Chromone derivatives, method for preparing them and therapeutic uses thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chromone derivatives of general formula

,

wherein: R1 represents one or more identical or different substitutes on a benzene ring, each of which independently represents a hydrogen atom, or a halogen atom, or C_1-4 alkoxy group, or OH group. or group -O(CH₂)_nO-, wherein n=1 or 2, R2 represents a hydrogen atom, or C_1-4 alkyl group; A and B independently represent either a nitrogen atom, or a carbon atom; R3 represents a hydrogen atom or one or more identical or different substitutes specified in a group consisting of: a halogen atom, C_1-4 alkyl group, C_1-4 alkoxy group, group -O(CH₂)_nO-, wherein n=1 or 2, group NO₂, group NHSO₂R4, group NHR5, OH group, C_1-4 halogenoalkyl group, CN group, or R3 makes a ring condensed with a benzene ring bearing it, specified in a group consisting of indole, benzimidazole, carbostyril, benzoxazolone and benzoxazolone and benzimidazolone, R4 represents C_1-4 alkyl group, or C_1-4 dialkylamino group, or C_1-4 alkoxyalkyl group, or C_1-4 dialkylaminoalkyl group, R5 represents a hydrogen atom, or C_1-4 alkylcarbonyl group, or C_1-4 alkoxycarbonyl group, and to its pharmaceutically acceptable salts, as well as to methods for preparing them, and to based pharmaceutical compositions, and to using them as a therapeutic agent for central nervous system disorders, as long as they possess the D3 dopaminergic ligand properties.

EFFECT: preparing the compositions for treating central nervous system disorders, as long as they possess the D3 dopaminergic ligand properties.

17 cl, 1 dwg, 2 tbl, 33 ex

The present invention relates to a derivative of Romanov, to methods for their preparation, to contain their pharmaceutical compositions and to their therapeutic applications as agonists, partial agonists or antagonists of dopamine receptor D3 (DRD3) for the treatment of various neurological and psychiatric conditions.

Schizophrenia is a term used to describe a group of pathologies of unknown origin, which affects approximately 1% of the total population. This pathology is characterized by a variety of symptoms that are classified as positive symptoms (hallucinations, delusions, disordered thought) and negative symptoms (social withdrawal and affective stupidity) in the pubertal age of onset or age of onset of puberty, and can persist in the chronic form with episodes of exacerbation for many years.

Patients with schizophrenia can be treated with drugs called neuroleptics, also known as antipsychotics. therapeutic effect of antipsychotic drugs known as a result of the blockade of receptors of the neurotransmitter dopamine in the brain. There are five subtypes of dopamine receptors, called D1, D2, D3, D4 and D5 (Sokoloff, P. et al., Novel dopamine receptor subtypes as targets for antipsychotic drugs. Annals New York Academy of Sciences 1995, 757, 278), and �conventional antipsychotics are antagonists of D2 and D3 receptors. However, antipsychotics are often responsible for undesirable extrapyramidal side effects (APE) and abnormal movements called late dyskinesias, which are inherent to the blockade of the D2 receptor in striatal areas of the brain. Suggested that blockade of the receptor D3 (DRD3) is responsible for therapeutic effects of antipsychotic drugs (J. C. Schwartz et al., Eur. Neuropsychopharmacol. 2003, 13 fsuppl. 4): S 166). Therefore, pharmacological agents that selectively modulate the function of DRD3, is considered an effective antipsychotic drug, free from neurological side effects (international patent application WO91/15513).

Selective modulation of the DRD3 receptor can be achieved by using molecules that selectively bind with DRD3 and which act as agonists, antagonists or partial agonists. Antipsychotic activity as a result of modulating the function of DRD3 can be predicted on animals by the use of models of schizophrenia in mice (L. Leriche et al., Neuropharmacology 2003, 45, 174). In addition, it is demonstrated that selective blockade of DRD3, but not simultaneous blockade of DRD2 and DRD3, increases extracellular levels of dopamine and acetylcholine, another neurotransmitter, in the prefrontal cortex (L. P. Lacroix et al., Neuropsychophamacol. 2003, 28, 839). Dopamine and acetylcholine in the brain are �significant for cognitive function. Therefore, believe that selective DRD3 antagonists can improve cognitive ability, which is impaired in schizophrenia, as well as in neurodegenerative pathologies such as Alzheimer's disease.

Antipsychotics in General and aripiprazole, quetiapine and olanzapine in particular used in the treatment of acute manic phase of bipolar disorder. Antagonists or partial agonists DRD3, therefore, also considered as medicinal products for the treatment of bipolar disorder.

Genetically modified mice carrying a mutation that disables DRD3 (DRD3 "knockout"), are less anxious in behavioral tests that predict anxiogenic or anxiolytic activity (Steiner H. et al., 1: Physiol Behav. 1997, 63, 137-41). Therefore, pharmacological disabling DRD3, such as is obtained by applying antagonist DRD3 described in the present invention is also the treatment of anxiety.

Depression is a common pathology of mood characterized by feelings of deep anguish, pessimistic thoughts and lowering your self-esteem, often accompanied by loss of energy, enthusiasm and libido. The inability to feel pleasure from normally pleasurable impressions, also known as anhedonia, is also considered as General �ymptom for depression. A significant role in pleasure and motivation attributed to dopaminergic neurons in a brain region called the adjacent core (Koob G. F. et al., Sem. Neurosci. 1992, 4, 139; J. D. Salamone et al., Behav. Brain Res. 1994, 61, 117). Therefore, suggest that these neurons are involved in the neurobiology of depression, including anhedonia, and in therapeutic effects of some antidepressant drugs (S. Kapur and Mann J. Biol. Psychiatry 1992, 32, 1-17; Willner P., Int. Clin. Psychopharmacol. 1997, 12, S7-S14). Demonstrated that different antidepressant therapy selectively increase the expression of DRD3 in the nucleus accumbens (Lammers, C. H. et al., Mol. Psychiatry 2000, 5, 378), which suggests that improving the function of the DRD3 could be a new way of antidepressant therapy. Improving the function of the D3 receptor DRD3 can be achieved through the use of agonists or partial agonists DRD3, which can, therefore, be an effective therapy for depression.

Dependence on drugs or substances causing addiction, also known as drug dependence, is a chronic and relapsing pathology, in which the behavior, including risky reception and the search for substances, addictive, and compulsive behavior medication persists despite negative consequences received by the patient (Deroche-Gamonet, V. Et al., Science 2004, 305, 1014; Vanderschuren L. J. et al., Science 2004, 305, 1017). F�nomen cancel, that occurs during withdrawal from substances, addictive, can be triggered or exacerbated by environmental stimuli that acquire motivational force as a result of the fact that they repeatedly linked to effects of medication, as in humans (A. R. Childress et al., Am. J. Psychiatry 1999, 156, 11; Robinson, T. E. et al., Brain Research Reviews 1993, 18, 247) and in animals (Goldberg S. R. et al., NIDA Res. Monogr. 1981, 37, 241; M. Arroyo Psychopharmacology Is 1999, 140, 331). In animals highly selective agonists or partial antagonists DRD3 reduce specific responses to stimuli associated with cocaine (M. Pilla Nature, 1999, 400, 371; Le Foil, V. Eur. J. Neurosci. 2002, 15, 2016; Vorel, S. R. J. Neurosci. 2002, 22, 9595), opiate (Frances H. et al., Neuroreport 2004, 15, 2245) or nicotine (Le FoilB. et al., Mot. Psychiatry 2002, 8, 225), at the same time without affecting the primary effects of these drugs. The density of DRD3 is abnormally high in the brains of cocaine addicts (Staley, J. K. et al., J. Neurosci. 1996, 16, 6106). Therefore, partial agonists or antagonists DRD3 considered effective drugs to ease withdrawal symptoms and reduce the risk of relapse.

