The present invention relates to the field of predictive medicine in which for the purposes of forecasting using pharmacogenomics. Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered distribution of medicines and abnormal action in affected individuals (see, for example, Eichelbaum, Clin. Exp. Pharmacol. Physiol. 23:983-985 (1996) and Linder, Clin. Chem. 43:254-66 (1977)). In General, we can distinguish two types of pharmacogenetic conditions: a genetic condition associated with the individual factors that alter the course of action of drugs on the body (altered drug action), or a genetic condition associated with the individual factors that alter the way the impact of the body on drugs (altered drug metabolism). These pharmacogenetic conditions can occur as a naturally occurring polymorphisms.

One of pharmacogenomics approach to identifying genes that predicts the response to drug, known as "wide Association study genome", is based mainly on the map high resolution human genome, consisting of well-known relating to gene markers (for example, the map "biallelic" genetic markers, which consists of 6000-100000 polymorphic or variable sites in the human genome, each of which has two variants). Such a genetic map high resolution can be compared with the map of the genome of any statistically significant number of patients participating in the trial of a medicinal product in phase II/III, to identify markers associated with specific observable reaction to a drug or side effects. In the alternative case, such a map high resolution can be obtained from a combination of approximately ten million known single nucleotide polymorphisms (SNPs) in the human genome. Used here is "SNP" is a common change that occurs in a single nucleotide base in the DNA. For example, a SNP may occur once every 1000 bases of DNA. SNP may participate in the disease process, although the vast majority may not be associated with the disease. This genetic map of individuals, based on the presence of these SNPs can be grouped into genetic categories depending on the specific pattern SNPs in their individual genome. In this way it is possible to develop a treatment regimen for groups of genetically similar individuals, taking into account features that may be common in such genetically similar individuals.

Another option to identify genes that before the show reaction to the drug, you can use a method called "approach for gene-candidate". In accordance with this method, if a gene that encodes the target of medicines known (for example, a protein or the receptor of the present invention), all common variants of that gene can be identified in the population. It can be easily identified by standard methods, a particular version associated with the reaction of the gene for a certain drug.

In the alternative case, in order to identify genes that predict response to drug, you can use a method called "analysis of gene expression profile". For example, expression of the gene of the animal, which was injected dose of the drug (for example, the compounds or compositions of the present invention)can give an indication to the included whether genetic path associated with toxicity.

The information obtained from more than one of the above approaches of pharmacogenomics can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment of an individual. This knowledge, when it is used to select doses or medication can prevent adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating with whom bhakta compound or composition of the present invention, such as a modulator identified by one of these sample analyses of screening. These approaches can also be used to identify the new receptor candidate or other genes that are suitable for further pharmacological characterization in vitro and in vivo.

Accordingly, another aspect of the present invention describes methods and kits for identification of genetic polymorphism leading to a predisposition of the subject to susceptibility to the connection described here. The method includes introducing to a subject an effective amount of compounds; identification of susceptible subject, having reduced the intensity of the symptoms of the disease condition (not clinically expressed)associated with cholinergic receptor, and the identification of genetic polymorphism in susceptible subject, where genetic polymorphism leads to a predisposition of the subject to susceptibility to the compound. Identification of genetic polymorphism in susceptible subject can be performed by any means known in this field, including the methods described above. In addition, the set, which is used to identify genetic polymorphism leading to a predisposition of the subject to susceptibility to the connection according to the invention, includes the connection of this image is the shadow and preferably, the reagents and instructions for conducting the test on genetic polymorphism.

In one embodiment of the subject can be checked on a known polymorphism, which leads to a predisposition of the subject to susceptibility to the compound of the present invention. The presence of the polymorphism indicates that the subject is suitable for treatment.

In preferred embodiments of the compounds of the present invention can be represented, as shown in formulas (IIIa-e):

where W1represents O, S or NR5, W2is CR5or N and W3is CR5or N or where W3is NR5, S, or O, or their pharmaceutically acceptable salt, ester or prodrug.

Compounds of the present invention can be obtained by methods similar to the methods described in UK patent No. 1142143 and U.S. patent No. 3816433, each of which is incorporated herein by reference. Path modifications of these methods to include other reagents, etc. should be obvious to specialists in this field. For example, the compounds of formula III (e.g., IIIb, where W1the submitted is NR 5) can be obtained as indicated in the following reaction scheme.

The original compound having the formula (X)can be obtained by the General methods of organic synthesis. For General methods of preparing compounds of the formula (X) provides a link to the Fuller, et al., J. Med. Chem. 14:322-325 (1971); Foye, et al., J. Pharm. Sci. 68:591-595 (1979); Bossier, et al., Chem. Abstr. 66:46195h and 67:21527a (1967); Aldous, J. Med. Chem. 17:1100-1111 (1974); Fuller, et al., J. Pharm. Pharmacol. 25:828-829 (1973); Fuller, et al., Neuropharmacology 14:739-746 (1975); Conde, et al., J. Med. Chem. 21:978-981 (1978); Lukovits, et al., Int. J. Quantum Chem. 20:429-438 (1981); and Law, Cromatog. 407:1-18 (1987), the description of which is included here by reference in their entirety. The compounds of formula XI to receive, for example, as described in Darbre, et al., Helv. Chim. Acta, 67:1040-1052 (1984) or Ihara, et al, Heterocycles, 20:421-424 (1983), also incorporated herein by reference. Radiolabelled derivatives having the formula (XX)can be obtained, for example, using titiraupenga reducing agent for rehabilitation amination or by using14C-labeled source material.

To obtain the compounds of formula (I) can be used the compounds of formula (XXII). The compounds of formula (XXII) are obtained, for example, as described in Ishii, et al, J. Org. Chem. 61:3088-3092 (1996) or Britton, et al. Bioorg. Med. Chem. Lett. 9:475-480 (1999), also incorporated herein by reference. When the original connection comprises a carbonyl group is, the compound having the formula (XXII)can be restored, for example, AlH3system DIBORANE:metilsulfate or other standard reducing carbonyl reagents to obtain a ligand having the formula (XXX).

The receptor ligands having the formula (XXXII)can be obtained by nucleophilic substitution of a suitable nucleofuge (E) derivatives (XXXI). Examples nucleofuge that can be used for this purpose include halides, such as I, Cl, Br, or toilet or mesilate.

When Y in the formula (XXX) represents-C(O)-, this compound can be obtained by oxidation of the secondary alcohol, for example, chlorbromuron pyridinium, N-chlorosuccinimide, CrO3-H2SO4or Nickel by methods Swarna or dess-Martin.

When Y in the formula (XXX) represents-O-, this compound can be obtained by AllYouNeed alcohol aryl halides, for example, during the catalysis with Cu.

When Y in the formula (XXX) represents-S-, this compound can be obtained by AllYouNeed of the thiol aryl halides, for example, during the catalysis with Cu.

When Y in the formula (XXX) represents NON-, this compound can be obtained by recovering the corresponding ketone by catalytic hydrogenation or using NaBH4or LiAlH4.

Suitable pharmaceutically reception is going salts of the compounds of this invention include acid additive salt, who, for example, can be formed by mixing a solution of the compounds according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of the invention have acid part, suitable pharmaceutically acceptable salts include salts of alkali metals, e.g. sodium or potassium; salts of alkaline earth metals such as calcium salt or magnesium, and salts formed with suitable organic ligands, e.g. Quaternary ammonium salts. Examples of pharmaceutically acceptable salts include the acetate salt, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, clavulanate, citrate, dihydrochloride, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, nitrate, ammonium salt of N-methylglucamine, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannat, tartrate, tosylate, and triethiodide valerate.

The present invention includes in its the scope prodrugs of the compounds of the present invention. In General, such prodrugs are derivatives of the compounds of the present invention, which are easily converted in vivo into the required compound. Conventional procedures for the selection and obtaining the appropriate proletarienne derivatives described, for example, in Design of Prodrugs (Bundgaard, ed. Elsevier, 1985). Metabolites of these compounds include active species produced in the introduction of the compounds of this invention in a biological environment.

When the compounds according to the invention have at least one chiral center, they may exist in the form of racemates or enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. In addition, some of the crystalline forms of the compounds of the present invention may exist as polymorphs and as such, are assumed to be included in the present invention. In addition, some of the compounds of the present invention may form a solvate with water (i.e. hydrates) or common organic solvents. Such a solvate is also included in the scope of this invention.

When the means of obtaining the compounds according to the invention give a mixture of stereoisomers, these isomers can be divided by using common methods such as preparative chiral chromatography. Compounds can be obtained in racemic form, or individual enantiomers what you can get or stereoselective synthesis or by separation of the enantiomers. The connection can, for example, be divided into their enantiomeric components standard ways, such as education diastereomeric pair of salts with optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and the formation of free base. Compounds can also be separated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary substances.

In the course of any of the methods of obtaining the compounds of the present invention may be necessary and/or desirable to protect sensitive or reactive groups on any of the participating in the reaction molecules. This can be achieved using conventional protective groups such as the groups described in Protective Groups in Organic Chemistry (McOmie ed., Plenum Press, 1973) and Greene &Wuts, Protective Groups in Organic Synthesis (John Wiley and Sons, 1991). The protective group can be removed to acceptable a subsequent stage using methods known in this field.

Compounds of the present invention can be introduced in any of the described compositions and in accordance with schemes of medicine established in this area, whenever you need a specific pharmacological modification activity muscarin the o receptors.

The present invention relates also to pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable diluent or excipient. Such compositions preferably are standard dosage forms, such as tablets, pills, capsules (including finished formulation with prolonged or delayed release), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, device-autoinjector or suppositories; for oral, parenteral (e.g. intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal administration, or for administration by inhalation or insufflate and can be made suitable means and in accordance with conventional methods, such as the practices described in Remington''s Pharmaceutical Sciences (Gennaro, ed., Mack Publishing Co., Easton, PA, 1990). Alternatively the composition can be in the form of a sustained-release formulation suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as decanoate salt, can be adapted to receive the drug depot for intramuscular injection. The present image is the buy also considers appropriate local ready formulation for injection, for example, in the eye, causing the skin or mucous membrane.

For oral administration, for example, in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, when it is desirable or necessary, the mixture can also enter a suitable binders, lubricants, dezintegriruetsja agents, corrigentov and coloring agents. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums, such as Arabian gum, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

For solid compositions such as tablets, the active ingredient is mixed with a suitable pharmaceutical excipient, such as excipients, as described above, and other pharmaceutical diluents, for example, the ode, with the formation of the composition in the form of a solid ready formulation containing a homogeneous mixture of the compounds of the present invention or its pharmaceutically acceptable salt. The term "homogeneous" means that the active ingredient is uniformly dispersed throughout the volume of the composition so that the composition can easily be divided into equally effective standard dosage forms, such as tablets, pills and capsules. Solid pre-prepared composition can then be divided into standard dosage forms of the type described above containing from about 0.01 to about 50 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be covered with membrane or to make any other way to obtain a dosage form that provides the advantages of prolonged action. For example, the tablet or pill may include an inner core containing the active compound, and the outer layer as a coating surrounding the core. The outer layer may be intersolubility layer, which serves to obstruct disintegration in the stomach and allows the inner core to pass intact into the duodenum or to slow down the release. For such intersolubility layers or coatings can be used a variety of materials, and such materials VK is ucaut various polymeric acids and mixtures of polymeric acids with conventional materials, such as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the present composition can be enabled for injection, orally or by injection include aqueous solutions, syrups, appropriately processed to change the taste and smell, aqueous or oil suspensions and emulsions, treated for changes in taste and smell edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, such as tragakant, Arabian gum, alginate, dextran, sodium carboxymethyl cellulose, gelatin, methylcellulose and polyvinylpyrrolidone. Other dispersing agents that can be used include glycerin and the like. For parenteral administration is desirable sterile suspensions and solutions. Isotonic preparations, which usually contain suitable preservatives, used when it is desirable intravenous. The composition can also be manufactured in the form of an ophthalmic solution or suspension, i.e. eye drops for ocular injection.

Compounds of the present invention can be entered as a single daily dose or the total daily dose can be administered in wideranging doses of two, three or four times a day. In addition, the compounds of the present invention can be introduced in intranasal form via topical application of suitable intranasal fillers or via transdermal route using, for example, percutaneous patches on the skin, which are well known to specialists in this field. For administration in the form of a percutaneous delivery system, the dose should be continuous rather than intermittent throughout the dosage regimen of the drug.

The regimen of medicines that use compounds of the present invention, are selected in accordance with various factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition being treated; the route of administration, the kidneys and the liver of the patient and apply a specific connection. The doctor and veterinarian average skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or stop the development of the exposed treatment of diseases or disorders.

The daily dosage of the products may vary in a wide range from 0.01 to 100 mg per adult human per day. For oral administration the compositions are preferably provided in the form of tablets containing 0,01, 0,05, 0,1, 0,5, 1,0, 25, 5,0, 10,0, 15,0, of 25.0 or 50.0 mg of active ingredient for the symptomatic installation doses for exposed treatment of the patient. The standard dose is usually contains from about 0.001 mg to about 50 mg of active ingredient, preferably from about 1 mg to about 10 mg of the active ingredient. An effective quantity of a drug is usually used at a dose of approximately from 0.0001 mg/kg to about 25 mg/kg of body weight per day. The range of, preferably, approximately from 0.001 to 10 mg/kg body weight / day and, especially, from about 0.001 mg/kg to 1 mg/kg of body weight per day. Connections can be entered, for example, when the mode from 1 to 4 times a day.

Compounds of the present invention can be used, as taken separately at appropriate doses, defined in the usual testing for optimal pharmacological action on muscarinic receptor, especially the subtype m1 or m4 muscarinic receptor, while minimizing any potential toxicity or other undesirable actions. In addition, in some cases it may be desirable co-administration or sequential introduction of other agents that increase the activity of the connection.

Pharmacological properties and selectivity of the compounds of this invention for certain confirmation the surface muscarinic receptors can be demonstrated in various ways analysis using, for example, recombinant receptor subtypes, preferably receptors as available, for example, the standard of the second messenger, or analyses on binding. Especially suitable system functional analysis is the choice of the receptor and analysis of the amplification described in U.S. patent No. 5707798, which describes a method of selecting biologically active compounds through the use of the ability of cells transfected with the receptor DNA, for example, the coding of different muscarinic subtypes, amplificates in the presence of ligand receptor. The multiplication of cells is determined by elevated levels of the marker is also expressed by the cells.

The invention is hereinafter described in detail in the following examples, which in no case are not intended to limit the scope of the claimed invention.

EXAMPLES

Ways to get

Compounds in accordance with the present invention can be synthesized by the methods described below, or by modifications of these methods. Methods of modification techniques include, for example, changes in temperature, solvents, reagents, etc. they should be obvious to specialists in this field.

General procedure LC-MS: All spectra were obtained with the use of device HP1100 LC/MSD. Used the installation with a double pump, autopromotion, Ter is a mod for the columns diode matrix detector and interface the ionization electronegativities. Used a column of reversed phase (C18 Luna, particle size 3 mm, 7.5 cm×4.6 mm, EXT. diameter) with a protective cartridge. The column was kept at a temperature of 30°C. the Mobile phase was acetonitrile/8 mm aqueous ammonium acetate. Used 15 minute gradient program, which begins at 70% acetonitrile, reaches for 12 minutes 95% acetonitrile for 1 minute back to 70% acetonitrile and remains for 2 minutes. The flow rate was 0.6 ml/min values of trspecified in the specific examples below, were obtained using this procedure.

2-(3-(4-n-Butylpiperazine-1-yl)propyl)benzothiazole (5). 1-Benzyl-4-n-butylidenephthalide (2). 3-necked flask of 500 ml equipped with a stirrer, charged sodium hydride (1,61 g, 67 mmol) and DMSO (ml). The resulting suspension is heated to 90°C for 30 minutes prior to the cessation of hydrogen evolution. The suspension is cooled in an ice bath for 20 minutes followed by the addition of a suspension of the bromide butyldiphenylsilyl (26,6 g, 67 mmol) in DMSO (70 ml). The red mixture is stirred for 15 min at room temperature. Slowly over 30 min was added 1-benzyl-4-piperidone 1 (14.0 g, 74 mmol) and the mixture is stirred at room temperature during the night. To the reaction mixture N2O (200 ml) followed by extraction with heptane (4×100 ml) and ethyl acetate (2×100 ml). The combined organic phases are dried and evaporated to dryness, thus obtaining 38,1 g yellow oil. The oil is distilled to obtain 14.9 g (88%) of compound 2, BP. 101-105°C (0.1 mm Hg).1NMR (CDCl3) δ 0,90-0,95 (t, 3H), 1,25-of 1.41 (m, 2H), 1,90-of 2.20 (m, 2H), 2,18-of 2.30 (m, 4H), 2.40 a at 2.45 (m, 4H), 2.50 each (s, 2H), 5,17 (t, 1H), 7,20-7,42 (m, 5H).

4-n-Butylpiperazine (3). Into a flask of 500 ml equipped with a stirrer, was added a suspension of 2 (13,2 g, 58 mmol) and 10% palladium on coal (1.2 g) in ethanol (70 ml) followed by the addition of concentrated hydrochloric acid (1.5 ml). From the reaction flask suck the air through the reaction flask add hydrogen. Just absorbed 2,5 DM3of hydrogen. The reaction mixture is filtered and evaporated and the residue is dissolved in N2O (40 ml) and NaOH (20 ml, 2 M) followed by extraction with ethyl acetate (3×100 ml). The combined organic phases are washed with saturated salt solution (30 ml) and evaporated to dryness obtaining of 7.1 g of crude product 3. The crude product subjected to column chromatography (eluent: heptane:EtOAc (4:1)), thus obtaining the pure product 3 (2.7 g, 33%).1H NMR (CDCl3) δ of 0.85 (t, 3H), from 1.0 to 1.38 (m, 9H), of 1.65 (DD, 2H), 2,38 (s, 1H), 2,55 (dt, 2H), 3.04 from (dt, 2H).