Parkinson's disease is a pathology characterized by tremor at rest, rigidity of the limbs and akinesia (difficulty at the beginning of the movement). This disease is caused by degeneration of dopaminergic neurons. The treatment of Parkinson's disease based on the replacement of dopamine through the introduction�ia L-dihydroxyphenylalanine (L-DOPA) or direct dopamine agonists. Prolonged use of L-DOPA, however, associated with a very large number of cases of the appearance of abnormal movements called dyskinesias. In models of Parkinson's disease in nonhuman primates demonstrated that the modulation of DRD3 highly selective partial agonist attenuates dyskinesia (E. Bezard et al., Nat. Med. 2003, 6, 762). Compounds described herein, therefore, considered as an additive therapeutic agents in Parkinson's disease. However, it is demonstrated that agonist DRD3 increases neurogenesis in rats, therefore, agonists DRD3 may also be drugs that slow the progression of this disease.

Mutation in the gene DRD3 and associated segregates together with essential tremor, a common and inherited neurological disorder characterized by tremor of the action of all parts or body parts in the absence of any other neurological disorders (Jeanneteau et al., Proc. Natl. Acad. Sci. USA 2006, 103, 10753). This mutation increases the function of the DRD3. Normalizes the function of the DRD3 through the use of partial agonists or antagonists DRD3 could therefore be an effective therapy for essential tremor.

Dopamine controls erectile function, and dopaminergic agents proposed as a therapy for erectile dysfunc�AI (F. Guiliano, Ramplin O. Physiol Behav. 2004, 63, 189-201). More specifically, proerectile effects of dopaminergic agonists are mediated by the D3 receptor in rodents (G. T. Collins et al., J. Pharmacol. Exp. Ther., 2009, 329, 210-217), and selective D3 receptor antagonist delays ejaculation during coitus in rats (P. Clement et al., J. Sex. Med., 2009, 6, 980-988). Agonists, partial agonists and antagonists DRD3, such as those described in the present invention can, thus, be a therapy for various dysfunctions erectile function.

In the literature mentioned phenylpiperazine for use in malaria control in Biochemical and Biophysical Research Communications 2007, 358(3), 686. In Indian J. Chem., section B, 2002, 41 B(4), 817 described compounds phenylpiperazines. Maniowy base using methoxyamine known from Farmaco Edizione Scientifica 1977, 32(9), 635. In the description of the patent US 3410851 described flavones having anticonvulsant, analgesic and bronchodilatators properties. Compounds of the present invention are characterized by the fact that they have a carbon chain of 4 metileno between romanovas grouping and phenylpiperazine, which gives them the property of the ligands of the dopamine D3 receptor.

In the patent applications WO 2003028728, WO 2004004729 and WO 2006077487 and in the patent specification EP 1841752 described as ligands DRD3. In the patent application WO 2008009741 mentioned chromen - and t�komentarbellamy, showing affinity for the dopamine D3 receptor, for use as an antipsychotic. In the patent application WO 2006072608 mentioned arylpiperazine with modulating properties in respect of dopaminergic and serotonergic receptors, for use in neuropsychiatric disorders such as schizophrenia. In the publication J. Med. Chem. 2009, 52, 151 also mentioned the same derivative. All of these products are described in the above quoted descriptions of inventions, have carboxamido chain in its structure. The products of the present invention differ from the compounds described in that they do not have carboxamide chain, but are unexpectedly effective ligands dopaminergic D3 receptor.

As used above, the term "dopamine receptor D3", "D3 receptor" or "DRD3" means the subtype of dopamine receptor, mainly expressed in the limbic system (Sokoloff P, et al., Nature, 1990, 347, 146-151). DRD3 described in international patent application WO 91/15513.

As used above, the term "partial agonist of the receptor D3" means a compound which forms a complex with DRD3 and acts as a combined agonist-antagonist, meaning it induces a physiological response of the lower intensity than the natural neurotransmitter, dopamine. In vitro in a cell expressing DRD3, a partial agonist of the DRD3 producere� active response, the maximum intensity of which is lower than the response produced by dopamine or full agonist, such as quinpirole (TRANS(-)-4aR-and 4,4,5,6,7,8,8 and,9 octahydro-5-propyl-1H(or 2H)pyrazolo [3,4 g]quinoline). Partial agonist DRD3 may also partly to prevent the response produced by dopamine or its agonists. In vivo partial agonist DRD3 produces dopaminergic responses, in particular, when the level of dopamine is reduced, as is the case in rats with damage caused by 6-hydroxydopamine, or in monkeys with intoxication 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). In addition, in vivo partial agonist DRD3 may act as antagonist, in particular when DRD3 subjected to limited stimulation by dopamine.

"Antagonist DRD3" means a molecule that forms a complex with DRD3 and is able to prevent response triggered by dopamine or its agonist in a cell expressing DRD3.

As used in this application, the term "salt" means a salt of accession inorganic acid or base compounds of the present invention. Preferably the salts are pharmaceutically acceptable, i.e. they are non-toxic to the patient, to whom they are administered.

The expression "pharmaceutically acceptable" refers to molecular substances and compositions that do not produce any harmful alle�environmental effect or other adverse reactions when administered to an animal or person.

When used in this application, the expression "pharmaceutically acceptable excipient" includes any diluent, adjuvant or excipient, such as a preservative, filler, disintegrant, wetting agent, emulsifier, dispersing agent, an antibacterial or antifungal agent or agents, which will give the opportunity to slow absorption and resorption in the small intestine and the digestive system. The use of these environments or vectors well known in the art. Except in those cases where the agent is chemically compatible derivative chromone, consider its application to pharmaceutical compositions containing the compounds in accordance with the invention.

In the context of the invention, the term "treatment" as used in this application, means the prevention or inhibition of the occurrence or progression of the condition to which apply the term, or one or more than one symptom of this condition.

"Therapeutically effective amount" means the amount derived chromone that is effective in obtaining the desired therapeutic effect in accordance with the invention. According to the invention, the term "patient" refers to a person or a mammal other than the person affected or prone to lesion pathology. Preferred�positive patient is a human.

In the context of the present invention With_1-4alkyl group is understood as a normal or branched hydrocarbon chain containing from 1 to 4 carbon atoms, such as methyl group, ethyl group, propyl group or butyl group.

In the context of the present invention With_1-4alkoxy group is understood as a normal or branched hydrocarbon chain containing from 1 to 4 carbon atoms and an oxygen atom, such as methoxy group, ethoxy group, propoxy group or butoxy group.

In the context of the present invention With_1-4dialkoxy group understand how normal or branched hydrocarbon chain containing from 1 to 4 carbon atoms, an oxygen atom and a sulfur atom, for example, dimethoxy group, tiaoxi group, dipropoxy group or dibutoxy group.

In the context of the present invention With_1-4dialkylamino understand how Amin, disodium normal or branched C_1-4alkyl groups such as a dimethylamino group, a group of diethylamino, a group of dipropylamino or group of dibutylamine.

In the context of the present invention, the halogen means fluorine, chlorine or bromine.

In the context of the present invention With_1-4halogenoalkane group understand how_1-4alkyl group, monosubstituted, disubstituted or trisubstituted ha�ogena, for example a group of CF₃group CHF₂, a group of CH₂F, group CCl₃group CHCl₂, a group of CH₂Cl, CBr group₃group CHBr₂or a group CH₂Br group.

In the context of the present invention With_1-4dialkylaminoalkyl group understand how_1-4dialkylamino, as defined above, associated with C_1-4alkyl group of a carbon atom, for example dimethylaminomethylene group, dimethylaminoethyl group, diethylaminomethyl group or diethylaminoethyl group. In the context of the present invention, C_1-4alkoxyalkyl group understand how_1-4alkyl group, as defined above, associated with C_1-4alkyl group of a carbon atom, for example methoxymethyl group, ethoxymethyl group, methoxyamino group or ethoxyethylene group.