Methyl ester of 4-(4-n-butylpiperazine-1-yl)butyric acid (4). Into the flask to 50 ml of the loaded who have a mixture of compound 3 (2.7 g, 15 mmol), methyl ester 4-pamakani acid (9,9 g, 55 mmol) and potassium carbonate (8.6 g, 62 mmol) in acetonitrile (25 ml). The mixture is stirred at room temperature for 72 hours, followed by evaporation to dryness. The crude product subjected to column chromatography (eluent: CH2Cl2:CH3HE (96:4)) to obtain the pure product 4 (3.4 g, 94%).1H NMR (CDCl3) δ to 0.89 (t, 3H), 1,20-of 1.39 (m, 9H), 1.69 in (d, 2H), 1,89 (square, 2H), 1,98 (t, 2H), a 2.36 (t, 2H), 2,43 (t, 2H), 3,99 (d, 2H), to 3.67 (s, 3H).

A General procedure for obtaining 2-(3-(4-n-butylpiperazine-1-yl) propyl)heteroaromatic compounds(5, 6, 7, 8, 9, 10, 11, 12, 13). A small sealed vial equipped with a magnetic stirrer and loaded connection 4 (121 mg, 0.50 mmol), the appropriate bastianini (as defined under each of the compounds) (0.55 mmol) and polyphosphoric acid (2.1 g), heated to 150°C for 2 hours. The reaction mixture was poured into water and neutralized with sodium bicarbonate and filtered. Further processing of the filtrate 2M NaOH get more crystals, which are filtered and combined with the first portion followed by washing, drying and recrystallization from ether.

Example 1. 2-(3-(4-n-Butylpiperazine-1-yl)propyl)benzothiazole (5) (34JJ15). 2-Aminobenzoyl used as starting material and the General technique used to obtain pure compound 5 (70 mg, 43%).1H NMR (CDC 3) δ to 0.88 (t, 3H), 1,08 is 1.20 (m, 2H), 1,50 (m, 2H), 1,55-1,70 (m, 7H), 1,72 (square, 2H), 1,73 is 1.75 (m, 2H), 2,35-2,39 (m, 2H), 2,41 (t, 2H), 2,61 (t, 2H), 7,39(dt, 2H), 7,89(DD, 2H).

Example 2. 2-(3-(4-n-Butylpiperazine-1-yl)propyl)benzoxazol (6) (34JJ17). 2-Aminophenol is used as the source material and the General technique used to obtain pure compound 6 (137 mg, 83%).1H NMR (CDCl3) δ to 0.88 (t, 3H), 1.18 to 1.32 to (m, 10H), of 1.65 (d, 2H), 1,95 (t, 2H), 2,12 (square, 2H), 2.49 USD (t, 2H), 2,92-3,00 (m, 3H), 7,28-to 7.32 (m, 2H), 7,45 is 7.50 (m, 1H), of 7.64-to 7.68 (m, 1H).

Example 3. 4,5-Debtor-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol (7) (34JJ21). 3,4-Debtor-1,2-diaminobenzene used as starting material and the General technique used to obtain pure compound 7 (55 mg, 30%).1H NMR (CDCl3) δ of 0.93 (t, 3H), 1.30 and the 1.44 (m, 9H), is 1.82 (d, 2H), 1,98 (square, 2H), 2,09 (t, 2H), 2.63 in (dt, 2H), of 3.07 (d, 2H), 3,14 (dt, 2H), 6,95-7,03 (m, 1H), 7,16-7,21 (m, 1H).

Example 4. 4-Fluoro-5-nitro-2-(3-(4-n-butylpiperazine-1-yl) propyl)-1H-benzoimidazol (8) (34JJ13). 4-Fluoro-5-nitro-1,2-diaminobenzene used as starting material and the General technique used to obtain pure compound 8 (12 mg, 6%).1H NMR (CDCl3) δ of 0.93 (t, 3H), 1.30 and of 1.54 (m, 7H), 1,60 (K., 2H), 1.93 and (d, 2H), 2,22 (square, 2H), 2,42 (t, 2H), 2,82 (t, 2H), 3,24 (t, 2H), and 3.31 (d, 2H), 7,34 (d, 1H), 8,29 (d, 1H).

Example 5. 5-tert-Butyl-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol (9) (23JJ83). 4-tert-Butyl-1,2-diaminobenzene used as starting material and the General technique used is t to obtain pure compound 9 (74 mg, 38%).1H NMR (CDCl3) δ of 0.93 (t, 3H), 1.30 and of 1.42 (m, 18H), is 1.81 (d, 2H), 1,96 (square, 2H), 2,04 (t, 2H), by 2.55 (t, 2H), to 3.02 (d, 2H), of 3.07 (t, 2H), 7,26 (DD, 1H), 7,45 (d, 1H), 7,53 (d, 1H).

Example 6. 5-Chloro-6-methyl-2-(3-(4-n-butylpiperazine-1-yl) propyl)-1H-benzoimidazol (10) (23JJ93). 4-Chloro-5-methyl-1,2-diaminobenzene used as starting material and the General technique used to obtain pure compound 10 (7 mg, 3%).1H NMR (CDCl3) δ to 0.94 (t, 3H), 1.30 and of 1.41 (m, 9H)and 1.83 (d, 2H), 1,95 (square, 2H), 2,08 (t, 2H), 2,46 (s, 3H), 2.57 m (t, 2H), 3.04 from (d, 2H), to 3.09 (t, 2H), 7,32 (s, 1H), 7,50 (s, 1H).

Example 7. 4,6-Debtor-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol (11) (23JJ77). 3,5-Debtor-1,2-diaminobenzene used as starting material and the General technique used to obtain pure compound 11 (50 mg, 27%).1H NMR (CDCl3) δ to 0.92 (t, 3H), 1,22 was 1.43 (m, 7H), and 1.56 (K., 2H), 1,87 (d, 2H), 2,13 (square, 2H), of 2.38 (t, 2H), 2,87 (t, 2H), 3,19 (t, 2H), 2,29 (d, 2H), 6,69 (dt, 1H), 7,02 (DD, 1H).

Example 8. 2-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-imidazo [4,5-c]pyridine (12) (23JJ81). Pyridine-3,4-diamine used as starting material and the General technique used to obtain pure compound 12 (18 mg, 11%).1H NMR (CDCl3) δ to 0.94 (t, 3H), 1.30 and of 1.42 (m, 9H), to 1.87 (d, 2H), 2,01 (square, 2H), 2.13 in (t, 2H), 2,64 (t, 2H), is 3.08 (d, 2H), 3,17 (t, 2H), 7,41 (d, 1H), 8,35 (d, 1H), of 8.90 (s, 1H).

Example 9. 8-(3-(4-n-Butylpiperazine)-1-ylpropyl)-N-purine (13) (34JJ27). Pyrimidine-4,5-diamine used as starting material and the General technique applies the Ute to obtain pure compound 13 (94 mg, 57%).1H NMR (MeOD) δ to 0.92 (t, 3H), 1,29-of 1.39 (m, 6H), 1,43 is 1.60 (m, 3H), 2.00 in (d, 2H), 2,43 (square, 2H), 3.00 for (t, 2H), 3,21-to 3.35 (m, 4H), to 3.64 (d, 2H), 9,25 (s, 1H), 9,38 (s, 1H).

Example 10. 7-(3-(4-n-Butylpiperazine)-1-ylpropyl)-3,8-dihydroimidazo[4',5':3,4]benzo[1,2-d][1,2,3]triazole (14) (34JJ39). 1H-Benzotriazol-4,5-diamine used as starting material and the General technique used to obtain pure compound 14 (24 mg, 13%).1H NMR (DMSO) δ or 0.83 (t, 3H), 1.00 m of 1.28 (m, 9H), 1.57 in (d, 2H), 1,80 (t, 2H), 1,94 (square, 2H), 2,32 (t, 2H), 2,82 (d, 2H), 2,88 (t, 2H), 7,49 (d, 1H), 7.62mm (d, 1H).

Example 11. 2-(3-(4-n-Butylpiperazine)-1-ylpropyl)-3A,4,5,6,7,7a-hexahydro-1H-benzoimidazol (15). Cyclohexane-1,2-diamine used as starting material and the General technique used to obtain pure compound 15 (79 mg, 47%).1H NMR (CDCl3) δ 0,80-of 1.05 (m, 11H), 1,27-of 1.75 (m, 17H), to 2.57 (t, 2H), 2,66 (t, 2H), 3,57 (K., 1H), 4,48 (K., 1H).

A General procedure for obtaining derivatives of substituted indole(16, 17, 18, 19, 20 and 21). 1,3-Dibromopropane (205 μl, 2.0 mmol) in 5 ml of DMF are placed in a 50 ml flask. The corresponding indole (2.0 mmol) and KOH (280 mg, 5.0 mmol) partially dissolved in 5 ml DMF and added dropwise with stirring. The resulting suspension is stirred over night at room temperature. Add 4-butylpiperazine (3) (178 mg, 1.0 mmol) in 5 ml DMF and the mixture is stirred over night at room temperature. Add ethyl acetate (20 ml) and water (20 ml). The phases are separated and the aqueous phase is again the extras is Giroud with ethyl acetate (20 ml). The combined organic phases are washed with saturated salt solution, dried over magnesium sulfate and evaporated to dryness, thus obtaining the crude product. The crude product is purified column chromatography (0-5% methanol:dichloromethane) to obtain the pure products.

Example 12. 1-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-indole (16) (35AKU-15). 1H-Indole used as starting material and the General technique used to obtain pure compound 16 (69 mg, 23%).1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 7H), 1,5 (K., 2H), 1,75 (d, 2H), to 2.1-2.3 (m, 4H), 2,5 (t, 2H), 3,1 (d, 2H), 4,25 (t, 2H), and 6.5 (d, 1H), and 7.1 (m, 2H), 7,2 (t, 1H), 7,35 (d, 1H), and 7.6 (d, 1H).

Example 13. 1-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-benzoimidazol (17) (35AKU-16). 1H-Benzoimidazol used as starting material and the General technique used to obtain pure compound 17 (69 mg, 23%).1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 7H), 1,5 (K., 2H), 1,75 (d, 2H, in), 2.25 (m, 4H), and 2.6 (t, 2H), 3,1 (d, 2H), 4,3 (t, 2H), 7,2-7,3 (m, 2H), 7,45 (d, 1H), of 7.75 (d, 1H), and 8.0 (s, 1H).

Example 14. 3-Methyl-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (18) (35AKU-22). 3-Methyl-1H-indole is used as the source material and the General technique used to obtain pure compound 18.1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 9H), of 1.65 (d, 2H), and 1.9 (t, 2H), 2.0 (m, 2H, in), 2.25 (m, 2H), 2,3 (s, 3H), 2,85 (d, 2H), 4,1 (t, 2H), 6,85 (s, 1H), and 7.1 (t, 1H), 7,2 (t, 1H), 7,55 (d, 1H).

Example 15. 5-Bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (19) (35AKU-23). 5-Bro who-1H-indole is used as the source material and the General technique used to obtain pure compound 19. 1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 9H), of 1.65 (d, 2H), 1,85 (t, 2H), 2.0 (t, 2H), 2,2 (t, 2H), and 2.8 (d, 2H), 4,15 (t, 2H), 6,4 (d, 1H), and 7.1 (d, 1H), 7,25 (m, 2H), of 7.75 (s, 1H).

Example 16. 3-Formyl-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (20) (35AKU-24). 3-Formyl-1H-indole is used as the source material and the General technique used to obtain pure compound 20.1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 9H), 1,7 (d, 2H), 1,95 (t, 2H), 2,1 (m, 2H), 2,3 (t, 2H), 2,9 (d, 2H), 4,3 (t, 2H), 7.3 to 7.5 (m, 3H), 8,3 (m, 1H), 10.0 g (s, 1H).

Example 17. 7-Bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (21) (35AKU-25). 7-Bromo-1H-indole is used as the source material and the General technique used for obtaining pure compounds 21.1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 9H), of 1.65 (d, 2H), and 1.9 (t, 2H), 2.05 is (m, 2H), 2,3 (t, 2H), 2,9 (d, 2H), 4,55 (t, 2H), 6,45 (d, 1H), 6,9 (t, 1H), and 7.1 (d, 1H), 7,35 (d, 1H), 7,55 (d, 1H).

Example 18. 1-(3-Bromopropyl)-1H-indazol (22). 1,3-Dibromopropane (508 μl, 5.0 mmol) dissolved in 10 ml of DMF and placed in a 100 ml flask. Add indazol (592 mg, 5.0 mmol) and KOH (282 mg, 5.0 mmol) and the suspension is stirred over night at room temperature. Add ethyl acetate (50 ml) and water (50 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (50 ml). The combined organic phases are washed with saturated salt solution, dried over magnesium sulfate and evaporated to dryness, thus obtaining 751 mg of yellow oil. The crude product is further purified column chromium is ografia (0-10% methanol:dichloromethane), while receiving a pure compound 22 (169 mg, 14%).

Example 19. 1-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-indazol (23) (35AKU-21). In a 50 ml flask add connection 22 (169 mg, 0.7 mmol) and 10 ml DMF. 4-Butylpiperazine (3) (142 mg, 1.0 mmol) and KOH (113 mg, 2.0 mmol) partially dissolved in DMF (5 ml) and add. The suspension is stirred over night at room temperature. Add ethyl acetate (20 ml) and water (20 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (20 ml). The combined organic phases are washed with saturated salt solution, dried over magnesium sulfate and evaporated to dryness, thus obtaining 192 mg of a light brown oil. The crude product is purified column chromatography (0-10% methanol:dichloromethane)to give the pure product 23 (61 mg, 29%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 9H), of 1.65 (d, 2H), and 1.9 (t, 2H), 2,15 (m, 2H), 2,3 (t, 2H), 2,85 (d, 2H), of 4.45 (t, 2H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (d, 1H), 7.7 (d, 1H), and 8.0 (s, 1H).

Example 20. The oxime 1-(2-hydroxyphenyl)ethanone (24). Chloride of hydroxylamine (of 6.96 g, 100 mmol) and sodium acetate·3H2About (to 13.6 g, 100 mmol) is dissolved in 150 ml of a mixture of ethanol:water (7:3) and added to a solution of 2-hydroxyacetophenone (for 6.81 g, 50 mmol) in 50 ml of a mixture of ethanol:water (7:3). pH adjust up to 4-5 4 n HCl (˜10 ml) and the reaction mixture is then heated at the boil with a reverse cold what linecom (100° C) for 1 hour. The oil bath is removed, and the mixture is left overnight under stirring. Ethanol is partially removed by evaporation, and the aqueous phase extracted with ethyl acetate twice. The combined organic phases are dried over magnesium sulfate and evaporated to dryness obtaining of 7.55 g of pure compound 24.

Example 21. 3 Methylbenzo[d]isoxazol (25). Into the flask to 100 ml with compound 24 (of 7.55 g, 50 mmol) is added acetic anhydride (7,1 ml, 75 mmol). The mixture is heated to 60°C for 3 hours followed by evaporation to dryness. Potassium carbonate (8.7 g, 63 mmol) partially dissolved in 40 ml of DMF and added dropwise to the mixture. The mixture is stirred at room temperature overnight and finally heated to 100°C for 30 minutes. Add ethyl acetate and water. The phases are separated, and the aqueous phase extracted with ethyl acetate and dichloromethane. The combined organic phases are dried over magnesium sulfate and evaporated to dryness, thus obtaining 5.6 g of a yellow oil. The crude product is purified column chromatography (100% dichloromethane)to give the pure compound 25 (4.6 g).1H NMR (CDCl3) δ 2,6 (s, 3H), and 7.3 (m, 1H), 7,55 (m, 2H), 7,65 (m, 1H).

Example 22. 3-but-3-Universo[d]isoxazol (26). Dry THF in the amount of 3.0 ml add dried in a drying Cabinet flask of 25 ml and cooled to -78°C in a bath of dry ice/isopropanol. Add Diisopropylamine (840 μl, 6.0 mmol), then n-Bui (3.8 ml, 1.6 M, 6.0 mmol). The LDA solution, which was obtained, leave at room temperature. Compound 25 (666 mg, 5.0 mmol) dissolved in 10 ml of dry THF and added to the dried in a drying Cabinet flask of 50 ml, then add allylbromide (476 μl, 5.5 mmol). A freshly prepared solution of LDA is added slowly at -78°C and the mixture was incubated at room temperature for 30 minutes Add ethyl acetate and water. The phases are separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and evaporated to dryness, thus obtaining 893 mg of a light brown oil. The crude product is purified column chromatography (heptane:ethyl acetate; 9:1, isocratic), thus obtaining a pure compound 26 (355 mg, 41%).

Example 23. 3-(Benzo[d]isoxazol-3-yl)Propionaldehyde (27). Compound 26 (549 mg, 3.2 mmol), water (5 ml), 1,4-dioxane (15 ml) and osmium tetroxide (15 mg, 0.06 mmol) is stirred for 5 min in a small flask. For 30 min add metaperiodate sodium (1.56 g, 7,3 mmol) and the suspension is then stirred for 1 hour. Add ethyl acetate and water. The phases are separated, and the aqueous phase extracted with ethyl acetate and dichloromethane. The combined organic phases are dried over magnesium sulfate and evaporated to dryness, thus obtaining 784 mg of crude compound 27, which is used directly without further purification in the synthesis of the compound 28.

Example 24. 3-(3-(4-n-Butylpiperazine)-1-ylpropyl)benzo[d]isoxazol (28) (35AKU-2). Compound 27 (˜500 mg, 2.3 mmol) dissolved in 5 ml of methanol. 4-Butylpiperazine·HCl 3 (260 mg, 1.5 mmol) dissolved in 10 ml of methanol and add. Add cyanoborohydride sodium (188 mg, 3.0 mmol) in 10 ml of methanol, thus obtaining a dark brown solution, which is stirred overnight. Add water and methanol is partially removed by evaporation. The aqueous phase is extracted with ethyl acetate and dichloromethane. The combined organic phases are dried over magnesium sulfate and evaporated to dryness. The crude product is further purified preparative HPLC (mobile phase 0-80% acetonitrile in water (0.1% of TFU)), thus obtaining the compound 28 (244 mg, 54%). The HCl salt is obtained from 2 M HCl in diethyl ether. The crystals are filtered and washed with diethyl ether.1H NMR (CDCl3) δ and 0.9 (t, 3H), 1,2-1,3 (m, 9H), of 1.65 (d, 2H), and 1.9 (t, 2H), 2.05 is (m, 2H), of 2.45 (t, 2H), 2,9 (d, 2H), 3,0 (t, 2H), and 7.3 (m, 1H), 7,55 (m, 2H), 7.7 (d, 1H).