In the context of the present invention With_1-4hydroxyalkyloxy group know as the alkyl group, as defined above in which a hydrogen atom is substituted with a hydroxyl group, e.g. the group CH₂OH, group C₂H₄OH, group C₃N₆HE or group With₄N₈HE.

In the context of the present invention With_1-4alkylcarboxylic group know as the alkyl group, as defined above, linked to the carbonyl group carbon atom, for example a group of PINE trees_{3 group SOS2N5group SOS3N7or group COC4H9.}

In the context of the present invention With_1-4alkoxycarbonyl group understand how alkoxy group, as defined above, linked to the carbonyl group carbon atom, for example a group of SOON₃group SOOS₂N₅group SOOS₃N₇or group COOC₄H₉.

In the context of the present invention With_1-4phenylalkyl group understand how the phenyl group connected to the carbon atom with an alkyl group as defined above.

The invention relates to a derivative of Romanov, to methods for their preparation and to their use as a medicament, as ligands of the DRD3 receptor, for the treatment of neurological or psychiatric diseases, conditions or disorders. These compounds correspond to the General formula 1:

General formula 1

where:

R1 represents one or more than one identical or different substituents on the benzene ring, each of which independently represents a hydrogen atom or a halogen atom, or C_1-4alkoxy group or IT group, or C_1-4alkyl group or a group-O(CH₂)_nO-, in which n=1 or 2.

- R2 represents a hydrogen atom or a C_1-4alkyl group.

- R3 represents a hydrogen atom or one or more than one identical or different substituents selected from the group consisting of: halogen atom, a C_1-4alkyl group, a C_1-4alkoxy or C_1-4dialkoxy groups,- O(CH₂)_nO-, in which n=1 or 2, group NO₂group NHSO₂R4, NHR5 group, IT group_1-4halogenoalkanes group, CN group, a C_1-4alkoxycarbonyl group_1-4alkylcarboxylic group, a C_1-4hydroxyalkyloxy group and benzyl or phenyl Deputy, optionally substituted C_1-4alkoxy or C_1-4an alkyl group or a halogen atom,

or R3 is a ring condensed with a benzene ring, a carrier selected from the group consisting of naphthalene, indole, benzimidazole, barbastella, benzoxazolone and benzimidazolone.

- R4 represents a C_1-4alkyl group, or a C_1-4dialkylamino, or C_1-4alkoxyalkyl group, or C_1-4dialkylaminoalkyl group or phenyl or phenyl-C_1-4alkyl group,

R5 represents a hydrogen atom, or C_1-4alkylcarboxylic group, or C_1-4alkoxycarbonyl group,

and their pharmaceutically acceptable salts.

In accordance with the invention compounds of the General formula (I) are compounds where:

- R₁represents one or more than one identical or different substituents selected from the group consisting of C_1-4alkoxy groups, Oh groups and group-O(CH₂)_nO-, in which n=1 or 2.

In accordance with the invention compounds of the General formula (I) are compounds where:

- R₂represents a hydrogen atom.

In accordance with another embodiment of the invention compounds of the General formula (I) are compounds where R3 represents a hydrogen atom, when A and/or b represents a nitrogen atom.

In accordance with the invention compounds of the General formula (I) are compounds where:

- A and b simultaneously represent a carbon atom. In accordance with the invention compounds of the General formula (I) are compounds where:

- R3 represents one or more than one identical or different substituents selected from the group consisting of: halogen atom, a C_1-4alkoxy groups,- O(CH₂)_nO-, in which n=1 or 2, groups NHSO₂R4, Oh groups and CN groups.

In accordance with another embodiment of the invention compounds of the General formula (I) are compounds where:

-R3 together with baselinemag.com, a carrier, is an indole group, or benzimidazolyl group, or carboncillo group.

In accordance with another embodiment of the invention compounds of the General formula (I) are compounds where:

- R1 is one or two identical or different substituents, each independently represents a methoxy group or a group-O(CH₂)_nO-, in which n=1 or a group.

- R2 represents a hydrogen atom.

- A represents a carbon atom and represents a nitrogen atom or a carbon atom.

when A and b represent a carbon atom:

- R3 represents one or two identical or different substituents selected from the group consisting of: a hydrogen atom, a CN group, chlorine atom, fluorine atom, the Oh group, the group NO₂group NHSO₂R₄, NHR5 group, groups, CF₃, methoxy group,

or R3 forms a ring condensed with a benzene ring, a carrier selected from the group consisting of: benzimidazole, benzoxazole, indole, benzimidazole and barbastella.

when a is a carbon atom and represents a nitrogen atom:

- R3 represents a hydrogen atom

- R4 represents a methyl group, or ethyl group, or dimethylaminoethyl group, or ethoxymethyl group.

- R5 p�ecstasy a hydrogen atom, a group of PINE trees₃or group of SOON₃.

The following are examples of compounds in accordance with the invention are:

- 6,7-dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

- 3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-benzonitrile

- 3-{4-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

- 3-{4-[4-(3-hydroxyphenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

- 6,7-dimethoxy-3-[4-(4-pyrimidine-2-yl-piperazine-1-yl)-butyl]-chromen-4-he

- 6,7-dimethoxy-3-[4-(4-pyridin-2-yl-piperazine-1-yl)-butyl]-chromen-4-he

- 3-{4-[4-(2,3-differenl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

- 3-{4-[4-(1 N-benzimidazol-4-yl)piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

- 3-{4-[4-(1H-indol-4-yl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

- 5-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1H-quinolin-2-he

- 6,7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}-chromen-4-he

- 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl-]-butyl}-6,7-dimethoxyfuran-4-he

- N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide

- N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-Hairdryer yl)-acetamide

- methyl-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-carbamate

- 7-{4-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

- 7-{4-[4-(2,3-d�fluorophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

- 7-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

- 7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

- N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl-acetamide

- N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide

- N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-econsultant

- 2-dimethylaminoethanol acid(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-amide

- 2-methoxyethanol acid(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-amide

- 7-{4-[4-(1H-indol-4-yl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

- 3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

- 6-methoxy-3-[4-(4-phenylpiperazin-1-yl)-butyl]-chromen-4-he

- 6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

- 6-methoxy-3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-chromen-4-he

- 7-{4-[4-(2,3-dichlorophenyl)piperazine-1-yl-]-butyl}-6-methyl-[1,3]dioxolo[4,5-g]chromen-8-he

- 6,7-methoxy-7,6-hydroxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

- 7-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-3H-benzoxazol-2-he

- 4-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1,3-dehydrobenzperidol--he.

The invention also relates to pharmaceutically acceptable salts, as well as containing their pharmaceutical compositions and to their use as medicaments intended for the treatment of disorders of the Central nervous system.

The invention also relates to a method for producing these compounds.

Compounds of the General formula 1 are given in accordance with scheme 1.