Example 25. 3-(1H-Indol-3-yl)propan-1-ol (29). Suspension of sociallyengaged (4.68 g, 126 mmol) in 230 ml of anhydrous diethyl ether intensively stirred. 3-Indolepropionic acid (10.0 g, 53 mmol), dissolved in 460 ml of anhydrous diethyl ether, transferred to the addition funnel and added dropwise at such a rate to maintain a low boil under reflux. The reaction mixture is left for paramesh the cation at a temperature of phlegmy within 2 hours, then at room temperature overnight. Then boiling under reflux continued for 2 hours before cooling to room temperature. Slowly add 25 ml of N2Oh, then 70 ml of N2O/H2SO4(1:3 H2A:H2SO4). The resulting clear mixture is extracted with 110 ml of diethyl ether three times. The combined organic phases are washed with saturated salt solution, dried with Na2SO4, filtered and concentrated to a light oil which is used without further purification.

Example 26. 3-(1H-Indol-3-yl)propyl ether methanesulfonate acid (30). Compound 29 (1.8 g, 5,44 mmol) is transferred into in a flame dried flask with argon and dissolved in anhydrous THF, then cooled to -40°C. Syringe add triethylamine (0,72 g, 7,07 mmol), then MeSO2Cl (0.75 g, 6,53 mmol). The reaction mixture is left to raise the temperature to room temperature (10-15 minutes) before it quickly filtered and concentrated. The crude oil was dissolved in CH2Cl2and washed with N2O. the Organic phase is dried MgSO4, filtered and concentrated in vacuo to a dark brown oil. The crude product was used immediately in the next stage.

Example 27. 3-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-indole (31) (39MF34). Na2CO3(1.28 g, of $ 11.97 mmol) are added to a solution hydrochlor is Yes 4-butylpiperazine 3 (967 mg, 5,44 mmol) in anhydrous DME. The resulting suspension is stirred for 30 minutes, the Connection 30 is dissolved in anhydrous DME and added to the suspension. The resulting mixture is stirred in an argon atmosphere at 82°With during the night. The mixture is cooled, add EtOAc and H2Oh, divided in two phases, and the water extracted with EtOAc three times. The combined organic phases are washed with saturated salt solution, dried with Na2SO4, filtered and concentrated in vacuo. The crude oil was dissolved in anhydrous CH2Cl2and add HCl in dioxane (4M, 2 ml). The product (31) was isolated as white crystals by recrystallization from a mixture of Meon/diethyl ether.1H NMR (CDCl3) δ of 0.93 (t, 3H), 1,32 is 1.58 (m, 7H), 1,60 (K., 2H), 1.93 and (d, 2H), 2,22 (square, 2H), 2,42 (t, 2H), 2,82 (t, 2H), 3,24 (t, 2H), and 3.31 (d, 2H), 6,91-7,10 (m, 2H), 7,34 (d, 1H), 7,53 (d, 1H).

Example 28. 4-Nitro-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol (32) (29MF03). In the flask of 25 ml, equipped with a fridge and a magnetic stir bar, loads of 1,2-diamino-3-nitrobenzene (0,251 g of 1.64 mmol) and methyl ester of 4-(4-n-butylpiperazine-1-yl)butyric acid (4) (0,395 g of 1.64 mmol) in 5 ml of 4M HCl. The reaction mixture is refluxed for 24 hours followed by addition of 2.0 M NaOH to create the basic conditions, is stirred at room temperature for 1 hour and extracted with ethyl acetate (5×50 ml). The combined organic phase is raybaut 15 ml of saturated salt solution, then dried over MgSO4and evaporated to dryness, thus obtaining 0.45 g of crude product. The crude material is subjected to column chromatography (eluent: CH2Cl2:Meon (20:1)), thus obtaining the net specified in the title compound (32) (0.03 g, 5%).1H NMR (CDCl3) δ to 0.92 (t, 3H), 1,25-of 1.42 (m, 9H), 1,55-of 1.64 (m, 2H), 1,75-to 1.82 (m, 2H), 2,10-of 2.23 (m, 2H), 2,24-2,31 (m, 2H), 2,67-2,77 (m, 2H), 3,17-up 3.22 (m, 4H), 7,25-7,35 (m, 1H), 7,97-of 8.04 (m, 1H), 8,08-8,13 (m, 1H).

Example 29. 5-Nitro-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol (33) (29MF04). In the flask of 25 ml, equipped with a fridge and a magnetic stir bar, loads of 1,2-diamino-4-nitrobenzene (0,259 g, was 1.69 mmol) and methyl ester of 4-(4-n-butylpiperazine-1-yl)butyric acid (4) (0,408 g, was 1.69 mmol) in 5 ml of 4M HCl. The reaction mixture is refluxed for 24 hours followed by addition of 2.0 M NaOH to create the basic conditions, and then stirred at room temperature for 1 hour and extracted with ethyl acetate (5×50 ml). The combined organic phases are washed with 15 ml of saturated salt solution, then dried over MgSO4and evaporated to dryness, thus obtaining 0.27 g of crude material. The crude material is subjected to column chromatography (eluent: CH2Cl2:Meon (20:1)), thus obtaining the target compound (122 mg). This material is isolated and dissolved in 2.0 M HCl solution in ether, followed by evaporation to dryness, thus obtaining h the hundred, specified in the connection header (33) (80 mg, 10%).1H NMR (CD3OD) to 0.92 (t, 3H), of 1.34 (m, 6H), of 1.55 (m, 3H), 2.00 in (d, 2H), 2,45 (m, 2H), 3,01 (t, 2H), 3,29-3,37 (dt, 4H), to 3.64 (d, 2H), 7,94 (d, 1H), 8,43 (DD, 1H), 8,65 (d, 1H).

Example 30. 4-Hydroxy-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol (34) (29MF07). In the flask of 25 ml, equipped with a fridge and a magnetic stir bar, loads of 1,2-diamino-4-hydroxybenzo (0,177 g of 1.43 mmol) and methyl ester of 4-(4-n-butylpiperazine-1-yl)butyric acid (4) (0,345 g of 1.43 mmol) in 5 ml of 4 M HCl. The reaction mixture was refluxed for 20 h, followed by addition of 2.0 M NaOH to create the basic conditions. The mixture is evaporated to dryness in 10 ml of silicon dioxide and subjected to column chromatography (eluent: CH2Cl2:Meon (20:1), thus obtaining the crude product (0,145 g). The crude product is subjected to preparative HPLC (eluent: buffer A: 0.1% OF TFU; buffer B:80% CH3CN+0.1% of TFU) and the isolated product evaporated with 1.0 M TFU in the ether, thus obtaining the net specified in the title compound 34 (74 mg, 16%) as a salt triperoxonane acid.1H NMR (CD3OD) and 0.98 (t, 3H), 1.32 to the 1.45 (m, 6H), 1,51 was 1.69 (m, 3H), 1,97-2,08 (d, 2H), 2,37-2,47 (m, 2H), 2.95 and-of 3.12 (m, 2H), 3,26-to 3.41 (m, 4H), to 3.58-and 3.72 (m, 2H), 6,91-6,97 (d, 1H), 7,19-of 7.25 (d, 1H), 7,35-the 7.43 (t, 1H).

Example 31. 2-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-benzoimidazol (35) (21MF25). In the flask of 25 ml, equipped with a fridge and a magnetic stirrer, load 1,2-diaminobenzene (0,201 g of 18.6 mmol who) and the methyl ester of 4-(4-n-butylpiperazine-1-yl)butyric acid (4) (0.50 g, 2.1 mmol) in 6 ml of 4 M HCl. The reaction mixture was refluxed for 20 h, followed by addition of 2.0 M NaOH to create the basic conditions. The precipitate is filtered off and dried in vacuum with subsequent column chromatography (eluent: CH2Cl2:Meon (10:1)), thus obtaining the net specified in the title compound 35 (0.40 g, 73%). TPL 78-79°C.1H NMR (CDCl3) to 0.92 (t, 3H), of 1.33 (m, 6H), 1,50 (m, 3H), 1,80-of 1.95 (m, 2H), 2,02-of 2.15 (m, 2H), 2,16-of 2.24 (m, 2H), 2,62 is 2.75 (m, 2H), 3,17-is 3.21 (m, 4H), 7,20-of 7.23 (m, 2H), 7,52-to 7.59 (m, 2H).

Example 32. 4-Methyl-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol (36) (29MF08). In the flask of 25 ml, equipped with a fridge and a magnetic stir bar, loads of 1,2-diamino-3-methylbenzo (has 0.168 g, 1.37 mmol) and methyl ester of 4-(4-n-butylpiperazine-1-yl)butyric acid (4) (0,331 g, 1.37 mmol) in 5 ml of 4 M HCl. The reaction mixture is refluxed for 48 hours followed by addition of 4.0 M NaOH. The reaction mixture was extracted with dichloromethane (4×25 ml). The combined organic phases are dried over MgSO4and evaporated, thus obtaining 0.40 g of crude product. The crude material is subjected to column chromatography (eluent: CH2Cl2:Meon (20:1) and the isolated product evaporated to dryness with 1.0 M HCl in ether, thus obtaining the net specified in the title compound 36 (0,210 g, 44%).1H NMR (CD3OD) to 0.92 (t, 3H), of 1.33 (m, 6H), and 1.54 (m, 3H), 1,99 (d, 2H), 2,43 (m, 2H), 2,65 (m, 2H), 3.00 m, 2H), or 3.28 (m, 2H), 3,63 (m, 2H), 7,38 (d, 1H), 7,47 (t, 1H), to 7.59 (d, 1H).

Example 33. 3-(2-(4-n-Butylpiperazine)-1-retil)-1H-indole (37). In the flask of 25 ml, equipped with a magnetic stirrer, download hydrochloride 4-n-butylpiperazine 3 (0,256 g, 1.4 mmol) and potassium carbonate (0.5 g, 3.6 mmol) in dioxane (5 ml). The mixture is stirred at room temperature for 2 hours followed by addition of 3-(2-bromacil)indole (0,30 g, 1.3 mmol)dissolved in dioxane (5 ml). The mixture was then stirred at 50°C for 24 hours. Add water (15 ml) followed by extraction with ethyl acetate (3×50 ml). The combined organic phases are dried over MgSO4and evaporated, thus obtaining 1,02 g crude product. The crude product subjected to column chromatography (eluent: CH2Cl2:Meon (20:1)), thus obtaining the net specified in the title compound 37 (0.08 g, 21%).1H NMR (CDCl3) of 0.90 (t, 3H), 1,25-for 1.49 (m, 9H), 1,72-to 1.79 (m, 2H), 2,77 (t, 2H), 3,06 (t, 2H), and 3.16 (d, 2H), 7,03 (s, 1H), 7,11 (t, 1H), 7,19 (t, 1H), was 7.36 (d, 1H), to 7.61 (d, 1H), 8,09-is 8.16 (s, 1H).

Example 34. tert-Butyl ether (2-(4-chlorobutane-1-one)phenyl) carbamino acid (38). In a dry 100 ml odnogolosy flask equipped with a fridge, a magnetic stirrer and an introduction hole for argon, add 4-chlorbutanol (624 mg, 44 mmol) and bis(acetonitrile)dichloropalladium (34 mg) in 10 ml dry toluene. To the mixture of tert-butyl methyl ether (2-trimethylsilylethynyl)carbamino acid (1.5 g, 2 mmol) (Bioorg. Med. Chem., 6:811 (1998)), dissolved in 15 ml of dry toluene. The mixture was then refluxed for 1 hour and then stirred at room temperature for 17 hours. The reaction mixture is evaporated to dryness, giving the crude product (1.6 g), which is subjected to column chromatography (eluent:heptane:EtOAc, 10:1), thus obtaining the net specified in the title compound 38 (1,15 g, 92%).1H NMR (CDCl3) 1,52 (t, 9H), 2,22 (m, 2H), up 3.22 (t, 2H), 3,68 (t, 2H), 7,03 (t, 1H), 7,51 (t, 1H), to $ 7.91 (d, 1H), 8,48 (d, 1H), 10,90 (s, 1H).

Example 35. Tert-Butyl ether (2-(3-(4-n-butylpiperazine)-1-ylpropyl)phenyl)carbamino acid (39). In a dry flask 5 ml, equipped with a magnetic stirrer and input for argon, add 38 (0.5 g, 1.7 mmol) and 4-n-butylpiperazine 3 (1.5 g, 10.6 mmol) and left stirring at 60°C for 70 hours. The crude reaction mixture was subjected to column chromatography (eluent: CH2Cl2:Meon, 20:1), thus obtaining a pure compound 39 (0,49 g, 72%).1H NMR (CDCl3) of 0.87 (t, 3H), 1.18 to of 1.27 (m, 9H), of 1.52 (s, 9H), of 1.64 (m, 2H), was 1.94 (m, 4H), to 2.41 (t, 2H), 2.91 in (d, 2H), 3,03 (t, 2H), 7,00, (t, 1H), 7,49 (t, 1H), to $ 7.91 (d, 1H), 8,46 (d, 1H), 10,97 (s, 1H).

Example 36. 3-(3-(4-n-Butylpiperazine)-1-ylpropyl)-1H-indazol (40) (39MF34). Compound 39 (0.06 g, 0.15 mmol)dissolved in 2 ml of 4.0m HCl in dioxane, add 5 ml flask and stirred at room temperature for 1 hour. The mixture is evaporated to dryness and then dissolved in 1 ml of Koh is enteromonas HCl and regulate the temperature to 0° C using a bath of ice/water. To the cooled mixture is added sodium nitrite (0,010 g, 0.15 mmol)dissolved in 2 ml of water, and the reaction mixture was kept at 0°C for 1.5 hours followed by the addition of tin dichloride (0.08 g, 0.36 mmol)dissolved in 2 ml of concentrated HCl. After incubation for 1.5 hours at 0°C crystals are formed. The crystals are filtered and washed with water, thus obtaining the crude product (0.07 g). The crude product subjected to column chromatography (eluent: CH2Cl2:Meon, 20:1), thus obtaining a pure compound 40 (9.0 mg, 20%).1H NMR (CDCl3) to 0.88 (t, 3H), 1,19-of 1.33 (m, 9H), 1,67 (d, 2H), 1,95 (t, 2H), 2,08 (m, 2H), 2,50 (t, 2H), 2,93-3,20 (m, 4H), 7,12 (t, 1H), was 7.36 (t, 1H), 7,43 (d, 1H), 7,71 (d, 1H), 9,87 of 10.05 (s, 1H).

Example 37. 3-(2-Chloroethoxy)-7-methylbenzo[d]isoxazol (41). 1-Bromo-2-chlorate (168 μl, 2.0 mmol) are added to 5 ml of DMF in a 50 ml flask. Add 7-methylbenzo[d]isoxazol-3-ol (298 mg, 2.0 mmol), potassium carbonate (276 mg, 2.0 mmol) and additional DMF (5 ml) and the mixture is stirred for 12 hours. Add ethyl acetate (50 ml) and N2About (50 ml). The two phases are separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are washed with saturated salt solution, dried over MgSO4and evaporated to dryness, thus obtaining 420 mg of crude product. The crude product subjected to column chromatography (0-5% methanol in dichloromethane) to give the pure, pointed to by the th in the title compound 41 (290 mg, 70%).1H NMR (CDCl3) to 2.5 (s, 3H), at 3.9 (t, 2H), 4,7 (t, 2H), 7,2 (t, 1H), and 7.3 (d, 1H), 7.5 (d, 2H).

Example 38. 3-(2-(4-n-Butylpiperazine)ethoxy)-7-methylbenzo[d]isoxazol (42) (35AKU-41). Compound 41 (294 mg, 1.4 mmol) dissolved in DMF (5 ml) in a 50 ml flask, followed by addition of a mixture of 4-n-butylpiperazine (284 mg; 1.6 mmol) and potassium carbonate (442 mg; 3.2 mmol)dissolved in DMF (15 ml). The mixture is stirred for 2 days at 80°C. Add ethyl acetate (50 ml) and N2About (50 ml), the phases are separated and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and evaporated to dryness to obtain the crude product (454 mg). The crude product subjected to column chromatography (0-5% methanol in dichloromethane)to give the pure indicated in the title compound 42 (131 mg, 30%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CDCl3) of 0.9 (t, 3H), 1,2-1,3 (m, 9H), 1,7 (d, 2H), 2,1 (t, 2H), and 2.5 (s, 3H), 2,9 (t, 2H), 3.0 (d, 2H), 4,6 (t, 2H), 7,15 (t, 1H), and 7.3 (d, 1H), 7,45 (d, 1H).

Example 39. 1-(3-(4-Methylpiperidin)-1-ylpropyl)-1H-indazol (43) (46RO13.48). Hard To2CO3(70 mg, 0.5 mmol) are added to a mixture of 7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (96 mg, 0.4 mmol) and 4-methylpiperidine (30 mg, 0.3 mmol) in CH3CN (2 ml). The resulting suspension is stirred at 50°C for 48 hours and then ohlord the Ute to the ambient temperature. The slurry is then poured into water (10 ml) and treated as follows: extracted with ethyl acetate (3×10 ml), washed collected organic phase successively with water (3×5 ml) and saturated salt solution, followed by drying over MgSO4and removal of solvent by rotary evaporation. The residue is purified on an ISOLUTE SCX, while receiving the connection 43 (25 mg, 24%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CD3OD) δ and 0.9 (t, 3H), 1,2 (m, 2H), 1,6 (m, 1H), 1.8 m (d, 2H), 2,15 (m, 2H), 2,8 (m, 2H), 3.0 a (m, 2H), 3,4 (m, 2H), of 4.45 (t, 2H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 8.0 a (, 1H).

Example 40. 1-(3-(4-Pentylpyridine)-1-ylpropyl)-1H-indazole (44) (46RO13.57). Hard To2CO3(35 mg, 0.25 mmol) are added to a mixture of 7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (48 mg, 0.4 mmol) and 4-pentylpyridine (23 mg, 0.15 mmol) in CH3CN (2 ml). The resulting suspension is stirred at 50°C for 48 hours and then cooled to ambient temperature. The slurry is then poured into water (10 ml) and treated as follows: extracted with ethyl acetate (3×10 ml), washed collected organic phase successively with water (3×5 ml) and saturated salt solution, followed by drying over MgSO4and removal of solvent by rotary evaporation. The residue is purified on an ISOLUTE SCX, while receiving the connection 44 (25 mg, 40%). Oksala the percent salt derived from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether. 1H NMR (CD3OD) δ and 0.9 (t, 3H), 1,2 (m, 12H), 1,6 (m, 1H), 1.8 m (d, 2H), 2,15 (m, 2H), 2,8 (m, 2H), 3.0 a (m, 2H), 3,4 (m, 2H), of 4.45 (t, 2H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 8.0 a (, 1H).