Scheme 1

The reaction of the Friedel - crafts or reaction of fries with methoxy substituted aromatic compound 2 (Y=Me) or substituted phenol compound 3 (Y=N) gives an aromatic ketone 3 (Y= Me, H). In this reaction, use a halide omega-halogenated hexanoic acid, such as 6-bromohexadecane. Condensation occurs with the solvent or without solvent in the presence of a Lewis acid, such as AlCl₃in accordance with the method similar to that described in Chem. Ber. 1939, 72, 1414, or J. Org. Chem. 1955, 20, 38, chlorine - or bromoacetylation or bromide. In this application in this reaction are using bromohexadecane, which condenses in the ortho-position of the phenolic functional groups with the formation of the derivative 3. Where to use a solvent, it is possible to use chlorinated solvent such as methylene chloride, for reaction at ambient temperature or at low temperature if�about for the reaction at a higher temperature, for example, use dichloroethane or 1,1,2,2-tetrachlorethane. Used phenols with appropriate substituents are either commercially available or known from the literature, and they are obtained by demethylation in the presence of agents that are usually used for demethylation of aromatic methoxy compounds, such as NVH and of a Lewis acid (AlCl₃, BBr₃). The reaction of the Friedel - crafts may also be held on methoxylamine aromatic ring, rich in electrons. Stage demethylation with obtaining the intermediate 3 can go after the step of acylation. Phenol 3 (Y=H), acylated thus, it is possible to collisional dimethylformamide acetal (=DMF) or dimethylamine (DMA) when heated with obtaining halogenated chromone 4. This reaction circuit ring to form chromone can also be carried out in DMF in the presence of PCl₅and epirate BF₃and ethylformate in the presence of sodium in accordance with Bull. Soc. Chim. Fr. 1944, 5, 302. Then halogenmethyl-derived chromone 4 is combined with the substituted arylpiperazine or heteroarylboronic formula 5 in a standard way in the presence of base, such as₂CO₃or cesium carbonate in acetonitrile or methyl ethyl ketone to obtain derivatives of formula 1. This method is used with the piperazines of formula 5, where A, b and R3 are the main advantages of�are such, as defined above. You can use a variant of this method, which includes the introduction of piperazino group before the formation hramovogo ring: thus, condensation of piperazine of formula 5 with a halogenated phenol of the formula 3 in the conventional alkylation conditions in an alkaline medium (K₂CO₃/CH₃CN or methyl ethyl ketone) to give a compound of formula 6. Then education hramovogo ring can be realized by short-circuiting rings with DMF or DMF acetal or DMA. Using this method, the introduction of piperazine before cyclization to chromone allows to obtain more pure cyclosiloxane connection than by way of formation of chromone, since the derivative 3 (Y=N). Indeed, the conditions of heating to form a ring DMF at an elevated temperature forms dimethylamine, which can interact with halogenated derivatives 3 with obtaining a secondary product (formula 4, X=NMe₂) and requires additional purification. Specialist in the art will choose the appropriate method in accordance with the substituents borne by phenylpiperazin 5. Modification of the Vice-piperazine can also be implemented in the latter stages, as, for example, using piperazine of the formula 5 (A=b=C, R3=3-NO₂). The restoration of the nitro group in the product of formula 1 (A=b=C, R3=3-NO_{2 ) is usually carried out by catalytic reduction with hydrogen using palladium on carbon or Raney Nickel, or by treatment with a metal such as iron, in an acidic medium to provide the corresponding aniline (formula 1, A=b=C, R3=3-NH2). Aniline group can thus be allievate in the presence of pyridine or other base acetylchloride with getting acetamide derivative, methylchloroform with obtaining methylcarbamate or methanesulfonamido with obtaining methylsulfonate. The interaction of chloroethylsulphonic can be done in the same way, and then intermediate vinyl compound can be combined with dimethylamine or with sodium methoxide to obtain respectively the Deputy of dimethylbenzenesulfonamide or methoxyethylamine. In the literature mentioned heterocyclic arylpiperazine, such as 4-piperazine-1-yl-1H-indole piperazine-1-yl-1H-benzimidazole, 7-piperazine-1-yl-3H-benzoxazol-2-on, 4-piperazine-1-yl-1,3-dehydrobenzperidol-2-on, 5-piperazine-1-yl-1H-quinolin-2-it. Heterocyclic piperazines can be prepared by reacting the corresponding anilines with nitrous epitamy (mechlorethamine). These nitrogenous IPrice can be N-substituted with a protective group is benzyl, which can be removed by simple experimental data showed with Pd/C in atmospheres� hydrogen, when implemented condensation with piperazine (Fr2504532; Fr2524884; Bioorg. Med. Chem. Lett. 1998, 8, 2675; Bioorg. Med. Chem. Let. 2001, 11, 2345, J. Med. Chem. 2002, 45, 4128; J. Med. Chem. 2004, 47, 871; Synth. Commun. 2006, 36, 1983; Synthesis 1977, 33; Tet Let. 1970, 5265; Chem. Pharm. Bull. 1981, 29, or 651 1979, 27, 2627; Tet. 2000, 56, 3245).}

Thus, the invention also relates to methods described below:

A method of producing compounds of the General formula 1, characterized by the fact that may get substituted chroman formula 4 (X=Cl, Br, I), which is subjected to interaction with a piperazine of the formula 5.

The radicals R1, R2, R3, A and b have the meanings given above. A method of producing compounds of the General formula 1, characterized by the fact that may get substituted phenol derivative of formula 6, starting with the compound of formula 3 (X=Cl, Br), and subjected to interaction with DMF (dimethylformamide), or dimethylacetal DMF, or DMA (dimethylamine).

The radicals R1, R3, A and b have the meanings given above, in the alkylation conditions in the presence of base, such as₂CO₃Cs₂CO₃or NEt₃, in a solvent such as acetonitrile or methyl ethyl ketone.

The invention also relates to pharmaceutical compositions containing at least one compound of the General formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable� excipient.

With regard to selective modulation of transmission signals of dopamine, through the DRD3 receptor in limbic areas involved in emotional and cognitive processes, the compounds according to the invention is suitable for various therapeutic applications and does not interfere with the dopaminergic transmission signals extrapyramidal system, the system of the anterior pituitary or the autonomic system (for example, the rear of the field). The compounds according to the invention can thus be used to produce pharmaceutical compositions and medicaments for the treatment of neurological or psychiatric diseases, conditions or disorders that involve the DRD3 receptor, such as psychotic state.

In addition, because the effect of antidepressant drugs is to increase the expression of the DRD3 receptor in the brain regions involved in motivation, the compounds according to the invention is also able to simulate the action of antidepressant drugs. The compounds according to the invention can thus be used to produce pharmaceutical compositions and medicaments for the treatment of depression.

Given the role of DRD3 receptor in the States drug dependence pharmaceutical composition or the medicinal product on the basis of connections,�sannich in the present invention, it is possible to enter in the conditions, associated with abstinence, and/or to facilitate detoxification of individuals who are dependent on cocaine, heroin, alcohol, tobacco and other substances that cause addiction.

Compounds in accordance with the invention is similar to the partial DRD3 receptor agonists in General, it can also be used as an additional treatment to the treatment of Parkinson's disease L-DOPA.

Compounds in accordance with the invention is similar to the partial agonists and antagonists of the receptor DRD3 in General, it can also be used to treat essential tremor.

Accordingly, the compounds of formula 1, base or salt can be used for the treatment of neurological or psychiatric conditions, particularly conditions that can be treated with agonists, partial agonists or antagonists of the DRD3 receptor.

The invention also relates to a method for treating neurological or psychiatric conditions, diseases or disorders, which comprises administering the compound of formula 1 in a therapeutically effective amount to a patient that requires treatment. The invention furthermore relates to compounds of formula 1 for use as medicaments.

The invention also relates to compounds of formula 1 to obtain drugs for the treatment of neurolo�quarter or psychiatric disease or disorder, either erectile dysfunction or dependence on drugs or substances causing addiction.

The invention relates to compounds of the General formula (I) to obtain medicines for the treatment of Parkinson's disease, psychosis, schizophrenia, dyskinesia associated with Parkinson's disease, cognitive failure, possibly associated with age or with Alzheimer's disease, mood disorders, essential tremor, anxiety, depression, bipolar disorder, sexual impotence, premature ejaculation, alcoholism and nicotine dependence.

Compounds of formula 1 in accordance with the invention can be administered orally, systemic, parenteral, nazalnam or rectal means. The connection can in particular be administered orally by in the corresponding drug. The dosage of the compounds of formula 1 in the compositions according to the invention can be adjusted to get the number of the active substance that is effective in obtaining the desired therapeutic response for songs that are characteristic for the method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors.

Compounds of formula 1 were evaluated in vitro as ligands DRD3 and modulators of the activity of this� receptor in accordance with the invention in cells, expressing the recombinant receptor DRD3 person. The inhibition constants (K_i) was measured on the basis of inhibition of binding of [³H] spiperone, as described by the authors Cussac et al., in Naunyn-Schmiedeberg''s Arch. Pharmacol. 2000, 361, 569. The inventors have demonstrated that the compounds of formula 1 are effective ligands with values of K_ifrom 0.1 to 30 nanomol·liter^-1. The same compounds show a marked affinity for the dopamine receptor D2, which is in 10-200 times weaker. Compounds of formula 1. were evaluated for their agonistic, partial agonistic or antagonistic activity by the use of MAR-kinase test activity on recombinant human receptors, as described Cussac D. et al., Mol. Pharmacol. 1999, 56, 1025-1030. Intrinsic activity of the compounds of formula 1 is 0 (antagonist) 0.80 (agonist).

Compounds of formula 1 were evaluated in vivo in the test hyperactivity induced by MK-801, mouse (L. Leriche et al., Neuropharmacology 2003, 45, 174). The values of the ED₅₀compounds of formula 1 comprise from 0.01 to 6 mg/kg.

The total daily dose of the compounds for use in accordance with this invention, administered in a single dose or in fractional doses may be in amounts, for example, from about 0.001 to about 100 mg/kg of body weight per day.

The specific dose level for any particular patient is up by a number of factors, including body weight, General health, sex, diet, time and route of administration, the levels of absorption and resorption in the small intestine and excretion, combination with other drugs and the severity of the particular condition being treated.

For example, as a non-limiting example of the formation of compounds according to the invention is demonstrated in the Examples below:

Example 1: 6,7-Dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

Stage 1: 6-Bromo-1-(2,4,5-trimethoxyphenyl)-hexane-1-he

6 ml (40 mmol) of 1,2,4-trimethoxybenzene bring in 80 ml dry CH₂Cl₂and the mixture was cooled to-10 ° C with stirring. Then added dropwise 6-bromohexadecane (6.2 ml, 40 mmol) dissolved in 20 ml of CH₂Cl₂·AlCl₃(5.6 g, 42 mmol) gradually introduce small portions to the reaction mixture. The reaction mixture was kept under stirring for 8 h with a return to ambient temperature. Then the reaction mixture is poured on ice (200 ml) and acidified to pH 1 using HCl. The mixture was stirred until her return to ambient temperature, 1 h. After evaporation CH₂Cl₂the mixture was extracted with AcOEt and the organic phase is separated, dried over MgSO₄, filtered and evaporated. �the STATCOM is subjected to flash chromatography on SiO ₂with a gradient from pure heptane to heptane-AcOEt 50-50. The pure fractions are evaporated to obtain 13.6 g (yield =99%) of crystals. TLC SiO₂(heptane-ACOEt 70-30) Rf=0,5;¹H NMR (CDCl₃): 7,41 (s, 1H), 6,50(s, 1H), 3,95 (s, 3H), of 3.91 (s, 3H), of 3.87(s, 3H), 3.43 points (t, 2H, J=6,76 Hz), 2,98 (t, 2H, J=6.32 per Hz) of 1.91 (m, 2H), 1,71 (m, 2H) of 1.51 (m, 2H).

Stage 2: 6-Bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexane-1-he

13.6 g of the product obtained in the above stage are dissolved in 80 ml of 48% HBr. The mixture was heated at 90 ° C for 5 h. Then the reaction mixture is poured on ice (300 ml) and extracted with AcOEt. The organic phase is separated, dried over MgSO₄, filtered and evaporated to a green oil which was subjected to flash chromatography on SiO₂with a gradient from pure heptane to heptane-AcOEt 85-15. Get to 7.33 g (yield =56%) of 6-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexane-1-one,¹H NMR (CDCl₃): 12,7 (s, 1H), to 7.08 (s, 1H), of 6.46 (s, 1H), of 3.91 (s, 3H), of 3.87 (s, 3H), 3,44 (t, 2H, J=8 Hz), to 2.92 (t, 2H, J=7,2 Hz) to 1.93 (m, 2H), 1,78 (m, 2H), 1.55 V (m 2H); and 1.4 g of di-demetilirovannogo connection, 6-bromo-1-(2,4,5-dihydro-5,4-methoxyphenyl)hexane-1-one,¹H NMR (CDCl₃): 12,5 (s, 1H), 7,22 (s, 1H), 6,45 (s, 1H) 5,20 (s, 1H), 3,93 (s, 3H), 3,42 (t, 2H, J=6,68 Hz), 2,89 (t, 2H, J=7,32 Hz) of 1.91 (m, 2H), and 1.76 (m, 2H), 1.53 m (m, 2H).

Stage 3: 3-(4-Bromobutyl)-6,7-dimethoxyfuran-4-he

1 method: Solution A is prepared from 500 mg of the compound of the above stages, 6-bromo-1-(2-hydro�si-4,5-dimethoxyphenyl)-hexane-1-one (1.5 ml, dissolved 0.60 ml (4.5 mmol) Et₂O-BF₃), and this solution was cooled to 10 ° C. Then added 2.3 ml DMF. In addition, prepare a solution In 4 ml of DMF and added thereto in small portions at 10 ° C 470 mg (2,25 mmol) PCl₅. The solution was heated at 55 ° C for 20 min, and then injected dropwise into the solution As described at the beginning, with a return to ambient temperature. The mixture becomes orange-yellow and precipitates. Inject 50 ml of 0.1 n HCl, and the mixture was extracted with AcOEt, the organic phase washed with saturated NaCl solution, separated, dried over MgSO₄, filtered and evaporated. The residue is subjected to flash chromatography on SiO₂with a gradient from pure heptane to heptane-AcOEt 70-30. The purified fractions are crystallized after evaporation. Receive 300 mg of 3-(4-bromobutyl)-6,7-dimethoxyfuran-4-in the form of crystals (yield =59%); TLC SiO₂heptane-AcOEt 50-50 Rf=0,4.

2 method: a Solution of 500 mg (1.5 mmol) of the compound of the above stages, 6-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexane-1-one in 30 ml of dry toluene is brought to reflux with stirring with 0.6 ml (4.5 mmol) of DMF dimethylacetal. Boiling to reflux was continued for 5 h. After concentration and purification flash chromatography with a gradient from pure heptane to heptane-ACOEt 80-20 get 270 mg (yield =53%) of 3-(4-bromobutyl)-6,7-dimethoxyfuran-4-after she viparis�Deposit in the form of white crystals, identical received 1 way. TLC SiO₂heptane-ACOEt 70-30 Rf=0,3.¹H NMR (DMSO): to 8.19 (s, 1H), of 7.36 (s, 1H), made 7.16 interest (s, 1H), 3.89 points (s, 3H), 3,84 (s, 3H), 3,65 (t, 2H, J=6.3 Hz), of 2.38 (t, 2H, J=7.3 Hz), 1,72 (m, 2H), of 1.64 (m, 2H), 1.55 V (m, 2H).

Stage 4: 6,7-Dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

Brominated derivative obtained in the above stage 3 (150 mg, 0.44 mmol) suspended in 10 ml of methyl ethyl ketone and added to 120 mg (0,62 mmol) 2-methoxyphenylpiperazine and 121 mg (0.87 mmol) To₂CO₃and 10 mg of tetrabutylammonium bromide. The mixture is brought to reflux for 20 h, and then concentrated. The residue was dissolved in water and extracted with ethyl acetate. The organic phase is separated, dried over MgSO₄, filtered and evaporated to give a colorless oil. Flash chromatography on SiO₂the elution gradient from CH₂Cl₂until CH₂Cl₂-MeOH 90-10 gives you the opportunity to obtain an oil, which crystallizes in iPr₂O. Get 128 mg (yield =60%) of white crystals. T. PL. ° C=124-130; MS (EMI) m/z=453 (MH+);¹H NMR (CDCl₃): 7,72 (s, 1H), 7,55 (s, 1H), at 6.92 (m, 5H), at 3.97 (s, 3H), of 3.86 (s, 3H), 3,12 (m, 4H), of 2.69 (m, 4H), 2.49 USD (m, 4H), of 1.64 (m, 4H).