Example 41. 1-(3-(4-Propylpiperidine)-1-ylpropyl)-1H-indazol (45) (46RO13.55LH). Hard To2CO3(35 mg, 0.25 mmol) are added to a mixture of 7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (48 mg, 0.2 mmol) and 4-propylpiperidine (19 mg, 0.15 mmol) in CH3CN (2 ml). The resulting suspension is stirred at 50°C for 48 hours and then cooled to ambient temperature. The slurry is then poured into water (10 ml) and treated as follows: extracted with ethyl acetate (3×10 ml), washed collected organic phase successively with water (3×5 ml) and saturated salt solution, followed by drying over MgSO4and removal of solvent by rotary evaporation. The residue is purified on an ISOLUTE SCX, while receiving specified in the title compound 45 (16 mg, 28%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CD3OD) δ and 0.9 (t, 3H), 1,2 (m, 6H), 1,6 (m, 1H), 1.8 m (d, 2H), 2,15 (m, 2H), 2,8 (m, 2H), 3.0 a (m, 2H), 3,4 (m, 2H), of 4.45 (t, 2H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 8.0 a (, 1H).

Example 42. 1-(3-(4-(3-Methylbutyl)piperidine)-1-ylpropyl)-1H-indazol (46) (46RO13.58). Hard To2CO3(35 mg, 0.25 mmol) are added to a mixture of 7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (48 mg, 0.2 mmol) and 4-(3-methylb the Teal) piperidine (23 mg, 0.15 mmol) in CH3CN (2 ml). The resulting suspension is stirred at 50°C for 48 hours and then cooled to ambient temperature. The slurry is then poured into water (10 ml) and treated as follows: extracted with ethyl acetate (3×10 ml), washed collected organic phase successively with water (3×5 ml) and saturated salt solution, followed by drying over MgSO4and removal of solvent by rotary evaporation. The residue is purified on an ISOLUTE SCX, while receiving specified in the title compound 46 (18 mg, 30%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CD3OD) δ and 0.9 (t, 6H), 1.2 to 1.5 (m, 8H), 1.8 m (d, 2H), 2,15 (m, 2H), 2,8 (m, 2H), 3.0 a (m, 2H), 3,4 (m, 2H), of 4.45 (t, 2H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (d, 1H), 7.7 (d, 1H), and 8.0 (s, 1H).

Example 43. 1-(3-(4-Interidentified)-1-ylpropyl)-1H-indazol (47) (46RO13.46). Hard To2CO3(35 mg, 0.25 mmol) are added to a mixture of 7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (48 mg, 0.2 mmol) and 4-inteligentaindigena (23 mg, 0.15 mmol) in CH3CN (2 ml). The resulting suspension is stirred at 50°C for 48 hours and then cooled to ambient temperature. The suspension is poured into water (10 ml) and treated as follows: extracted with ethyl acetate (3×10 ml), washed collected organic phase successively with water (3×5 ml) and saturated of rest the rum salt, followed by drying over MgSO 4and removal of solvent by rotary evaporation. The residue is purified on an ISOLUTE SCX, while receiving specified in the title compound 47 (3 mg, 5%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CD3OD) δ and 0.9 (t, 3H)and 1.3 (m, 4H), 2.0 (m, 2H), 2,3 (m, 3H), 2,35 (d, 2H), and 2.7 (m, 2H), 3,1 (m, 3H), 3,4 (m, 2H), of 4.45 (t, 2H), 5,3 (m, 1H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (d, 1H), 7.7 (d, 1H), and 8.0 (s, 1H).

Example 44. 1-(3-(4-Propylenpipeline)-1-ylpropyl)-1H-indazol (48) (46RO13.45). Hard To2CO3(35 mg, 0.25 mmol) are added to a mixture of 7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole (48 mg, 0.2 mmol) and 4-propylenpipeline (18 mg, 0.15 mmol) in CH3CN (2 ml). The resulting suspension is stirred at 50°C for 48 hours and then cooled to ambient temperature. The slurry is then poured into water (10 ml) and treated as follows: extracted with ethyl acetate (3×10 ml), washed collected organic phase successively with water (3×5 ml) and saturated salt solution, followed by drying over MgSO4and removal of solvent by rotary evaporation. The residue is purified on an ISOLUTE SCX, while receiving specified in the title compound 48 (10 mg, 25%). Oxalate salt obtained from oxalic acid (1.1 EQ.) in a mixture of methanol/diethyl ether.1H NMR (CD3OD) δ and 0.9 (t, 3H), 2.0 (t, 2H), 2,4 (m, 6H), 3,1 (m, 4H), 3,4 (m, 2H), of 4.45 (t, 2H), to 5.35 (t, 1H), and 7.1 (t, 1H), 7,35 (m, 1H), 7.5 (a is, 1H), 7.7 (d, 1H), and 8.0 (s, 1H).

Example 45. 1-Benzo[b]thiophene-2-yl-4-(4-butylpiperazine-1-yl) butane-1-he (49) (45NK99/oxalate). n-BuLi in heptane (of 0.77 ml, 1.0 mmol, 1.3 M) is added dropwise to a benzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at -78°C in argon atmosphere. The reaction mixture was stirred at -78°C for 15 min, then add 4-(4-butylpiperazine-1-yl)-N-methoxy-N-methylbutyrate (135 mg, 0.5 mmol) in THF (1 ml). The reaction mixture was stirred at -78°C for 30 min, then add the NH4Cl (feast upon., aq., 1 ml) and the reaction mixture is heated to room temperature. The product is extracted with ethyl acetate (2×20 ml) and the organic layer washed with water (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-25% ethyl acetate in heptane + 0,1% Et3N) Yield 94 mg (55%). Oxalate salt is produced by adding oxalic acid in a mixture of diethyl ether:methanol (10:1), thus obtaining a white precipitate, which is filtered off and dried.1H NMR (DMSO): δ of 0.91 (t, 3H), 1,24-of 1.56 (m, 9H), 1,87 (shirt, 2H), 2,08 (m, 2H), 2,93 (m, 2H), 3,14 (m, 2H), 3,24 (m, 2H), 3,47 (m, 2H), 7,46-to 7.59 (m, 2H), with 8.05 (m, 2H), at 8.36 (s, 1H).

Example 46. 4-(4-Butylpiperazine-1-yl)-1-(3-methylbenzofuran-2-yl)butane-1-on (50) (45NK100/oxalate). n-BuLi in heptane of 0.85 ml, 1.1 mmol, 1.3 M) is added dropwise to 3-methylbenzofuran (132 mg, 1.0 mmol) in THF (4 ml) at -78°C in argon atmosphere. The reaction mixture per mesilat at -78° C for 20 min, then add 4-(4-butylpiperazine-1-yl)-N-methoxy-N-methylbutyrate (135 mg, 0.5 mmol) in THF (1 ml). The reaction mixture was stirred at -78°C for 45 min, then add the NH4Cl (feast upon., aq., 1 ml) and the reaction mixture is heated to room temperature. The product is extracted with ethyl acetate (2×20 ml) and the organic layer washed with water (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-20% ethyl acetate in heptane + 0,1% Et3N). Yield 38 mg (22%). Oxalate salt is produced by adding oxalic acid in a mixture of diethyl ether:methanol (10:1), thus obtaining a white precipitate, which is filtered off and dried.1H NMR (CD3OD): δ of 0.91 (t, 3H), 1,32 (m, 6H), 1,42-of 1.64 (m, 3H), 1,89 (shirt, 2H), 2,15 (TT, 2H), 2,58 (s, 3H) 2,96 (m, 2H), 3,17 (m, 4H), of 3.60 (m, 2H), 7,33 (m, 1H), 7,52 (m, 2H), 7,71 (m, 1H).

Example 47. 4-(4-Butylpiperazine-1-yl)-1-(5-fluoro-3-methylbenzo[b] thiophene-2-yl)butane-1-he (51) (45NK105). n-BuLi in heptane (0,50 ml, 0.8 mmol, 1.6 m) is added dropwise to 5-fluoro-3-methylbenzo[b]thiophene (166 mg, 1.0 mmol) in THF (4 ml) at -40°C in argon atmosphere. The reaction mixture was stirred at -40°C for 40 min, then add 4-(4-butylpiperazine-1-yl)-N-methoxy-N-methylbutyrate (135 mg, 0.5 mmol) in THF (1 ml). The reaction mixture was stirred at -40°C for 30 min, then add the NH4Cl (feast upon., aq., 1 ml) and the reaction is mesh warmed to room temperature. The product is extracted with ethyl acetate (2×20 ml) and the organic layer washed with water (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified on Isco CombiFlash Sq 16x (column with 4.1 g of silica, elution with heptane (5 min), 0-15% ethyl acetate in heptane (20 min), 15% ethyl acetate in heptane (15 min), all solvents + 0,1% Et3N). Yield 39 mg (21%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4M in dioxane) and recrystallized from methanol-diethyl ether, thus obtaining a white precipitate, which is filtered off and dried.1H NMR (free base CDCl3): δ of 0.87 (t, 3H), 1,10-of 1.35 (m, 9H), 1,62 (shirt, 2H), 1,96 (m, 4H), 2,42 (t, 2H), 2,71 (s, 3H), of 2.93 (m, 4H), 7,34 (dt, 1H), 7,49 (DD, 1H), 7,76 (DD, 1H).

Example 48. 1-Benzofuran-2-yl-4-(4-butylpiperazine-1-yl)butane-1-he (52) (45NK106). n-BuLi in heptane (0,50 ml, 0.8 mmol, 1.6 m) is added dropwise to benzofuran (118 mg, 1.0 mmol) in THF (4 ml) at -40°C in argon atmosphere. The reaction mixture was stirred at -40°C for 40 min, then add 4-(4-butylpiperazine-1-yl)-N-methoxy-N-methylbutyrate (135 mg, 0.5 mmol) in THF (1 ml). The reaction mixture was stirred at -40°C for 30 min, then add the NH4Cl (feast upon., aq., 1 ml) and the reaction mixture is heated to room temperature. The product is extracted with ethyl acetate (2×20 ml) and the organic layer washed with water (10 ml), dried (K2CO33N). Yield 61 mg (50%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4M in dioxane) and recrystallized from methanol-diethyl ether, thus obtaining a white precipitate, which is filtered off and dried.1H NMR (free base CDCl3): δ of 0.87 (t, 3H), 1,10-1,30 (m, 9H), 1,59 (shirt, 2H), 1.93 and (m, 2H), 1,99 (TT, 2H), 2.40 a (t, 2H), 2,87 (m, 2H), 2,96 (t, 2H), 7,30 (m, 1H), 7,45 (m, 1H), of 7.48 (m, 1H), EUR 7.57 (m, 1H), 7,69 (m, 1H).

Example 49. 1-(3-Bromobenzo[b]thiophene-2-yl)-4-(4-butylpiperazine-1-yl)butane-1-on (53) (45NK108). n-BuLi in pentane (of 0.48 ml, 0.8 mmol, 1,7M) is added dropwise to 3-bromobenzo[b]thiophene (213 mg, 1.0 mmol) in THF (4 ml) at -78°C in argon atmosphere. The reaction mixture was stirred at -78°C for 40 min, then add 4-(4-butylpiperazine-1-yl)-N-methoxy-N-methylbutyrate (135 mg, 0.5 mmol) in THF (1 ml). The reaction mixture was stirred at -78°C for 30 min, then add the NH4Cl (feast upon., aq., 1 ml) and the reaction mixture is heated to room temperature. The product is extracted with ethyl acetate (2×20 ml) and the organic layer washed with water (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified on Isco CombiFlash Sq 16x (number of the NCA with 4.1 g of silicon dioxide, elution with heptane (5 min), 0-15% ethyl acetate in heptane (20 min), 15% ethyl acetate in heptane (15 min), all solvents + 0,1% Et3N). Yield 18 mg (4%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4 M in dioxane) and recrystallized from methanol-diethyl ether, thus obtaining a white precipitate, which is filtered off and dried.1H NMR (free base CDCl3): δ to 0.88 (t, 3H), 1,12-of 1.28 (m, 9H), 1,62 (shirt, 2H), was 1.94 (m, 2H), 2,02 (TT, 2H), of 2.45 (t, 2H), 2,92 (shirt, 2H), 3,18 (t, 2H), 7,51 (m, 2H), 7,83 (m, 1H), 7,98 (m, 1H).

Example 50. 1-(3-Benzo[b]thiophene-2-ylpropyl)-4-butylpiperazine (54) (45NK124). N-BuLi in heptane (0.75 ml, 1.2 mmol, 1.6 M) is added dropwise to a benzo[b]thiophene (134 mg, 1.0 mmol) in THF (4 ml) at -5°C in argon atmosphere. The reaction mixture is stirred at -5°C for 15 min, then was added 1-chloro-3-iodopropane (151 μl, 1.2 mmol) and copper iodide (I) (19 mg, 0.1 mmol). The reaction mixture is stirred at -5°C for 1 hour, then at room temperature for 0.5 hours. Add water (5 ml), the product extracted with diethyl ether (2×10 ml) and the organic layer dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-2% ethyl acetate in heptane), thus obtaining 2-(3-chloropropyl)benzo[b]thiophene (93 mg, 44%).1H NMR (CDCl3): δ 2,22 (TT, 2H), 3,10 (dt, 2H), 3,61 (t, 2H), 7,06 (m, 1H), 7,30 (m, 2H), 7,69 (m, 1H), 7,78 (m, 1H).

2-(3-Chlorpro who yl)benzo[b]thiophene (53 mg, 0.25 mmol), 4-butylpiperazine (36 mg, 0.25 mmol), sodium iodide (75 mg, 0.5 mmol) and sodium carbonate (53 mg, 0.5 mmol) in acetonitrile (2 ml) is shaken at 80°C for 18 h, then the reaction mixture is cooled to room temperature. Add water (5 ml) and the product extracted with ethyl acetate (2×10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-15% ethyl acetate in heptane + 0,1% Et3N), while receiving specified in the header of the connection 54. Yield 29 mg (37%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4M in dioxane) and recrystallized from methanol-diethyl ether to obtain a white precipitate, which is filtered off and dried.1H NMR (CD3OD): δ of 0.91 (t, 3H), 1,32 (m, 6H), 1.39 in (m, 2H), 1.55V (m, 1H), 1,96 (shirt, 2H), 2,19 (TT, 2H), 2,93 (m, 2H), 3.04 from (t, 2H), 3,14 (m, 2H), 3,53 (m, 2H), 7,14 (Sirs, 1H), 7,26 (m, 1H), 7,31 (m, 1H), 7,68 (m, 1H), to 7.77 (m, 1H).

Example 51. 1-(3-Benzofuran-2-ylpropyl)-4-butylpiperazine (55) (56NK03). n-BuLi in heptane (1.5 ml, 2.4 mmol, 1.6 m) is added dropwise to benzofuran (236 mg, 2.0 mmol) in THF (5 ml) at -20°C in argon atmosphere. The reaction mixture is stirred at -15°C for 30 min, then was added 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper iodide (I) (38 mg, 0.2 mmol). The reaction mixture is stirred at -15°C for 1 hour, then add the NH4Cl (feast upon. aq., 5 ml). The product is extracted with diatrofi the ether (2× 30 ml) and the organic layer was washed with saturated salt solution (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-1% diethyl ether in heptane), thus obtaining 2-(3-chlorpropyl)benzofuran (101 mg, 26%).1H NMR (CDCl3): δ 2,23 (TT, 2H), 2,97 (dt, 2H), 3,62 (t, 2H), 6,45 (K., 1H), 7,21 (m, 2H), 7,42 (m, 1H), 7,50 (m, 1H).

2-(3-Chlorpropyl)benzofuran (101 mg, 0.52 mmol), 4-butylpiperazine (74 mg, 0.52 mmol), sodium iodide (156 mg, 1.04 mmol) and sodium carbonate (110 mg, 1.04 mmol) in acetonitrile (2 ml) is shaken at 80°C for 18 h, then the reaction mixture is cooled to room temperature. Add water (1 ml), the product extracted with ethyl acetate (2×2 ml) and the organic layer is loaded into the ion exchange column Varian SCX. The column is washed with methanol (2 column volume) and the product to elute from the column using 10% ammonium hydroxide in methanol (2 column volume). The sorbate was concentrated in vacuo, dissolved in acetone, dried (K2CO3) and concentrated in vacuo. The product was then purified column chromatography (0-12% ethyl acetate in heptane + 0,1% Et3N), while receiving specified in the header of the connection 55. Yield 86 mg (55%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4M in dioxane) and recrystallized from methanol-diethyl ether to obtain white flake solid, it is which is filtered off and dried. 1H NMR (CD3OD): δ of 0.90 (t, 3H), of 1.30 (m, 6H), to 1.48 (m, 3H), 1,95 (shirt, 2H), of 2.21 (m, 4H), 2.91 in (m, 4H), and 3.16 (m, 2H), 3,55 (shirt, 2H), to 6.57 (s, 1H), 7,17 (m, 2H), 7,38 (m, 2H), of 7.48 (m, 1H).

Example 52. 4-Butyl-1-[3-(3-methylbenzofuran-2-ylpropyl] piperidine (56) (56NK04). n-BuLi in heptane (1.5 ml, 2.4 mmol, 1.6 m) is added dropwise to 3-methylbenzofuran (264 mg, 2.0 mmol) in THF (5 ml) at -20°C in argon atmosphere. The reaction mixture is stirred at -15°C for 30 min, then was added 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper iodide (I) (38 mg, 0.2 mmol). The reaction mixture is stirred at -15°C for 1 hour, then add the NH4Cl (feast upon. aq., 5 ml). The product is extracted with diethyl ether (2×30 ml) and the organic layer was washed with saturated salt solution (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-1% diethyl ether in heptane), thus obtaining 2-(3-chlorpropyl)-3-methylbenzofuran (25 mg, 6%).1H NMR (CDCl3): δ: 2,19 (TT, 2H), 2,22 (s, 3H), equal to 2.94 (t, 2H), only 3.57 (t, 2H), 7,22 (m, 2H), 7,38 (m, 1H), 7,44 (m, 1H).