The products of the Examples below are obtained by the same sequence of reactions:

Example 2: 3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-benzonitrile

By condensation of the brominated derivative, 3-(4-bromobutyl)-6,7-dimethoxyfuran-4-she obtained in stage 3 of Example 1 from 3-get cyanophenylpyridines 3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-benzonitrile at exit 40%. T. PL. ° C=154-155; analytical HPLC Sym C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄30-70-6,8 g/l, pH 4, r.t.=9,72 min; MS IDE, m/z=448 (MH+);¹H NMR (DMSO): 8,17 (s, 1H), 7,13-7,39 (m, 6H), 3.89 points (s, 3H), 3,84 (s, 3H), 3,19 (m, 4H), 2,47 (m, 4H), of 2.38 (t, 2H, J=6.8 Hz), 2,32 (t, 2H, J=6.8 Hz), 1,50 (m, 4H).

Example 3: 3-{4-[4-(2,3-Dichlorophenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

Like example 1, but using 2,3-dichloronitrobenzene, get 3-{4-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-on when the output is 62%. T. PL. ° C=160-162; analytical HPLC Sym C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄40-60-6,8 g/l, pH 4, r.t.=8,80 min; MS IDE, m/z=491;¹H NMR (CDCl₃): 7,72 (s, 1H), 7,55 (s, 1H), 7,14 (m, 2H), 6,95 (m, 1H), 6,83 (s, 1H), 3,97 (s, 6H, och₃), of 3.07 (m, 4H), of 2.64 (m, 4H), to 2.48 (m, 4H), of 1.64 (m, 4H).

Obtaining hydrochloride: 2,64 g of the base obtained above was dissolved in a mixture of 100 ml acetone-MeOH (50-50). Add a solution of isopropanol and 2 N HCl. The precipitated salt was filtered to obtain after drying in a vacuum 2,02 g of the hydrochloride (yield =72%). T. PL. ° C=252-254.

Example 4: 3-{4-[4-(3-Hydroxyphenyl)-piperazine-1-yl]-butyl}-6,7-dimetho�chromen-4-he

Using the same basic substance, 3-(4-bromobutyl)-6,7-dimethoxyfuran-4-he, obtained in stage 3 of Example 1, but with 3-hydroxyphenyltriazine, and using the vessel for a reaction (15 min, 160º, 150 W), receive 3-{4-[4-(3-hydroxyphenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-it is similar to example 1, with the output of 17%. T. PL. ° C=177-180 of; analytical HPLC Sym C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-N₂Oh, KH₂PO₄25-75-6,8 g/l, pH 4, r.t.=9,99 min; MS IDE, m/z=439 (MH+);¹H NMR (CDCl₃): 7,72 (s, 1H), 7,55 (s, 1H), between 7.09 (t, 1H, J=8 Hz), 6,83 (s, 1H), of 6.49 (d, 1H, J=8,28 Hz), 6,39 (s, 1H), 6,31 (d, 1H, J=7,84 Hz), at 3.97 (s, 6H, och₃), of 3.18 (m, 4H), 2,58 (m, 4H), 2.49 USD (m, 2H), 2,43 (m, 2H), 1.62 V (m, 4H).

Example 5: 6,7-Dimethoxy-3-[4-(4-pyrimidine-2-yl-piperazine-1-yl)-butyl]-chromen-4-he

Like example 1, but using 2-pyrimidinylpiperazine receive 6,7-dimethoxy-3-[4-(4-pyrimidine-2-reparation-1-yl)-butyl]-chromen-4-on when the output is 77%. T,PL º C=123-124; analytical HPLC Sym C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄20-80-6,8 g/l, pH 4, r.t.=14,31 min; MS IDE, m/z=425 (MH+);¹H NMR (CDCl₃): of 8.34 (d, 2H, J=a 4.64 Hz), 8,17 (s, 1H), of 7.36 (s, 1H), 7,15 (s, 1H), 6,60 (t, 1H, J=4,6 Hz), 3.89 points (s, 3H), 3,84 (s, 3H), of 3.69 (m, 4H), of 2.38 (m, 6H), was 2.31 (m, 2H) of 1.51 (m, 4H).

Example 6: 6,7-Dimethoxy-3-[4-(4-pyridin-2-yl-piperazine-1-yl)-butyl]-chromen-4-he

Like example 1, but using 2-pyridinylmethyl, �Holocaust 6,7-dimethoxy-3-[4-(4-pyridin-2-reparation-1-yl)-butyl]-chromen-4-on when the output is 50%. T. PL. ° C=41-143; analytical HPLC XBridge, a 4.6×250 mm to 8.5 μm, eluent: CH₃CN-H₂O, KH₂PO₄20-80-6,8 g/l, pH 4, r.t.=14,21 min; MS IDE, m/z=424 (MH+);¹H NMR (DMSO): 8.17 (s, 1H), 8.09 (d, 1H, J=4.28 Hz), 7.5 (t, 1H, J=7.6 Hz), 7.36 (s, 1H), 7.15 (s, 1H), 6.79 (d, 1H, J=8.6 Hz), 6.61 (t, 1H, J=5.8 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.43 (m, 4H), 2.39 (m, 6H), 2.33 (m, 2H), 1.51 (m, 4H).

Example 7: 3-{4-[4-(2,3-Differenl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

Like example 1, but using 2,3-diferentiebaren described in J. Med. Chem. 2006, 49, 3628, get 3-{4-[4-(2,3-differenl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-on when the output is 33%. T. PL. ° C=148-151; Analysis: C₂₅H₂₈N₂O₄F₂=458,51 calculated% 65,49, N% 6,16, N% 6,11 detected% 65,44, N% 6,29, N% 6,26; MS IDE, m/z=459 (MH+);¹H NMR (DMSO): 8,18 (s, 1H), of 7.36 (s, 1H), made 7.16 interest (s, 1H), to 7.08 (dd, 1H, J=14,4 Hz, J'=6,8 Hz) of 6.96 (dd, 1H, J=17.2 per Hz, J'=8 Hz), 6,83 (t, 1 H, J=7,6 Hz), 3,89 (s, 3H), 3,84 (s, 3H), 3,32 (m, 4H), by 3.02 (m, 4H), 2,36 (m, 4H), 1,50 (m, 4H).

Example 8: 3-{4-[4-(1H-Benzimidazol-4-yl)piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

Like example 1, but using 4-benzamidopiperidine described in Tet. 2000, 56, 3245, get 3-{4-[4-(1 N-benzimidazol-4-yl)piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-on when the output is 66%. T. PL. ° C=175 to 179; analytical HPLC XBridge, a 4.6×250 mm to 8.5 μm, eluent: CH₃CN-H₂O, KH₂PO₄20-80-6,8 g/l, pH 4, r.t.=9,41 min; MS IDE, m/z=463 (MH+);¹H NMR (DMSO): 12,3 (m, 1H), ,19 (s, 1H), and 8.04 (s, 1H), value of 7, 37 (s, 1H), made 7.16 interest (s, 1H), 7,03 (m, 2H), 6,48 (m, 1H), 3.89 points (s, 3H), 3,85 (s, 3H), 3.45 m (m, 4H), 3,32 (m, 4H), 2,57 (m, 4H), to 2.40 (m, 4H), of 1.54 (m, 4H).

Example 9: 3-{4-[4-(1H-Indol-4-yl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

Like example 1, but using 4-indolylbutyric described in J. Med. Chem. 2002, 45, 4128, get 3-{4-[4-(1H-indol-4-yl)piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-on when the output is 69%. T. PL. ° C = 197-199; analytical HPLC XBridge, a 4.6×250 mm to 8.5 μm, eluent: CH₃CN-N₂Oh, KH₂PO₄30-70-6,8 g/l, pH 4, r.t.=8,15 min; MS IDE, m/z = 462 (MH+);¹H NMR (DMSO): 11,0 (m, 1H), to 8.19 (s, 1H), value of 7, 37 (s, 1H), 7,22 (m, 1H), of 6.96 (m, 2H), 6,43 (m, 1H), 6.35 mm (m, 1H), 3.89 points (s, 3H), 3,85 (s, 3H), of 3.09 (m, 4H), 2,57 (m, 4H), to 2.40 (m, 4H), of 1.54 (m, 4H).

Hydrochloride: T. PL. ° C=244; Analysis of C₂₇H₃₁N₃O₄, HCl=510,43 (+5,88% H₂O) calculated% 63,26, N% 6,37, N% 8,20 detected% 62,95, N% 6,15, N% 7,98.

Example 10: 5-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1H-quinolin-2-he

Stage 1: 5-Amino-1H-quinolin-2-he

A solution of 2.1 g (11 mmol) of 5-nitro-1H-quinolin-2-one (Chem. Pharm. Bull. 1981, 29, 651) in 40 ml of Acoh hydrogenizing with 210 mg of 10% Pd/C in the presence of hydrogen for 24 h with vigorous stirring. The catalyst was filtered off and the mixture evaporated. The residue is subjected to flash chromatography on SiO₂with a gradient from pure CH₂Cl₂until CH₂Cl₂-MeOH 99-1 by. After in�of pariwana get to 1.67 g (yield 97%) of yellow crystals. ¹H NMR (DMSO): 11,38 (s, 1H), 8,08 (d, 1H, J=8 Hz), 7,10 (t, 1H, J=7,6 Hz), is 6.44 (d, 1H, J=8 Hz), 6,33 (d, 1H, J=8 Hz), a 6.26 (d, 1H, J=10 Hz) of 5.85 (s, 2H).

Stage 2: 5-Piperazine-1-yl-1H-quinolin-2-he

800 mg of the derivative of the above stage (4.96 mmol) make the vessel for microwave reactions with 890 mg (4.96 mmol) of bis-2-chloroethylamine with 1.25 ml of 2-(2-methoxyethoxy)of ethanol and heated at 150 º C for 20 h. After adding 1 n sodium hydroxide solution the mixture was extracted with CH₂Cl₂. The organic phase is separated, dried over MgSO₄, filtered and evaporated. Flash chromatography with a gradient from pure CH₂Cl₂until CH₂Cl₂-MeOH-NH₄OH 90-9-1 allows you to select after evaporation and trituration in ethyl ether 260 mg (yield =23%) of yellow crystals. MS, EMI m/z=230 (MH+);¹H NMR (DMSO): 11,67 (s, 1H), 7,99 .(d, 1H, J=10 Hz), 7,39 (t, 1H, J=8 Hz), 6,98 (d, 1H, J=8.4 Hz), of 6.79 (d, 1H, J=7,6 Hz), 6,45 (d, 1H, J=10 Hz), 2,90 (m, 4H), to 2.86 (m, 4H).

Stage 3: 5-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1H-quinolin-2-he

Piperazine obtained in the above stage, and then condense the same as in stage 4 of Example 1, with brominated derivatives 3-(4-bromobutyl)-6,7-dimethoxyfuran-4-one, obtained in stage 3 of Example 1, but using acetonitrile as the solvent. Receive 300 mg (yield = 54%) of pale-yellow crystals. T. PL. ° C=243-246; and�litijska HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄20-80-6,8 g/l, pH 4, r.t.=12,69 min; MS IDE, m/z=490 (MH+).

Example 11: 6,7-Dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}- chromen-4-he

Like example 1, but using 3-nitrophenylhydrazine receive 6,7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}-chromen-4-on when the output is 16%. T. PL. ° C=149-151; analytical HPLC Sym C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄30-70-6,8 g/l, pH 4, r.t.=12,11 min; MS APCI, m/z=468;¹H NMR (CDCl₃): 7,72 (s, 1H), 7,71 (d, 1H, J=7,8 Hz) of 7.64 (d, 1H, J=8,04 Hz), to 7.55 (s, 1H), of 7.36 (t, 1H, J=8,2 Hz), up 7.17 (d, 1H, J=8,16 Hz), 6,83 (s, 1H), 3,97 (s, 6H), of 3.29 (m, 4H), 2,61 (m, 4H), 2,47 (m, 4H), of 1.63 (m, 4H).

Example 12: 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl-]-butyl}-6,7-dimethoxyfuran-4-he

Nitrosoaniline the above-described Example 11 (910 mg, of 1.95 mmol) hydrogenizing in a mixture of 50 ml of CH₂Cl₂and 50 ml of EtOH with 91 mg of 10% Pd/C in an atmosphere of hydrogen for 24 h with vigorous stirring. After removal of the catalyst by filtration and isolated after evaporation of 720 mg of pink crystals. Flash chromatography on SiO₂the elution gradient from pure CH₂Cl₂until CH₂Cl₂-MeOH 95-5 allows you to allocate 550 mg (yield =64%) of beige crystals by grinding with iPr₂O. T. PL. ° C=175-176; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH PO₄20-80-6,8 g/l, pH 4, r.t.=11,46 min; MS IDE, m/z=438 (MH+).

Example 13: N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide

427 mg (0.98 mmol) of the compound 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-she obtained in the above Example 12, suspended in 10 ml of CH₂Cl₂, was added 0.16 ml (1,95 mmol) of pyridine at 0 º C and added dropwise 75 μl (0.98 mmol) of methylchloride dissolved in 2 ml of CH₂Cl₂. Stirring is maintained at ambient temperature for 8 h. the Mixture was poured into water and extracted with CH₂Cl₂. The organic phase is separated, dried over MgSO₄, filtered and evaporated. The residue is subjected to flash chromatography SiO₂and eluted with a gradient from 2 to CH₂Cl₂-MeOH 90-10. After evaporation, the resulting oil was crystallized in iPr₂O obtaining 272 mg of beige crystals (yield =54%). T. PL. ° C=186-189; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄30-70-6,8 g/l, pH 4, r.t.=6,91 min; MS IDE, m/z=516 (MH+);¹H NMR (CDCl₃): 7,72 (s, 1H), 7,55 (s, 1H), of 7.19 (t, 1H, J=8,2 Hz), 6,83 (s, 1H), 6,78 (s, 1H), 6,73 (d, 1H, J=8,52 Hz) of 6.63 (d, 1H, J=7,4 Hz), 6,29 (m, 1H), 3,97 (s, 6H), is 3.19 (m, 4H), of 2.99 (s, 3H), to 2.59 (m, 4H)that is 2.49 (m, 2H), 2.44 mm (m, 2H), 1,59 (m, 4H).

Example 14: N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-acetamide

Similarly to Example 13, but using acetyl chloride and 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he, obtained in Example 12, N get-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-acetamide.

Example 15; Methyl-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-carbamate

Similarly to example 13, but using methylchloroform and 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he, obtained in Example 12, methyl get-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-carbamate.

Example 16: 7-{4-[4-(2,3-Dichlorophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-d]chromen-8-he

Stage 1: Obtain 6-bromo-1-(6-hydroxybenzo[1,3]dioxol diokso-5-yl)-hexane-1-one

A solution of 1 g (7.2 mmol) of sesamol in 20 ml of CH₂Cl₂cooled to-10 ° C with stirring. Add 1.1 ml (7.2 mmol) of 6-bromohexadecane, and then 1 g (7.6 mmol) AlCl₃small portions. The temperature is allowed to rise to ambient temperature and stirring was continued for 18 h. Hydrolysis was carried out by adding ice, and acidification is carried out with concentrated HCl (2 ml). The extraction is carried out CH₂Cl₂, the organic phase is separated, dried over MgSO₄, filtered and �Privat, subjected to flash chromatography on SiO₂with a gradient from pure heptane to heptane-AcOEt 80-20 with receiving 500 mg of pale yellow crystals after evaporation (yield =22%) MS, EMI, m/z=314 to 316.¹H NMR (CDCl₃): 7,26 (s, 1H), 7,07 (s, 1H), 6,45 (s, 1H), 5,98 (s, 2H), 3,42 (t, 2H, J=6.8 Hz), to 2.87 (t, 2H, J=7,6 Hz) of 1.92 (m, 2H), and 1.76 (m, 2H), a 1.54 (m, 2H).