2-(3-Chlorpropyl)-3-methylbenzofuran (25 mg, 0.12 mmol), 4-butylpiperazine (17 mg, 0.12 mmol), sodium iodide (35 mg, 0.24 mmol) and sodium carbonate (25 mg, 0.24 mmol) in acetonitrile (2 ml) is shaken at 80°C for 18 h, then the reaction mixture is cooled to room temperature. Add water (1 ml), the product extracted with ethyl acetate (2×2 ml) and the organic layer is loaded into the ion exchange column Varian SCX. The column is washed with methanol (2 column volume), then the product elute from the column using 10% ammonium hydroxide in methanol (2 column volume). The sorbate was concentrated in vacuo, dissolved in acetone, dried (K2CO3) and concentrated in vacuo. The product was then purified column chromatography (0-12% ethyl acetate in heptane + 0,1% Et3N), while receiving specified in the header of the connection 56. Yield 14 mg (38%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4M in dioxane) and recrystallized from methanol-diethyl ether to obtain white solid, which is filtered off and dried.1H NMR (CD3OD): δ of 0.91 (t, 3H), 1,28-of 1.45 (m, 8H), of 1.55 (m, 1H), 1,96 (shirt, 2H), 2,17 (m, 2H), 2,22 (s, 3H), 2,89 (t, 2H), equal to 2.94 (m, 2H), 3,14 (m, 2H), 3,54 (m, 2H), 7,20 (m, 2H), 7,34 (m, 1H), 7,45 (m, 1H).

Example 53. 4-Butyl-1-[3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl) propyl]butylpiperazine (57) (56NK05). n-BuLi in heptane (1.5 ml, 2.4 mmol, 1.6 m) is added dropwise to 5-fluoro-3-methylbenzo[b]thiophene (332 mg, 2.0 mmol) in THF (5 ml) at -20°C in argon atmosphere. The reaction mixture is stirred at -15°C for 30 min, then was added 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper iodide (I) (38 mg, 0.2 mmol). The reaction mixture is stirred at -15°C for 1 hour, then add the NH4Cl (feast upon. aq., 5 ml). The product is extracted with diethyl ether (2×30 ml) and the organic layer washed with saturated dissolve the Ohm salt (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was then purified column chromatography (0-1% diethyl ether in heptane), thus obtaining 2-(3-chloropropyl)-5-fluoro-3-methylbenzo[b]thiophene (180 mg, 37%).1H NMR (CDCl3): δ 2,19 (TT, 2H), 2,22 (s, 3H), equal to 2.94 (t, 2H), only 3.57 (t, 2H),? 7.04 baby mortality (dt, 1H), 7,28 (DD, 1H), 7,66 (DD, 1H).

2-(3-Chloropropyl)-5-fluoro-3-methylbenzo[b]thiophene (180 mg, of 0.74 mmol), 4-butylpiperazine (212 mg, of 0.74 mmol), sodium iodide (225 mg, 1.48 mmol) and sodium carbonate (159 mg, 1.48 mmol) in acetonitrile (2 ml) is shaken at 80°C for 18 h, then the reaction mixture is cooled to room temperature. Add water (1 ml), the product extracted with ethyl acetate (2×2 ml) and the organic layer is loaded into the ion exchange column Varian SCX. The column is washed with methanol (2 column volume) and the product to elute from the column using 10% ammonium hydroxide in methanol (2 column volume). The sorbate was concentrated in vacuo, dissolved in acetone, dried (K2CO3) and concentrated in vacuo. The product was then purified column chromatography (0-12% ethyl acetate in heptane + 0,1% Et3N), while receiving specified in the header of the connection 57. Yield 185 mg (72%). Cleaners containing hydrochloride salt is obtained by addition of HCl (4M in dioxane) and recrystallized from methanol-diethyl ether to obtain white crystals, which are filtered and dried.1H NMR (CD3OD: δ of 0.90 (t, 3H), of 1.31 (m, 6H), 1,37-of 1.62 (m, 3H), 1,94 (shirt, 2H), 2,15 (m, 2H), 2,31 (s, 3H), 2,92 (shirt, 2H), 3,01 (TM, 2H), 3,14 (m, 2H), 3,54 (shirt, 2H), 7,06 (dt, 2H), 7,34 (DD, 1H), 7,73 (DD, 1H).

Example 54. 2-(3-Improper)benzo[b]thiophene (58). A mixture of 2-(3-Chloropropyl)benzo[b]thiophene (902 mg, 4,28 mmol) and sodium iodide (1.29 g, 8.6 mmol) is heated to 50°C in acetone (5 ml) for 72 h, then cooled to room temperature. Add aqueous sodium thiosulfate (1 M, 10 ml) and the product extracted with diethyl ether (2×20 ml). The organic layer is dried (K2CO3), filtered and concentrated in vacuo, obtaining white solid, which was filtered through celite and elute heptane. The filtrate was concentrated in vacuo to obtain a white solid. Output 1.038 g (80%).1H NMR (CDCl3): δ 2,24 (TT, 2H), 3.04 from (dt, 2H), 3.27 to (t, 2H), 7,07 (kV, 1H), 7,28 (m, 2H), 7,68 (m, 1H), to 7.77 (m, 1H).

General procedure for alkylation of amines

2-(3-Improper)benzo[b]thiophene (33 mg, 0.11 mmol) in DCM (240 μl) is added to the amine (0.10 mmol) in DCM (200 μl) and the reaction mixture is shaken at room temperature for 18 hours. Add DCM (1 ml) followed by loading of macroporous trimetilammoniietilakrilata (50 mg, a 3.06 mmol/g, Agronaut Technologies) and the reaction mixture is shaken at room temperature for 1 hour. Add politicalmilitary (60 mg, 1.25 mmol/g, Argonaut Technologies) and the reaction mixture stryahivayte room temperature for 2 hours. The reaction mixture was then loaded into the ion exchange column Varian SCX. The column is washed with methanol (2 column volume) and the product to elute from the column using 10% ammonium hydroxide in methanol (2 column volume). The sorbate was concentrated in vacuo, dissolved in acetone, dried (K2CO3) and concentrated in vacuo.

Example 55. 1-(3-Benzo[b]thiophene-2-ylpropyl)-4-methylpiperidin (59) (56NK38). The interaction is conducted according to the General procedure using 4-methylpiperidine (17 mg, 0.10 mmol)to give 14 mg (53%) of 1-(3-benzo[b]thiophene-2-ylpropyl)-4-methylpiperidine.1H NMR (CD3OD): δ to 0.92 (d, 3H), 1.27mm (m, 2H), 1,34 (m, 1H), and 1.63 (m, 2H), was 1.94 (m, 4H), 2.40 a (t, 2H), 2.91 in (m, 4H), of 7.00 (d, 1H), 7,28 (m, 2H), 7,66 (m, 1H), 7,76 (m, 1H).

Example 56. 1-(3-Benzo[b]thiophene-2-ylpropyl)-4-benzylpiperidine (60) (56NK40). The interaction is conducted according to the General procedure using 4-benzylpiperidine (17 mg, 0.10 mmol), while receiving 16 mg (45%) of 1-(3-benzo[b]thiophene-2-ylpropyl)-4-benzylpiperidine.1H NMR (CD3OD): δ of 1.29 (m, 2H), 1,47-to 1.67 (m, 4H), of 1.92 (m, 4H), of 2.38 (m, 2H), 2,52 (m, 3H), 2,88 (m, 4H), 7,03 (m, 1H), 7,10-to 7.15 (m, 3H), 7.18 in-7,28 (m, 4H), 7,63 (m, 1H), 7,72 (m, 1H).

Example 57. 1-(3-Benzo[b]thiophene-2-ylpropyl)-4-(2-methoxyphenyl) piperidine (61) (56NK42). The interaction is conducted according to the General procedure using 4-(2-methoxyphenyl)piperidine (17 mg, 0.10 mmol), while receiving 17 mg (47%) of 1-(3-benzo [b]thiophene-2-ylpropyl)-4-(2-methoxyphenyl)piperidine.1H NMR (CD 3OD): δ or 1.77 (m, 4H), to 1.98 (m, 2H), 2,10 (m, 2H), 2,46 (m, 2H), 2,94 (m, 3H), 3.04 from (m, 2H), 3,79 (s, 3H), to 6.88 (m, 2H), 7,06 (Sirs, 1H), 7,13 (m, 2H), 7,26 (m, 2H), 7,65 (m, 1H), 7,73 (m, 1H).

Example 58. 2-(3-Bromopropyl)-2H-benzotriazole (35AKU-17-2) (62). To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) in dimethylformamide (10 ml) add benzotriazol (600 mg, 5.0 mmol) and KOH (430 mg, 7.7 mmol). After stirring for 20 h at room temperature, add water (10 ml) and ethyl acetate (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are dried over MgSO4and concentrated in vacuo, while receiving 1.44 g of crude material. The crude product was purified flash chromatography (0-10% methanol in DCM) to give 274 mg (23%) specified in the connection header 62. TLC (5% methanol in DCM): Rf=0,7.1H NMR (400 MHz, CDCl3): δ=7,88-7,83 (2H, m); 7,41 and 7.36 (2H, m); 4,91 (2H, t); 3,44 (2H, t); of 2.66 (2H, m).

Example 59. 2-[3-(4-Butylpiperazine-1-yl)propyl]-2H-benzotriazole (63)(35AKU-18). To a solution of 2-(3-bromopropyl)-2H-benzotriazole (274 mg, to 1.14 mmol) in dimethylformamide (5 ml) add a solution of 4-butylpiperazine (142 mg, 1.0 mmol) and KOH (125 mg, 2.2 mmol) in dimethylformamide (5 ml). The mixture is stirred for 20 hours at room temperature and then added ethyl acetate (10 ml) and water (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×20 ml). The combined organic phases are dried over MgSO4 and concentrated in vacuo to obtain 383 mg of crude material. The crude product was purified flash chromatography (0-10% methanol in DCM), while receiving 232 mg (77%) specified in the connection header 63. Oxalate salt obtained from oxalic acid (1.1 EQ.) in diethyl ether. TLC (10% methanol in DCM): Rf=0,4. HPLC-MS (method A): M+=301,2 (UV/MS(%)=100/89).1H NMR (400 MHz, CDCl3): δ=7,86 (2H, m); 7,37 (2H, m); 4,78 (2H, t); with 2.93 (2H,d); of 2.45 (2H, d); of 2.34 (2H, m); of 1.94 (2H, t); to 1.61 (2H, d); 1,32 is 1.13 (9H, m); to 0.88 (3H, t).

Example 60. 1-(3-Bromopropyl)-1H-benzotriazol (35AKU-17-1) (64). To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) in dimethylformamide (10 ml) add benzotriazol (600 mg, 5.0 mmol) and KOH (430 mg, 7.7 mmol). After stirring for 20 h at room temperature, add water (15 ml) and ethyl acetate (15 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×20 ml). The combined organic phases are dried over MgSO4and concentrate to obtain 1.44 g of crude product. The crude product was purified flash chromatography (0-10% methanol in DCM), while receiving 705 mg (59%) specified in the connection header 64. TLC (5% methanol in DCM): Rf=0,4. HPLC-MS (method A): M+=239,9 (UV/MS(%)=52/58).

Example 61. 1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-benzotriazol (65)(35AKU-19). To a solution of 1-(3-bromopropyl)-1H-benzotriazole (705 mg, 1.6 mmol) in dimethylformamide (5 ml) add a solution of 4-butylpiperazine (140 mg, 1.0 mm is l) and KOH (240 mg, 4.3 mmol) in dimethylformamide (5 ml). The mixture is stirred for 20 hours at room temperature. Then add ethyl acetate (10 ml) and water (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and evaporated to dryness to obtain 776 mg of crude material. The crude product was purified flash chromatography (0-10% methanol in DCM), while receiving 146 mg (49%) specified in the connection header 65. Oxalate salt obtained from oxalic acid (1.1 EQ.) in diethyl ether. TLC (10% methanol in DCM): Rf=0,4. HPLC-MS (method A): M+=301,2 (UV/MS(%)=100/99).1H NMR (400 MHz, CDCl3): δ=8,05 (1H, m); a 7.62 7,33 (3H, m); 4,71 (2H, t); 2,85 (2H, d); of 2.34 (2H, m); 2,22 (2H, m); 1,90 (2H, t); 1,67 (2H, d); 1,33-of 1.16 (9H, m); to 0.89 (3H, t).

Example 62. 1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indole-3-carbaldehyde (66)(35AKU-24). To a solution of 1,3-dibromopropane (410 μl, 4.0 mmol) in dimethylformamide (5 ml) add a solution of 1H-indole-3-carboxaldehyde (582 mg, 4.0 mmol) and KOH (456 mg, 8.1 mmol) in dimethylformamide (5 ml). After stirring for 24 hours add 4-butylpiperazine (359 mg, 2.0 mmol) and KOH (200 mg, 3.6 mmol). After stirring for 20 h, water is added and the ethyl acetate. The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are washed with saturated is the first salt solution, dried over MgSO4and evaporated to dryness to obtain 1.04 g of crude product. The crude product was purified flash chromatography (0-10% methanol in DCM), while receiving 252 mg (39%) specified in the connection header 66. TLC (10% methanol in DCM): Rf=0,5. HPLC-MS (method A): M+=327,2 (UV/MS(%)=99/96).

Example 63. {1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indol-3-yl} methanol (67) (35AKU-26). To a solution of 1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indole-3-carbaldehyde (120 mg, of 0.37 mmol) in methanol (2 ml) is added slowly a solution of NaBH4(9,2 mg, 0.24 mmol) in 20 ál of 2 M NaOH/1 ml of water. The mixture was then stirred for 20 hours at room temperature. Add additional NaBH4(12 mg, 0.32 mmol) and the mixture is stirred for additional 2 hours. Add another portion of NaBH4(14 mg, and 0.37 mmol) and the mixture is stirred over night. The methanol is partially removed using a Rotavap and add ethyl acetate (10 ml) and water (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are dried over MgSO4and evaporated to dryness, thus obtaining 93 mg (71%) specified in the connection header 67. TLC (10% methanol in DCM): Rf=0,4. HPLC-MS (method A): M+=329,2 (UV/MS(%)=98/79).1H NMR (400 MHz, CDCl3): δ=7,72 (1H, d); of 7.36 (1H, d); 7,25-7,10 (3H, m); a 4.86 (1H, s); 4,15 (2H, t); 2,84 (2H, d); and 2.26 (2H, t); 1,99 (2H, m); to 1.86 (2H, t); 1,71-of 1.62 (4H, m); 1,34 is 1.16 (9H, m); of 0.90 (3H, t).

Example 64. 1-[3-(4-BU is reprein-1-yl)propyl]-2-phenyl-1H-benzoimidazol (68)(35AKU-28). To a solution of 1,3-dibromopropane 205 μl, 2.0 mmol) in dimethylformamide (5 ml) is added 2-phenylbenzimidazol (389 mg, 2.0 mmol) and KOH (266 mg, 4.7 mmol). After stirring for 16 h at room temperature add the hydrochloride of 4-butylpiperazine (176 mg, 1.0 mmol). After 24 hours stirring an additional KOH (270 mg, 4.8 mmol) and the mixture is heated at 90°C for 3 hours. After cooling, add water (10 ml) and ethyl acetate (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrated in vacuo to obtain 643 mg of crude product. The crude product was purified flash chromatography (0-10% methanol in DCM), while receiving 71 mg (19%) specified in the connection header 68. TLC (10% methanol in DCM): Rf=0,7. HPLC-MS (method A): M+=376.3 on (UV/MS(%)=100/100).1H NMR (400 MHz, CDCl3): δ=a 7.85-7,27 (9H, m), 4,32 (2H, t); 2,73 (2H, d); of 2.25 (2H, t); of 1.95 (2H, m); is 1.81 (2H, t); of 1.62 (2H, d); 1,33-a 1.08 (9H, m); of 0.90 (3H, t).

Example 65. 1-[3-(4-Butylpiperazine-1-yl)propyl]-3-chloro-1H-indazol (69)(35AKU-34). To a solution of 1,3-dibromopropane (205 μl, 2.0 mmol) in dimethylformamide (5 ml) is added 3-chlorinator (306 mg, 2.0 mmol) and KOH (400 mg, 7.1 mmol). After stirring the suspension for 16 h add hydrochloride 4-butylpiperazine (180 mg, 1.0 mmol) and dimethylformamide (2 ml). After stirring 20 cha is add water (10 ml) and ethyl acetate (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrated in vacuo to obtain 500 mg of crude product. The crude product was purified flash chromatography (0-10% methanol in DCM)to give 121 mg (36%) specified in the connection header 69. Oxalate salt obtained from oxalic acid (1.1 EQ.) in diethyl ether. TLC (10% methanol in DCM): Rf=0,5. HPLC-MS (method A): M+=334,1 (UV/MS(%)=100/100).1H-NMR (400 MHz, CDCl3): δ=7,68-7,16 (4H, m); to 4.46 (2H, t); 3,13 (2H, d); 2,62 (2H, t); 2,35 (2H, m); 2,22 (2H, t); of 1.76 (2H, d); 1,61 of 1.46 (2H, m); 1,36-1,24 (7H, m)to 0.89 (3H, t).

Example 66. 1-[3-(4-Butylpiperazine-1-yl)propyl]-6-nitro-1H-indazole (70)(35AKU-40). To a solution of 1,3-dibromopropane (205 μl, 2.0 mmol) in dimethylformamide (20 ml) is added 6-nitroindazole (325 mg, 2.0 mmol) and K2CO3(590 mg, 4.3 mmol). After stirring the suspension for 20 h add hydrochloride 4-butylpiperazine (178 mg, 1.0 mmol) and dimethylformamide (5 ml). After stirring 20 h, water is added (15 ml) and ethyl acetate (15 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×20 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrated in vacuo to obtain 511 mg of crude product. The crude product is purified by ion-exchange chromatography (in myauth 10% aqueous NH 4OH (25%) in methanol) and flash chromatography (0-10% methanol in DCM)to give 21 mg (6%) specified in the connection header 70. Oxalate salt obtained from oxalic acid (1.1 EQ.) in diethyl ether. TLC (10% methanol in DCM): Rf=0,4. HPLC-MS (method A): M+=345,1 (UV/MS(%)=97/96).1H-NMR (400 MHz, CDCl3): δ=8,70 (1H, m); 8,07 (1H, m); of 7.90 (1H, m); of 7.75 (1H, m); 4,56 (2H, t); 2,86 (2H, d); 2,32 (2H, t); 2,24 (2H, m); of 1.92 (2H, t); by 1.68 (2H, m); 1,35-of 1.16 (9H, m); to 0.89 (3H, t).

Example 67. Benzo[d]isoxazol-3-ol (35AKU-44) (71). To a solution of salicylhydroxamic acid (1,53 g, 10 mmol) in THF (40 ml) add a solution of carbonyldiimidazole (1,62 g, 20 mmol) in tetrahydrofuran (20 ml). The mixture is stirred while boiling under reflux for 4 h before evaporation to dryness. Add water (20 ml) and conc. HCl (aq.) (5 ml) and the solution is cooled (5° (C) within 30 minutes the precipitate is collected by filtration and washed with 2 M HCl. The solid material was dissolved in methanol and concentrated in vacuo, while receiving 725 mg (54%) specified in the connection header 71. TLC (10% methanol in DCM): Rf=0,2. HPLC-MS (method A): M+=136,1 (UV/MS(%)=they set the 94/100).1H-NMR (400 MHz, CDCl3, MeOD): δ=7,73 (1H, m); 7,56 (1H, m), 7,38 (1H, m), 7,28 (1H, m); a 3.87 (1H, s).

Example 68. 3-(2-Chloroethoxy)benzo[d]isoxazol (35AKU-45 (72)). To a solution of 1-bromo-2-chlorethane (250 μl, 3.0 mmol) in dimethylformamide (10 ml) was added benzo[d]isoxazol-3-ol (400 mg, 3.0 mmol) and K2What about 3(440 mg, 3.2 mmol). The mixture is stirred for 20 h and then heated at 80°C for 1 hour. Add ethyl acetate (10 ml) and water (10 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×15 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrated in vacuo to obtain 543 mg of crude product. The crude product was purified flash chromatography (0-10% methanol in DCM), while receiving 378 mg (64%) specified in the connection header 72. TLC (10% methanol in DCM): Rf=0,8.1H-NMR (400 MHz, CDCl3): δ=to 7.68 (1H, d); at 7.55 (1H, t); 7,44 (1H, d); 7,28 (1H, t); 4,72 (2H, t); of 3.94 (2H, t).

Example 69. 3-[2-(4-Butylpiperazine-1-yl)ethoxy]benzo[d] isoxazol (73) (35AKU-46). A solution of 3-(2-chloroethoxy)benzo[d] isoxazol (378 mg, 1.9 mmol), hydrochloride 4-butylpiperazine (270 mg, 1.5 mmol) and K2CO3(537 mg, 3.9 mmol) in dimethylformamide (15 ml) is heated to 80°C and stirred for 24 hours. After cooling to room temperature, add water (15 ml) and ethyl acetate (15 ml). The phases are separated and the aqueous phase is again extracted with ethyl acetate (3×20 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and concentrated in vacuo to obtain 586 mg of crude material. The crude product was purified flash chromatography (0-5% methanol in DCM), while receiving 157 mg (35%) specified in the header with the organisations 73. Oxalate salt obtained from oxalic acid (1.1 EQ.) in diethyl ether. TLC (5% methanol in DCM): Rf=0,3. HPLC-MS (method A): M+=303,1 (UV/MS(%)=100/100).1H-NMR (400 MHz, CDCl3): δ=7,69-7,22 (4H, m); of 4.57 (2H, t); 2,99 (2H, d); is 2.88 (2H, t); 2,11 (2H, t); by 1.68 (2H, m); 1.32 to of 1.18 (9H, m); to 0.89(3H, t).

Example 70. 3-(1H-Indol-3-yl)propan-1-ol (74) (32HS28). Suspension of sociallyengaged (4.68 g, 126 mmol) in anhydrous diethyl ether (230 ml) was vigorously stirred. 3-Indolepropionic acid (10.0 g, 53 mmol) is dissolved in anhydrous diethyl ether and added dropwise by boiling the reaction mixture under reflux. The reaction mixture is then refluxed for 2 h and then stirred at room temperature (RT) overnight. Slowly add water (25 ml), then aqueous solution of H2SO4(1:3 H2O/conc. H2SO4) (20 ml). The resulting clear mixture is extracted with diethyl ether (3×110 ml) and the combined organic phases are washed with saturated salt solution, dried (Na2SO4), filtered and concentrated in vacuo, while receiving crude oil specified in the title compound (74) (1.8 g). The crude product is used without further purification.

Example 71. Hydrochloride 3-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indole (75) (32HS34). Crude 3-(1H-indol-3-yl)propan-1-ol (1.8 g) is dissolved in anhydrous THF and cooled to -4° C. Syringe add triethylamine (720 mg, 7.1 mmol) and then adding methanesulfonanilide (750 mg, 6.5 mmol). The mixture is left to warm to 20°C and then filtered and concentrated under vacuum, thus obtaining the crude product, which is again dissolved in DCM and washed with water. The organic phase is dried over MgSO4, filtered and concentrated in vacuo to obtain a brown oil. This material was used immediately without further purification.

The hydrochloride of 4-n-butylpiperazine (967 mg, 5.4 mmol) and Na2CO3(1.28 g, 12 mmol) is suspended in DME, stirred at RT for 30 min and then added to the raw material in DME. The resulting mixture was stirred at 82°C during the night. The mixture is cooled before adding ethyl acetate (15 ml) and water (15 ml), extracted with ethyl acetate (3×20 ml). The combined organic phases are washed with saturated salt solution, dried (Na2SO4) and concentrated in vacuo. Purification preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml) gives specified in the title compound (75) in the form of white crystals after washing DCM. Yield: 130 mg, 0.3 percent (total). HPLC-MS (method A): M+=298,3 (UV/MS(%)=100/100).1H-NMR (400 MHz, CD3OD): δ at 7.55 (d, 1H); 7,34 (d, 1H), to 7.09 (m, 2H), 7,01 (t, 1H), 3.46 in (m, 2H), to 3.09 (m, 2H), 2,87 (m, 5H), and 2.14 (m, 2H), 1.91 a (2, 2H), 1,58-of 1.24 (m, 9H), of 0.90 (t, 3H).

Example 72. Methyl ester of 4-(4-butile Eridan-1-yl)butyric acid (76) (40-LH-58). To a solution of methyl ester 4-pamakani acid (1.35 g, 7.5 mmol) in dry acetonitrile (10 ml) is added 4-butylpiperazine (1,00 g, 7.1 mmol) and K2CO3(1.10 g, 7.8 mmol). After stirring at RT for 12 h, the reaction mixture was evaporated to dryness followed by addition of water (15 ml). The aqueous phase is extracted with ethyl acetate (3×20 ml) and the combined organic phases are dried (Na2SO4) and concentrated in vacuo to obtain 1,71 g wet specified in the connection header 76. The crude product was purified flash chromatography (Meon:ethyl acetate 2:8), thus obtaining the net specified in the header connection. Yield 1.27 g (74%).1H-NMR (CD3OD): δ the 3.65 (s, 3H), of 2.93 (d, 2H), 2,33 (K., 4H), to 1.98 (t, 2H), 1,81 (square, 2H), 1.69 in (d, 2H), 1,35-of 1.18 (m, 9H), of 0.90 (t, 3H).

Example 73. 2-[3-(4-Butylpiperazine-1-yl)propyl]-1-methyl-1H-benzimidazole (77) (40-LH-W). A mixture of N-methylbenzol-1,2-diamine (68 mg, 0,56 mmol) and methyl ester of 4-(4-butylpiperazine-1-yl)butyric acid (130 mg, 0.54 mmol) in polyphosphoric acid (1 ml) was heated and shaken in a sealed vial at 150°C for 1.5 hours. The reaction mixture was poured into a cooled ice bath (NaOH (4 n): ice, 1:1) with stirring, and then formed a grey precipitate. Grey precipitate is filtered off and washed with cold ether. Oxalate salt obtained from oxalic acid (1.1 EQ.) in diethyl ether. Yield 141 mg (92%).1H-NMR (CDCl3 ): δ 7,71 (m, 1H), 7,30-7,19 (m, 3H), 3,74 (s, 3H), 2,90 (K., 4H), 2,43 (t, 2H), 2.06 to (square, 2H), 1,89 (t, 2H), 1,65 (d, 2H), 1,31-to 1.14 (m, 9H), to 0.89 (t, 3H).

Example 74. (2-(4-Butylpiperazine)-1-retil)amide 1H-indazol-3-carboxylic acid (78) (40-LH-70-17V). To shake a solution of 1H-indazol-3-carboxylic acid (49 mg, 0.30 mmol) and N-hydroxysuccinimide (36 mg, 0.31 mmol) in dry DMF (2 ml) add a solution of dicyclohexylcarbodiimide (62 mg, 0.30 mmol) in dry DMF (1 ml). The mixture is shaken for 16 hours followed by addition of 2-(4-butylpiperazine-1-yl)ethylamine (28 mg, 0.15 mmol). The reaction mixture is then shaken for a further 24 hours, followed by filtration. The organic phase is loaded into the ion exchange column Varian SCX. The column is washed sequentially with methanol (5 ml), isopropanol (5 ml) and methanol (5 ml). Product elute from the column using 5% ammonia in methanol (5 ml). The sorbate was concentrated in vacuo, dissolved in acetone, dried (K2CO3) and concentrated in vacuo, while receiving specified in the header of the connection 78. Yield 47 mg (95%).1H-NMR (CD3OD): δ 8,21 (d, 1H), 7,56 (d, 1H), 7,40 (dt, 1H), 7,24 (dt, 1H)and 3.59 (t, 2H), 3,01 (shirt, 2H), 2.63 in (t, 2H), 2,08 (t, 2H), 1,71 (d, 2H), 1,34-to 1.21 (m, 9H), of 0.90 (t, 3H).

Example 75. 1-[3-(4-Butylpiperazine-1-yl)propyl]-5-nitro-1H-indazole (79) (64LHY29-1). Example 76. 2-[3-(4-Butylpiperazine-1-yl)propyl]-5-nitro-2H-indazole (80) (64LHY29-2). To a cooled solution (-78°C) 5-nitroindazole (41,20 mg, 0,25 shall mol) in THF (1 ml) add a solution of n-utility in hexane (1,5M, 0.17 ml, 0.25 mmol) followed by addition of 1-bromo-3-iodopropane (27 μl, 0.25 mmol). After incubation for 16 h at RT the mixture was concentrated in vacuo. Add ethyl ketone (1 ml) and 4-butylpiperazine (35,3 mg, 0.25 mmol). The reaction mixture was shaken for 16 h at 60°C, followed by filtration and the organic layer is then evaporated to dryness. The solid is dissolved in methanol (1 ml) before loading the column with ion exchange resins Varian SCX. The column is washed with methanol (3×6 ml) and elute the product with 10% NH3in methanol (5 ml). The sorbate was concentrated in vacuo. Formed two isomers in the ratio of 1:1 according to the analysis of LC-MS of the crude mixture. Two isomers emit after purification preparative HPLC. 79 (64LHY12-1):1H-NMR (CDCl3): δ to 0.88 (t, 3H), 1,l8 and 1.33 (m, 9H), 1,73-1,64 (shirt, 2H), 1,92 (shirt, 2H), of 2.21 (DDD, 2H), 2,30 (DD, 2H), 2,85 (shirt, 2H), 4,55 (t, 2H), of 7.75 (DDD, 1H), 8,10 (DD, 1H), 8,24 (d, 1H), 8,73 (DD, 1H);13C-NMR (CDCl3): δ=14,0, 22,8, 27,3, 28,9 (2C), 32,3, 35,6, 36,1, 52,1, 53,9 (2C), 54,7, 118,2, 119,2, 119,9, 120,1, 127,3, 143,0, 149,8; LC-MS: (M+H)+445,2, trof 3.69 min, 80 (64LHY29-2):1H-NMR (CDCl3): (from 0.90 (t, 3H), 1,14-to 1.38 (m, 9H), 1,62 (shirt, 2H), 1,86 (sird, 2H), 2,16 (DDD, 2H), 2,21 (DD, 2H), 2,75 (shirt, 2H), 4,50 (t, 2H), to 7.59 (DDD, 1H), 8,21 (d, 1H), 8,25 (DD, 1H), 8,73 (DD, 1H);13C-NMR (CDCl3): (14,3, 23,1, 27,3, 29,2, 32,8 (2C), 36,0, 36,5, 47,2, 54,2 (2C), 55,2, 110,0, 119,1, 121,3, 123,0, 136,0, 141,8, 142,5; LC-MS: (M+H)+445,2, tr5,30 min.

A General procedure for obtaining derivatives of indole

And the $ (1.20 mmol) dissolved in dry DMF (3 ml) before the addition of sodium hydride (2,50 mmol) at RT followed by addition of 3-chloro-1-iodopropane (0.20 g, 1.0 mmol). The reaction mixture was shaken in a sealed ampoule at CT. within 16 hours. Add 4-butylpiperazine (130 mg, 0.9 mmol) and the reaction mixture is then shaken at 50°C for 72 hours. The mixture is filtered and the filtrate is loaded into the ion exchange column Varian SCX. The column is washed with methanol (10 ml, 2 volume of the column and elute the product from the column using 5% ammonium hydroxide in methanol (5 ml, 1 column volume). The sorbate was concentrated in vacuo, while receiving specified in the title compound (79, 80).

Example 77. 1-[3-(4-Butylpiperazine-1-yl)propyl]-2-methyl-1H-indole (81) (55-LH-1-1-(1402). The interaction is conducted according to the General procedure using 2-methyl-1H-indole (157 mg, 1.20 mmol). The crude product is further purified flash chromatography (Meon:ethyl acetate, 1:4), while receiving specified in the header connection 81. Yield 19 mg (21%). (UV/MS(%)=98/89);1H-NMR (CDCl3): δ 7,50 (d, 1H), 7,31 (d, 1H), 7,12 (dt, 1H),? 7.04 baby mortality (dt, 1H), 6,23 (s, 1H), 4,12 (t, 2H), 2,87 (d, 2H), 2,44 (s, 3H), 2,31 (t, 2H), 1,98 of-1.83 (m, 4H), 1,67 (d, 2H), 1.32 to-1,19 (m, 9H), to 0.89 (t, 3H).

Example 78. 1-{1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indol-3-yl}Etalon (82) (55-LH-1-2-(1403). The interaction is conducted according to the General procedure using 1-(1H-indol-3-yl)ethanone (191 mg, 1.20 mmol), while receiving specified in the header connection 82. Yield 33 mg (32%). (UV/MS(%)=99/91);1H-NMR (CDCl3): δ 8,39-to 8.34 (m, 1H), 7,80 (s, 1H), 7,41 and 7.36 (m, 1H), 7,30-7,25 (m, 2H), 4,24 (t, 2H), 2,80 (d, 2H), of 2.21 (t, 2H) 2,01 (square, 2H), 1,86 (t, 2H), 1.69 in (d, 2H), 1.32 to-1,19 (m, 9H), to 0.89 (t, 3H).

Example 79. {1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indol-3-yl}acetonitrile (83) (55-LH-1-3-(1404). The interaction is conducted according to General procedure using (1H-indol-3-yl)acetonitrile (187 mg, 1.20 mmol), while receiving specified in the header connection 83. Yield 33 mg (11%). (UV/MS(%)=99/92);1H-NMR (CDCl3): δ at 7.55 (d, 1H), 7,38 (d, 1H), 7,24 (t, 1H), 7,15 (t, 1H), 4,17 (t, 2H), 3,82 (s, 2H), 2,82 (d, 2H), 2,23 (t, 2H), 1,98 (square, 2H), 1,85 (t, 2H), 1,67 (d, 2H), 1,33-1,17 (m, 9H), to 0.89 (t, 3H).

Example 80. 1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indol-3-carbonitrile (84) (55-LH-1-4-(1405). The interaction is conducted according to the General procedure using 1H-indole-3-carbonitrile (170 mg, 1.20 mmol), while receiving specified in the header of the connection 84. Yield 30 mg (31%). (UV/MS(%)=99/96);1H-NMR (CDCl3): δ of 7.75 (d, 1H), 7,63 (s, 1H), 7,45 (d, 1H), 7,35-7,25 (m, 2H), 4,25 (t, 2H), and 2.79 (d, 2H), measuring 2.20 (t, 2H), 1,99 (square, 2H), 1,86 (t, 2H), 1,68 (d, 2H), 1,33-of 1.18 (m, 9H), to 0.89 (t, 3H).

A General procedure for obtaining derivatives of benzimidazole

The benzimidazole (0,60 mmol) dissolved in dry THF (1 ml) before adding dropwise n-BuLi (1.6 m in hexane) (413 μl, 0.66 mmol) at RT. The mixture is stirred for 15 min followed by the addition of 1,3-dibromopropane (100 mg, 0.50 mmol) and then incubated at RT for 16 hours. Add 4-butylpiperazine (64 mg, 0.45 mmol) and the reaction mixture was shaken at 60°C for 72 hours. The mixture is filtered and the filtrate is concentrated is in vacuum before cleaning preparative HPLC.

Example 81. 1-[3-(4-Butylpiperazine-1-yl)propyl]-5,6-dimethyl-1H-benzoimidazol (85) (55-LH-8-2 (1387)). The interaction is conducted according to the General procedure using 5,6-dimethylbenzimidazole (88 mg, of 0.60 mmol), while receiving specified in the header connection 85. Yield 20 mg (14%). (MS(%)=100);1H-NMR (CDCl3): δ for 7.78 (s, 1H), 7,55 (s, 1H), 7,18 (d, 1H), 4,20 (t, 2H), 2,81 (d, 2H), 2,39 (s, 3H), is 2.37 (s, 3H), 2,22 (t, 2H), 2.00 (evens square, 2H), 1,85 (t, 2H), 1,68 (d, 2H), 1,33-of 1.18 (m, 9H), of 0.90 (t, 3H).

Example 82. 1-[3-(4-Butylpiperazine-1-yl)propyl]-5(6)-dimethyl-1H-benzoimidazol (86) (55-LH-8-3 (1388)). The interaction is conducted according to the General procedure using 5-methylbenzimidazole (79 mg, of 0.60 mmol), while receiving specified in the title compound (86) in the form of a 50/50 mixture of the two regioisomers according to the1H NMR. Yield 42 mg (30%). (UV/MS(%)=100/100).

Example 83. 1-[3-(4-Butylpiperazine-1-yl)propyl]-5-methoxy-1H-benzoimidazol (87) (55-LH-8-6(1393)). The interaction is conducted according to the General procedure using 5-methoxybenzimidazole (89 mg, of 0.60 mmol), while receiving specified in the title compound (87) in the form of a 50/50 mixture of the two regioisomers according to the1H NMR. Yield 62 mg (42%). (UV/MS(%)=100/100).

Example 84. {1-[3-(4-Butylpiperazine-1-yl)propyl]-1H-benzoimidazol-2-yl}methanol (88) (55-LH-8-9(1400)). The interaction is conducted according to the General procedure using 1H-benzoimidazol-2-yl)methanol (89 mg, of 0.60 mmol), while receiving specified in the title compound (88). The output 56 is g (38%). (UV/MS(%)=95/85).1H-NMR (CDCl3): δ 7,69-the 7.65 (m, 1H), 7,32-7,28 (m, 1H), 7,21-to 7.18 (m, 2H), 4,88 (s, 2H), to 4.38 (t, 2H), 2,70 (d, 2H), 2,18-to 2.06 (m, 4H), 1,74 (t, 2H), 1,58 (d, 2H), 1,24-to 1.14 (m, 9H), 0,81 (t, 3H).

Example 85. 1-[3-(4-Butylpiperazine-1-yl)propyl]-2-trifluoromethyl-1H-benzoimidazol (89) (55-LH-8-10 (1401)). The interaction is conducted according to the General procedure using 2-trifluoromethyl-1H-benzoimidazole (112 mg, of 0.60 mmol), while receiving specified in the title compound (89). Yield 48 mg (29%). (UV/MS(%)=100/95).1H-NMR (CDCl3): δ for 7.78 (d, 1H), 7,74 (d, 1H), 7,49 (t, 1H), 7,41 (t, 1H), 4,48 (t, 2H), 2,86 (d, 2H), 2,41 (t, 2H), 2,08 (square, 2H), 1,92 (t, 2H), 1,67 (d, 2H), 1,31-of 1.15 (m, 9H), to 0.89 (t, 3H).

Example 86. tert-Butyl ether (2-trimethylsilylethynyl) carbamino acid (90) (53MF36). To a solution of tert-butyl methyl ether phenylcarbinol acid (10,02 g, 52 mmol) in dry DMF (150 ml) is added dropwise tert-BuLi (1.7 M in hexane) (80 ml, 0.14 mol) at -70°C. the Reaction mixture was stirred for 30 min at -70°C and 2 hours at -20°C before adding a solution of trimethylacetylchloride in dry THF (1M) (77.0 ml, 78 mol). The reaction mixture is then stirred at -20°C for 1 hour followed by the addition of an aqueous solution of ammonium chloride (15%) (100 ml). The mixture is extracted with diethyl ether (3×300 ml) and the combined organic phases are dried over MgSO4and evaporated in vacuum, thus obtaining the crude specified in the title compound (90) (17.0 g), which used the coziness in the next reaction without further purification.

Example 87. tert-Butyl ether [2-(4-chlorobutyryl)phenyl] carbamino acid (91) (53MF37). To a solution of tert-butyl methyl ether (2-trimethylsilylethynyl)carbamino acid (17.0 g, 36 mmol) in dry toluene (300 ml) is added 4-chlorobutyrate (5.3 g, 38 mmol) and dichlorobis(acetonitrile) palladium(II) (300 mg, 1.2 mmol). The reaction mixture is heated to boiling under reflux and leave for 12 hours followed by evaporation to dryness and column chromatography (heptane:ethyl acetate 10:1), while receiving specified in the header connection 91. Yield 7.2 g (47%) from tert-butyl ether phenylcarbinol acid).

Example 88. tert-Butyl ether {2-[4-(4-butylpiperazine-1-yl)butyryl]phenyl}carbamino acid (92)(53MF38). In the flask is charged with tert-butyl methyl ether [2-(4-chlorobutyryl)phenyl] carbamino acid (2.1 g, 7.1 mmol) and 4-butylpiperazine (1.2 g, 8.5 mmol) before adding pyridine (5 ml). To the reaction mixture is added potassium carbonate (1,17 g, 8.5 mmol) and the mixture was stirred at 100°C for 12 hours. Add water (50 ml) followed by extraction with ethyl acetate (3×150 ml). The combined organic phases are dried over MgSO4, filtered and evaporated to dryness. The crude material is subjected to column chromatography (DCM:methanol; 20:1), which gives a net specified in the title compound (92) (1.48 g, 52%).

Example 89. 3-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indazol, HCl 93) (53MF39). A solution of tert-butyl methyl ether {2-[4-(4-butylpiperazine-1-yl)butyryl]phenyl}carbamino acid (1.48 g, 3.7 mmol) in a solution of HCl in dioxane (4 n) (20 ml) is stirred at RT for 1 h before evaporation to dryness. The residue is dissolved in HCl (conc.) (15 ml) before adding a solution of sodium nitrite (255 mg, 3.7 mmol)dissolved in water (3 ml). The mixture was stirred at 0°C for 1 hour before adding channelclosed (1.7 g, 7.4 mmol) and then stirred at RT. within 3 hours. the pH of the reaction mixture regulate NaOH (2 n) to achieve the basic value, followed by extraction with ethyl acetate (3×400 ml). The combined organic phases are dried over MgSO4, filtered and evaporated in vacuum. The crude material is subjected to column chromatography (DCM:methanol; 20:1), which gives a crude specified in the header connection 93. The crude compound was dissolved in diethyl ether followed by the addition of HCl in ether (1.0m) and stirred for 0.5 hour. The solution is evaporated to dryness and the solid material is recrystallized twice from a mixture of DCM:diethyl ether, thus obtaining the net specified in the header connection. The yield of 0.44 g (32%). (UV/MS(%)=100/100); TPL 160,5-164,0°C;1H-NMR (CD3OD): δ of 7.96 (d, 1H), 7.62mm (d, 2H), 7,33 (d, 1H), to 3.58 (dt, 2H), 3,24-3,19 (m, 4H), 2.95 and (t, 2H), 2,33 (square, 2H), 1,97 (d, 2H), 1,65 of 1.28 (m, 9H), of 0.91 (t, 3H).13C-NMR (CD3OD): δ 143,9, 141,0, 130,3, 122,5, 120,8, 120,5, 110,9, 56,4, 3,2, 35,4, 33,6, 29,7, 28,5, 23,1, 22,7, 22,6, 13,1.

Example 90. 3-[3-(4-Butylpiperazine-1-yl)propyl]-5-nitro-1H-indazole (94) (39MF43NO2).

Example 91. 3-[3-(4-Butylpiperazine-1-yl)propyl]-5,7-dinitro-1H-indazol (95) (39MF43DiNO2). A solution of 3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazole (120 mg, 0.4 mmol) in a mixture of 1:1 nitric acid (fuming) and sulfuric acid (conc.) (2 ml) stirred at 0°C for 1.5 hours. the pH of the mixture regulate NaOH (8 n), resulting yellow oily material is deposited. The material was filtered and subjected to preparative TLC (DCM:methanol; 10:1), which gives two clear specified in the connection header. Yield: 25 mg (18%) (3-[3-(4-butylpiperazine-1-yl)propyl]-5-nitro-1H-indazole (94).1H-NMR (CDCl3): δ to 8.45 (s, 1H), 8,01 (d, 2H), of 7.48 (d, 1H), 3,48 (d, 2H), 3,18-2,95 (m, 4H), 2,62 (t, 2H), and 2.27 (square, 2H), equal to 1.82 (d, 2H), 1,58 (square, 2H), 1,44-to 1.38 (m, 1H), 1.30 and 1,19 (m, 6H), of 0.91 (t, 3H),13C-NMR (CDCl3): 147,4, 143,4, 141,9, 121,6, 121,1, 117,7, 111,3, 57,4, 53,6, 35,4, 34,4, 30,0, 28,9, 24,2, 23,5, 22,9, 14,2. Yield: 10 mg (6%) (3-[3-(4-Butylpiperazine-1-yl)propyl]-5,7-dinitro-1H-indazole (95).1H-NMR (CDCl3): δ 9,18 (d, 1H), 9,05 (d, 1H), 3,18-3,10 (m, 4H), 2,68 (t, 2H), 2,25-2,l4 (m, 4H), 1,74 (d, 2H), 1,45-1,22 (m, 7H), of 0.91 (t, 3H).

Example 92. 4-(4-Butylpiperazine-1-yl)-1-(2-methylsulfinylphenyl) butane-1-on (96) (65MF07). To a stirred solution of 2-bromothioanisole (12,85 g, 63.3 mmol) in dry THF (60 ml) at -78°C add n-BuLi (1.6 n in hexane) (41 ml, 65.3 mmol) via syringe over 30 minutes, the Reaction mixture is then PE is amerivault at -78° C for 30 min before adding a solution of 4-(4-butylcyclohexyl)-N-methoxy-N-methylbutylamine (11,41 g, to 42.2 mmol) in dry THF (10 ml). The mixture was kept at -78°C for 0.5 hour and at RT for 0.5 h before the addition of water (100 ml) and extraction with ethyl acetate (3×150 ml). The combined organic phases are dried over MgSO4, filtered and evaporated in vacuum, thus obtaining the crude specified in the title compound 96 (11.9 g). Purity analysis LC-MS: UV/MS(%)=90/91).

Example 93. 3-[3-(4-Butylpiperazine-1-yl)propyl]benzo[d]isothiazol (97) (65MF08). A mixture of crude 4-(4-butylpiperazine-1-yl)-1-(2-methylsulfinylphenyl)butane-1-it (11.9 g, 36 mmol) and hydroxylamine-O-sulfonic acid (6.11 g, 54 mmol) in acetic acid (500 ml) is stirred at RT for 72 h followed by heating at 100°C for 24 hours. The reaction mixture is cooled to CT and regulate pH 2 n NaOH until basic conditions (pH 9) before extraction with ethyl acetate (3×400 ml). The combined organic phases are dried over MgSO4, filtered and evaporated in vacuum, thus obtaining 12,1 g crude product. The crude product is purified column chromatography (DCM:MeOH; 20:1), while receiving specified in the header connection 97. Output to 3.67 g (18,3%) from 2-bromoanisole. Oxalate salt is produced by adding oxalic acid and recrystallized from methanol-diethyl ether to obtain white Cree is of metal, which is filtered and dried. (UV/MS(%)=90/91), TPL 193,4-194,0°C.1H-NMR (CDCl3): δ 7,98 (d, 1H), to $ 7.91 (d, 1H), 7,50 (t, 1H), 7,41 (t, 1H), 3,14 (t, 2H), 2,92 (d, 2H), 2,46 (t, 2H), 2,18 (square, 2H), 1,92 (t, 2H), of 1.66 (d, 2H), 1,35-of 1.18 (m, 9H), to 0.88 (t, 3H),13C-NMR (CDCl3): 166,6, 152,5, 134,9, 127,6, 124,5, 123,6, 120,0, 58,5, 54,2, 36,4, 35,9, 32,5, 29,7, 25,5, 23,1, 14,2.

Example 94. 3-[3-(4-Butylpiperazine-1-yl)propyl]-5-methoxy-1H-indazole (98) (53MF35). In a small flask is charged with 1-(2-amino-5-methoxyphenyl)-4-(4-butylpiperazine-1-yl)butane-1-he (1,58 g, 47 mmol) in conc. HCl (15 ml). The mixture is cooled to 0°C followed by the addition of sodium nitrite (0,61 g, 88 mmol) and water (3 ml) and stirring at 0°C for 2 hours. Adding chloride dihydrate tin(II) (2,68 g, to 11.9 mmol) to give the precipitate, which is filtered, washed twice in ice water and dried. The filtrate was dissolved in ethyl acetate (100 ml) and 1 n NaOH (150 ml) followed by extraction with ethyl acetate (3×150 ml). The combined organic phases are dried over MgSO4, filtered and evaporated in vacuum, thus obtaining 1.30 grams of crude product. The crude product is purified column chromatography (DCM:MeOH; 20:1) to obtain specified in the connection header 98. Oxalate salt is produced by adding oxalic acid and recrystallized from methanol-diethyl ether, to thereby obtain white crystals, which are filtered and dried. Yield 0.97 g (49%).1H-NMR (CDCl3): δ to 7.32 (DD, 1H), 7,03 (DD, 1H), 6,98 (d,1H), of 3.85 (s, 3H), 3,10 (d, 2H), 2,96 (t, 2H), 2,61 (t, 2H), 2,15-2,05 (m, 4H), 1,68 (d, 2H), 1,40-of 1.20 (m, 9H), of 0.87 (t, 3H).13C-NMR (CDCl3): 177,2, 154,5, 145,6, 137,4, 122,4, 119,0, 111,2, 99,6, 58,0, 55,9, 53,5, 36,1, 35,5, 31,5, 29,1, 25,2, 24,9, 23,4, 23,0, 14,2.

Example 95. 3-[3-(4-Butylpiperazine-1-yl)propyl]-4-methoxy-1H-indazole (99) (53MF47). To a solution of 3-(3-chloropropyl)-4-methoxy-1H-indazole (0,99 g, to 4.41 mmol) in acetonitrile (25 ml) is added 4-butylpiperazine (0,61 g, to 4.41 mmol) at RT. The reaction mixture was stirred at RT. for 3 days before adding water (50 ml). The aqueous phase is extracted with ethyl acetate (3×50 ml) and the combined organic phases are dried over MgSO4, filtered and evaporated in vacuum to obtain 1.40 g of crude product. The crude product is purified column chromatography (ethyl acetate:Meon:Et3N; 10:5:3), while receiving specified in the header connection 99. Yield 0.65 g (45%).1H-NMR (CDCl3): δ from 7.24 (d, 1H), 7,00 (d, 1H), 6,41 (t, 1H), 3,91 (s, 3H), to 3.58 (d, 2H), 3,20-to 2.99 (m, 4H), to 2.55 (t, 2H), 2,22 (square, 2H), 1,81 (d, 2H), 1,61 (K., 2H), 1.41 to a 1.08 (m, 7H), of 0.87 (t, 3H).13C-NMR (CDCl3): 154,9, 144,3, 143,3, 129,2, 113,1, 103,1, 99,8, 57,1, 55,4, 53,3, 35,3, 34,3, 29,5, 28,8, 25,6, 23,1, 22,8, 14,1.

Example 96. 3-[3-(4-Butylpiperazine-1-yl)propyl]-6-methoxy-1H-indazole (100) (53MF47). To a solution of 3-(3-chloropropyl)-6-methoxy-1H-indazole (0,99 g, to 4.41 mmol) in acetonitrile (25 ml) is added 4-butylpiperazine (0,61 g, to 4.41 mmol) at RT. The reaction mixture was stirred at RT. for 3 days before adding water (50 ml). The aqueous phase extrage the comfort with ethyl acetate (3× 50 ml) and the combined organic phases are dried over MgSO4, filtered and evaporated in vacuum to obtain 0.85 grams of crude product. The crude product is purified column chromatography (ethyl acetate:Meon:Et3N; 10:5:3), while receiving specified in the header of the connection 100. Yield 0.55 g (38%).1H-NMR (CDCl3): δ 7,42 (d, 1H), 6,80-6,72 (3, 2H), 3,80 (s, 3H), 3,60 (d, 2H), 3,11 of 2.92 (m, 4H), to 2.55 (t, 2H), 2,23 (square, 2H), 1,79 (d, 2H), 1.57 in (K., 2H), 1,40-1,08 (m, 7H), or 0.83 (t, 3H).13C-NMR (CDCl3): 160,8, 143,8, 142,6, 120,7, 116,2, 114,0, 91,2, 57,1, 55,6, 53,4, 35,3, 34,3, 29,5, 28,8, 23,7, 22,8, 22,7, 14,1.

Example 97. 3-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indazol-4-ol (101) (53MF51). 3-[3-(4-Butylpiperazine-1-yl)propyl]-4-methoxy-1H-indazole (28 mg, 0.09 mmol) dissolved in dry DCM (1.0 ml) and cooled to 0°C before adding a 1M solution of bromotryptamine in DCM (of 0.50 ml, 0.50 mmol). The reaction mixture was kept at RT. within 12 hours followed by addition of water (5 ml) and 2 n NaOH (10 ml). The aqueous phase is extracted with DCM (3×25 ml) and the combined organic phases are dried over MgSO4, filtered and evaporated in vacuum, thus obtaining 13 mg of crude product. Purification preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml) gives specified in the title compound (101) in the form of white crystals after washing DCM. Output: 6.0 mg, 17%.1H-NMR (CDCl3): δ to 7.18 (t, 1H), for 6.81 (d, 1H), 6,50 (t, 1H), 2,85 (d, 2H), 2,23 (t, 2H), 1,98 (square, 2N)and 1.83 (t, 2H), 1,62 (d, 2H), 1,41 (d, 2H), 1,21-a 1.01 (m, 9H), to 0.78 (t, 3H).

Example 98. 3-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indazol-6-ol (102) (53MF52). 3-[3-(4-Butylpiperazine-1-yl)propyl]-6-methoxy-1H-indazole (28 mg, 0.09 mmol) dissolved in dry DCM (1.0 ml) and cooled to 0°C before adding 1 M solution of bromotryptamine in DCM (of 0.50 ml, 0.50 mmol). The mixture was kept at RT. within 12 hours followed by addition of water (5 ml) and 2 n NaOH (10 ml). The aqueous phase is extracted with DCM (3×25 ml) and the combined organic phases are dried over MgSO4, filtered and evaporated in vacuum, thus obtaining 17 mg of crude product. Purification preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml) gives specified in the title compound (102) in the form of white crystals after washing DCM. Yield: 10 mg, 17%.1H-NMR (CD3OD): δ rate of 7.54 (d, 1H), 6,77 (s, 1H), of 6.71 (d, 1H), 3,55 (d, 2H), 3.15 in (t, 2H), 3.04 from (t, 2H), 2,90 (dt, 2H), 2,22 (square, 2H), 1,97 (d, 2H), 1,58 of 1.28 (m, 9H), to 0.92 (t, 3H).13With NMR (CD3OD): 159,0, 145,5, 144,4, 121,7, 117,2, 113,7, 94,4, 58,2, 54,3, 36,5, 34,8, 31,0, 29,7, 24,7, 24,3, 23,7, 14,3.

Example 99. 3-[3-(4-Butylpiperazine-1-yl)propyl]-1H-indazol-5-ol (103) (53MF50). 3-[3-(4-Butylpiperazine-1-yl)propyl]-5-methoxy-1H-indazole (28 mg, 0.09 mmol) dissolved in dry DCM (1.0 ml) and cooled to 0°C before adding 1 M solution of bromotryptamine in DCM (of 0.50 ml, 0.50 mmol). The mixture was kept at RT. within 12 hours followed by addition of water (5 ml) and 2 n NaOH (10 ml). The aqueous phase is extracted with DCM (3×25 ml) and the combined organic phases are dried over MgSO 4, filtered and evaporated in vacuum, while receiving 14 mg of crude product. Purification preparative HPLC followed by treatment with HCl in dioxane (4M, 2 ml) gives specified in the header of the connection (103) in the form of white crystals after washing DCM. Yield: 16 mg, 60%.1H-NMR (CD3OD): δ rate of 7.54 (d, 1H), 6,77 (s, 1H), of 6.71 (d, 1H), 3,55 (d, 2H), 3.15 in (t, 2H), 3.04 from (t, 2H), 2,90 (dt, 2H), 2,22 (square, 2H), 1,97 (d, 2H), 1,58 of 1.28 (m, 9H), to 0.92 (t, 3H).13With NMR (CD3OD): 159,0, 145,5, 144,4, 121,7, 117,2, 113,7, 94,4, 58,2, 54,3, 36,5, 34,8, 31,0, 29,7, 24,7, 24,3, 23,7, 14,3.

Example 100. The selection of the tested compounds in the analysis using subtypes of muscarinic receptors m1, m2, m3, m4 and m5. Subtypes of muscarinic receptors m1, m2, m3, m4 and m5 cloned essentially as described by Bonner et al., Science 273:527(1987) and Bonner et al., Neuron 1:403 (1988). Analyses of the R-SAT was performed essentially as described in U.S. patent No. 5707798, 5912132 and 5955281, and Braüner-Osborne & Brann, Eur. J. Pharmacol. 295:93 (1995). Cells NIH-3T3 (available from American Type Culture Collection as ATCC CRL 1658) were transfusional plasmid DNA that encodes the receptor subtypes m1, m2, m3, m4 or m5, and plasmid DNA, encoding β-galactosidase. Transfetsirovannyh cells were grown in the presence of from 1 nm to 40 μm of the test compounds for 5 days. On day 5 the cells were literally using a 0.5% Nonidet-P and the expression β-galactosidase activity was quantitatively determined using the chromogenic substrate o-nitrophenyl-β-D-galactoside (ONGP).

Data were normalized relative to the maximum response of cells to the muscarinic agonist carbachol and this data corresponds to the following equation:

response = minimum + (maximum - minimum)/(1+EC50/ligand])

where [ligand] = concentration of ligand

% efficiency was defined as:

(maximum-minimum)/(maximum response of cells to carbachol).

RES=-Log (EC50).

When the data give kolokoloobraznuyu curve "maximum" is defined as the highest observed responses.

The results demonstrate a selective agonistic activity of some compounds of the invention are presented below in table 1.

Table 1

The selectivity of muscarinic agonists
m1m2m3m4m5
Example% Eff.RES% Eff.RES% Eff.RES% Eff.RES% Eff.RES
12595,9no reactionno reaction no reaction
19867,3no reactionno reaction706,5no reaction
24756,9no reactionno reaction416,3no reaction
28386,5no reactionno reactionno reaction
32526,4no reactionno reactionno reactionno reaction
41816,9no reactionno reaction696,231<5,5
42517,1
43666,3 306,0no reaction
44726,1
61596,3no reactionno reaction396,0no reaction
65456,0no reaction34<5,5
73376,2no reaction
77717,0966,3
81726,477<5,5
89 857,3no reactionno reaction536,8no reaction
93837,1no reactionno reaction586,4no reaction
% Eff.: % Efficiency

pEC50: - log EC50

No reaction: Efficiency <25% of the maximum response to carbachol. This level of activity is considered as not significantly different from the level of "no reaction".

Example 101. The influence of the connection 35AKU-21 on intraocular pressure in primates. All analyses were performed on fully conscious female cynomolgus monkeys (macaques-kraboedy, Macacca fascicularis), weighing 3-4 kg Unilateral ocular hypertension caused argon laser photocoagulation middle of the trabecular network (Sawyer & McGuigan, Invest. Ophthalmol. Vis. Sci. 29:81 (1988).

Animals were prepared so that they are enabled to measure the intraocular pressure (IOP) pneumotonometer model 30 Classic (Mentor O&O Co.). Throughout each survey monkey was seated in a specially designed chairs (Primate Products, San Francisco) and have received the fruit and juice on demand.

The drug was administered to the local way. The drug is produced in aqueous solution, such as distilled water, saline or citrate buffer at pH 5-7 and used one-way in the form of 35 µl drops; the other eye received the same volume of saline solution (or filler). Two baseline measurements were carried out before the introduction of drugs with subsequent periodic measurements up to 6 hours after administration of the drug. The results of this study are shown below in table 2.

Table 2

Ocular hypotensive effect 35AKU-21 on monkeys with glaucoma
TIME (hour)
1246
% change in IOP-9,3-21,3-25,9-29,2
SEM2,25,06,56,2
N6666
The value p.008.009.016.012
The value of R is presented for comparison with the control-filler in the other eye.

1. The compound of formula (I):

where Z1is CR1or N, Z2is CR2, Z3is CR3or N, and Z4is CR4;

W1represents O, S or NR5one of W2and W3is N or CR6and the other of W2and W3is CG; W1is NG, W2is CR5or N, and W3is CR6or N; or W1and W3represent N, and W2is NG;

G represents the formula (II):

Y represents Oh, -C(O) -, or absent;

p is 1, 2, 3, 4 or 5;

Z is absent;

each t is equal to 2;

each R1, R2, R3and R4, independently, is H, hydroxyl, halogen, or an unbranched or branched C1-6-alkyl or C1-6-halogenated, or NO2;

each of R5and R6, independently, is H, C1-6-alkyl; formyl; (C3-6-cycloalkyl or5-6-aryl;

R10is H, unbranched or branched C1-8-alkyl, C1-8-alkyliden, C1-8-alkoxy, C1-8-alkoxycarbonyl,5-6-aryl or-C(O)NR12R13;

R'10is H, unbranched or branched C1-8-alkyl, C1-8-and who kileen, C1-8-alkoxy or C1-8-alkoxycarbonyl;

each R12and R13, independently, is H, C1-6-alkyl, optionally substituted with halogen or C1-6-alkyl;

or its pharmaceutically acceptable salt or ester.

2. The compound according to claim 1, where R10represents an unbranched or branched C2-8-alkyl, C1-8-alkylidene or C1-8-alkoxy.

3. The compound according to claim 2, where R10represents n-butyl.

4. The compound according to claim 2, where each of R1, R2, R3and R4independently, represents H, halogen, -NO2or unbranched or branched C1-6-alkyl.

5. The compound according to claim 2, where Y is absent or represents O, and p is 0, 1, 2, or 3.

6. The compound according to claim 5, where Z is absent, Y is absent and R is 3.

7. The compound according to claim 2, having a structure selected from the

where W1represents O, S or NR5, W2is CR5or N and W3is CR5or N.

8. The connection according to claim 7, where R5represents N or C1-6-alkyl.

9. The compound according to claim 2, where the compound has the formula

or

where W3is NR5or O.

10. The compound according to claim 1, where the connection specified is a

2-(3-(4-n-butylpiperazine-1-yl)propyl)benzothiazole;

2-(3-(4-n-butylpiperazine-1-yl)propyl)benzoxazol;

4,5-debtor-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

6-fluoro-5-nitro-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

5-tert-butyl-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

5-chloro-6-methyl-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

4,6-debtor-2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-benzoimidazol;

2-(3-(4-n-butylpiperazine-1-yl)propyl)-1H-imidazo[4,5-C]pyridine;

8-(3-(4-n-butylpiperazine)-1-ylpropyl)-N-purine;

7-(3-(4-n-butylpiperazine)-1-ylpropyl)-3,8-dihydroimidazo[4',5':3,4]benzo[1,2-d][1,2,3]triazole;

2-(3-(4-n-butylpiperazine-1-yl)propyl)-3A,4,5,6,7,7a-hexahydro-1H-benzoimidazol;

1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

3-methyl-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

5-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

3-formyl-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

7-bromo-1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indole;

1-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indazol;

3-(3-(4-n-butylpiperazine)-1-ylpropyl)benzo[d]isoxazol;

3-(3-(4-n-butyl is peridin)-1-ylpropyl)-1H-indole;

4-nitro-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

5-nitro-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

4-hydroxy-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

4-methyl-2-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-benzoimidazol;

3-(2-(4-n-butylpiperazine)-1-retil)-1H-indole;

3-(3-(4-n-butylpiperazine)-1-ylpropyl)-1H-indazol;

3-(2-(4-n-butylpiperazine)ethoxy)-7-methylbenzo[d]isoxazol;

1-(3-(4-n-methylpiperidine)-1-ylpropyl)-1H-indazol;

1-(3-(4-pentylpyridine)-1-ylpropyl)-1H-indazol;

1-(3-(4-propylpiperidine)-1-ylpropyl)-1H-indazol;

1-(3-(4-(3-methylbutyl)piperidine)-1-ylpropyl)-1H-indazol;

1-(3-(4-interidentified)-1-ylpropyl)-1H-indazol;

1-(3-(4-propylenpipeline)-1-ylpropyl)-1H-indazol;

1-benzo[b]thiophene-2-yl-4-(4-butylpiperazine-1-yl)butane-1-it;

4-(4-butylpiperazine-1-yl)-1-(3-methylbenzofuran-2-yl)butane-1-it;

4-(4-butylpiperazine-1-yl)-1-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)butane-1-it;

1-benzofuran-2-yl-4-(4-butylpiperazine-1-yl)butane-1-it;

1-(3-bromobenzo[b]thiophene-2-yl)-4-(4-butylpiperazine-1-yl)butane-1-it;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-butylpiperazine;

1-(3-benzofuran-2-ylpropyl)-4-butylpiperazine;

4-butyl-1-[3-(3-methylbenzo the Uran-2-yl)propyl]piperidine;

4-butyl-1-[3-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)propyl]piperidine;

2-(3-improper)benzo[b]thiophene;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-methylpiperidin;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-benzylpiperidine;

1-(3-benzo[b]thiophene-2-ylpropyl)-4-(2-methoxyphenyl)piperidine;

2-(3-bromopropyl)-2H-benzotriazole;

2-[3-(4-butylpiperazine-1-yl)propyl]-2H-benzotriazole;

1-(3-bromopropyl)-1H-benzotriazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-1H-benzotriazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indole-3-carbaldehyde;

{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-yl}methanol;

1-[3-(4-butylpiperazine-1-yl)propyl]-2-phenyl-1H-benzoimidazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-3-chloro-1H-indazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-6-nitro-1H-indazol;

benzo[d]isoxazol-3-ol;

3-(2-chloroethoxy)benzo[d]isoxazol;

3-[2-(4-butylpiperazine-1-yl)ethoxy]benzo[d]isoxazol;

3-(1H-indol-3-yl)propan-1-ol;

hydrochloride 3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indole;

metrowater 4-(4-butylpiperazine-1-yl)butyric acid;

2-[3-(4-butylpiperazine-1-yl)propyl]-1-methyl-1H-benzimidazole;

(2-(4-butylpiperazine)-1-retil)amide 1H-indazol-3-carboxylic acid;

1-[3-(4-butylpiperazine-1-yl)propyl]-5-nitro-1H-indazol;

2-[3-(4-butile Eridan-1-yl)propyl]-5-nitro-2H-indazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-2-methyl-1H-indole;

1-{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-yl}Etalon;

{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-yl}acetonitrile;

1-[3-(4-butylpiperazine-1-yl)propyl]-1H-indol-3-carbonitrile;

1-[3-(4-butylpiperazine-1-yl)propyl]-5,6-dimethyl-1H-benzoimidazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-5(6)-dimethyl-1H-benzoimidazol;

1-[3-(4-butylpiperazine-1-yl)propyl]-5-methoxy-1H-benzoimidazol;

{1-[3-(4-butylpiperazine-1-yl)propyl]-1H-benzoimidazol-2-yl}methanol;

1-[3-(4-butylpiperazine-1-yl)propyl]-2-trifluoromethyl-1H-benzoimidazol;

tert-butyl ether (2-trimethylammoniumphenyl)carbamino acids;

tert-butyl ether [2-(4-chlorobutyryl)phenyl]carbamino acids;

tert-butyl ether {2-[4-(4-butylpiperazine-1-yl)butyryl]phenyl} carbamino acids;

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol, HCl;

3-[3-(4-butylpiperazine-1-yl)propyl]-5-nitro-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-5,7-dinitro-1H-indazol;

4-(4-butylpiperazine-1-yl)-1-(2-methylsulfinylphenyl)butane-1-it;

3-[3-(4-butylpiperazine-1-yl)propyl]benzo[d]isothiazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-5-methoxy-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-4-methoxy-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)p is filing]-6-methoxy-1H-indazol;

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol-4-ol;

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol-6-ol or

3-[3-(4-butylpiperazine-1-yl)propyl]-1H-indazol-5-ol.

11. The compound according to claim 1 as an active ingredient of a pharmaceutical composition that increases activity of muscarinic cholinergic receptors.

12. The method of increasing the activity of the muscarinic cholinergic receptor, comprising contacting the muscarinic cholinergic receptor or a system containing the specified receptor with an effective amount of at least one compound according to claim 1.

13. The method according to item 12, where muscarinic cholinergic receptor is a receptor selected from muscarinic receptor subtypes m1 and m4, and where muscarinic receptor is a receptor of the Central nervous system, receptors of the peripheral nervous system, receptor gastrointestinal system, heart, endocrine glands or lungs.

14. A method for the treatment of painful conditions associated with muscarinic cholinergic receptor or associated with reduced levels of acetylcholine, including introduction to the subject in need of such treatment, an effective amount of at least one compound according to claim 1, where the disease state is selected from the group consisting of reduced cognitive ability is, forgetfulness, confusion, memory loss, attention deficit, deficits in visual perception, depression, psychosis, hallucinations, aggressiveness, paranoia, increased intraocular pressure, Alzheimer's disease, schizophrenia, dementia, age-related variance in cognitive abilities and glaucoma.



 

Same patents:

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

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

9 cl, 1 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to an efficient and economical methods of producing intermediates for the synthesis of HIV protease inhibitors, related nelfinavir-mesilate and including nelfinavir-mesilate

The invention relates to a tool that activates the germination of wheat seeds, which means using 4-(5-R-2-furyl)methylidene-2-phenyl-5(4H)-oxazolone formula 1, in which 1.1 R=-C6H5; 1.2 R=p-CH3-C6H4; 1.3 R= p-Br-C6H4

The invention relates to new piperidine derivative of formula (I)

< / BR>
where X represents the group< / BR>
Ar represents phenyl, one-deputizing or disubstituted by a halogen atom or (C1-C3)alkyl, R1represents a chlorine atom, a bromine atom, (C1-C3)alkyl or trifluoromethyl, R2represents a group-CR3R4СОNR5R6, R3and R4represent identical radicals selected from methyl, ethyl, n-propyl or n-butyl, or R3and R4together with the carbon atom form a (C3-C6)cycloalkyl, R5and R6represent hydrogen, (C1-C3)alkyl or together with the nitrogen atom form a 4-morpholinyl, or their salts, solvate or hydrate

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

Chalcone coumarins // 2266291

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): or their pharmaceutically acceptable salts or solvates wherein Ar represents a substituted or unsubstituted (preferably aromatic one) carbocyclic or heterocyclic group wherein abovementioned carbocyclic or heterocyclic group comprises 5 or 6 atoms in cyclic structure wherein a heteroatom is taken among the group consisting of nitrogen (N) and sulfur (S) atom and any substitutes at Ar group are taken independently of one another of the group consisting of Cl, Br, F atoms and OR10 wherein R10 represents saturated or unsaturated lower hydrocarbon (C1-C6)-radical of normal or branched structure; R represents OR10 wherein R10 corresponds to above given value; R1 represents lower hydrocarbon (C1-C6)-radical of normal or branched structure under condition that if R1 represents -CH3 and R means -OCH3 or -OH then Ar group can't represent 4-methoxyphenyl or 3,4-dimethoxyphenyl. Also, invention proposes a component of medicinal agent used in treatment or prophylaxis of neoplasms. Also, invention proposes a pharmaceutical composition possessing with an anti-proliferative activity and comprising the effective amount of one or some compounds of the formula (I) in combination with one or some pharmaceutically acceptable additives. Invention provides the development of chalcone coumarins possessing with the enhanced anti-proliferative effect with respect to sensitive tumor cells, cells with resistance to conventional chemotherapeutic agents, among them, to anti-tumor medicinal agents of the last generation represented by paclitaxel and docetaxel.

EFFECT: valuable medicinal properties of compounds and compositions.

1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

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

25 cl, 1 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new 5-aryl-1-phenyl-4-heteroyl-3-hydroxy-3-pyrroline-2-ones of the formula:

wherein (1) X means sulfur atom (S); R means (CH3)2CH; (2) X means sulfur atom (S); R means (CH3)3C; (3) X means oxygen atom (O); R means (CH3)3C. Compounds of the formula (I) are prepared by interaction of the corresponding heteroylpyruvic acid methyl ester with mixture of aniline and aromatic aldehyde in acetic acid medium at short-time heating. Compounds elicit an anti-bacterial activity with value MIC = 3.9-7.8 mcg/ml as compared with 62-1000 mcg/ml for analogue.

EFFECT: valuable properties of compounds.

1 tbl, 3 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

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