6-Bromo-1-(2-hydroxy-5-methoxyphenyl)-hexane-1-get it identically.

Stage 2: Obtain 6-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-1-(6-hydroxybenzo[1,3]dioxol-5-yl)-hexane-1-one

950 mg (3 mmol) of the brominated derivative obtained in the above stage, 690 mg (3 mmol), 2,3-dichloronitrobenzene, 1.3 ml (9 mmol) of triethylamine and 500 mg (3 mmol) of KI are added to 10 ml of CH₃CN. The mixture is brought to reflux with stirring for 20 h. Add saturated solution of NaHCO₃(50 ml), and perform extraction with AcOEt. The organic phase is separated, dried over MgSO₄, filtered and evaporated. Flash chromatography on SiO₂the elution gradient from pure CH₂Cl₂until CH₂Cl₂-MeOH 90-10 allows to obtain after evaporation and crystallization from iPr₂O 960 mg (yield =69%) of beige crystals.¹H NMR (DMSO): USD 7.45 (s, 1H), 7,30 (m, 2H), 7,13 (m, 1H), 6,57 (s, 1H), 6,08 (s, 2H), 2,96 (m, 6H), of 2.50 (m, 4H), of 2.33 (m, 2H), 1,63 (m, 2H), of 1.48 (m, 2H), 1,36 (m, 2H).

Stage 3: 7-{4-[4-(2,3-Dichlorophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chrome�n-8-he

A solution of 600 mg (1,30 mmol) of the compound obtained in the above stage in 5 ml of dimethylformamide dimethylacetal heated at 90 ° C for 5 h with stirring. Add 50 ml of water and carry out extraction of CH₂Cl₂. The organic phase is separated, dried over MgSO₄, filtered and evaporated. Flash chromatography on SiO₂the elution gradient from CH₂Cl₂until CH₂Cl₂-MeOH 90-10 allows you to get after concentration and crystallization from iPr₂O 250 mg (yield =40%) of beige crystals. T. PL. ° C=140-142; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-N₂Oh, KH₂PO₄40-60-6,8 g/l, pH 4, r.t.=9,51 min; MS IDE, m/z=475-477; Analysis of C₂₄H₂₄N₂O₄Cl₂=475,38+0,21 H₂O calculated% 60,64, N% 5,09, N% 5,89 detected% 60,61, N% 5,07, N% 6,45;¹H NMR (DMSO): 8,17 (s, 1H), to 7.33 (s, 1H), 7,29 (m, 2H), 7,22 (s, 1H), 7,13 (m, 1H), is 6.02 (s, 2H), 2,96 (m, 4H), of 2.50 (m, 6H), of 2.35 (m, 2H) of 1.51 (m, 4H).

Example 17: 7-{4-[4-(2,3-Differenl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

Identical to that described above in example 16, but using diferentiebaren, get 7-{4-[4-(2,3-differenl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he. T. PL. ° C=140-142; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄35-65-6,8 g/l, pH 4, r.t.=9,59 min; MS IDE, m/z=43 (MH+); Analysis of C₂₄H₂₄N₂O₄F₂=442,46+0,78 H₂O calculated% 65,15, N% 5,47, N% 6,33 detected% 65,41, N% 5,71, N% was 6.77;¹H NMR (DMSO): 8,16 (s, 1H), to 7.33 (s, 1H), 7,22 (s, 1H), to 7.08 (m, 1H), of 6.96 (m, 1H), 6,83 (t, 1H, J=8 Hz), 6,20 (s, 2H), by 3.02 (m, 4H), of 2.50 (m, 4H), 2,34 (m, 4H), of 1.51 (m,4H).

Example 18: 7-{4-[4-(3-Nitrophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

Identical to that described above in example 16, but using 3-nitrophenylhydrazine, get 6-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he. MS IDE, m/z=452 (MH+);¹H NMR (DMSO): 8,17 (s, 1H), 7.62 mm (s, 1H), EUR 7.57 (d, 1H, J=7,6 Hz) of 7.46 (t, 1H, J=8.4 Hz), 7,39 (d, 1H, J=8.4 Hz), to 7.33 (s, 1H), 7,22 (s, 1H), 6,20 (s, 2H), 3,24 (m, 4H), of 2.50 (m, 4H), of 2.35 (m, 4H), of 1.50 (m, 4H).

Example 19: 7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

Identical to Example 12, but using the compound obtained in Example 18, aniline get 7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he. MS IDE, m/z=422 (MH+);¹H NMR (CDCl₃): 7,68 (s, 1H), 7,52 (s, 1H), 7,03 (t, 1H, J=8 Hz), is 6.81 (s, 1H), 6,36 (d, 1H, J=8 Hz), of 6.25 (d, 1H, J=2 Hz), 6,21 (d, 1H, J=7,6 Hz), 6,08 (s, 2H), 3,16 (m, 4H), 2,57 (m, 2H), 2,47 (t, 2H, J = 6,4 Hz), USD 2.41 (t, 2H, J=7,6 Hz), 1,59 (m, 4H).

Example 20: N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-elfenland

Identical to Example 14, but using 7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-d]chromen-8-o� instead 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl-]-butyl}-6,7-dimethoxyfuran-4-it, get N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-acetamide.

Example 21: N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-d]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide

Analogously to Example 13, but using 7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he obtained in Example 19, is 3-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-it, get N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide. T. PL. ºC=174; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄25-75-6,8 g/l, pH 4, r.t.=13,23 min; MS, EMI, m/z=499 (MH⁺);¹H NMR (DMSO): 9,51 (s, 1H), 8,16 (s, 1H), to 7.33 (s, 1H), 7,22 (s, 1H), 7,13 (t, 1H, J=8.4 Hz), 6,73 (s, 1H), 6.67 cm (d, 1H, J=8.4 Hz), of 6.63 (d, 1H), 6,20 (s, 2H), of 3.07 (m, 4H), to 2.94 (s, 3H), 2,47 (m, 4H), a 2.36 (t, 2H, J=6,4 Hz and 6.8 Hz) of 1.49 (m, 4H).

Hydrochloride: T. PL. ° C=260, Analysis of C₂₅H₃₀ClN₃O₆S=499,59+0,34% H₂O calculated% 56,02, N% 5,64, N% 7,84, S% 5,98 detected% 56,37, N% 5,69, N% 7,65, S% 6,89.

Example 22: N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-econsultant

Identical to Example 13, but using the appropriate reactants, get N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-econsultant. MS, EMI, m/z=514 (MN⁺);¹H NMR hydrochloride (L�CO): 9,69 (s,1H), 8,22 (s, 1H), 7,34 (s, 1H), 7,25 (s, 1H), of 7.19 (t, 1H, J=8.4 Hz), 6.80 per (s, 1H), 6,73 (m, 1H), 6,21 (s, 2H), 3,71 (m, 2H), was 3.54 (m, 2H), 3,08 (m, 6H), is 2.40 (m, 2H), 1,72 (m, 2H), 1.55 V (m, 2H).

Example 23: 2-Dimethylaminoethanol acid(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-amide

Step 1: Like the example 21, 7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-it is condensed with 2-chloroethylsulphonic. Get(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-tinsulanond.¹H NMR (DMSO): 9,79 (s, 1H), 8,16 (s, 1H), to 7.33 (s, 1H), 7,22 (s, 1H), between 7.09 (t, 1H, J=8 Hz), the 6.75 (dd, 1H, J=16,4 Hz and 10 Hz), 6.67 cm (d, 1H), of 6.63 (dd, 1H, J=10 Hz and 2 Hz), to 6.57 (dd, 1H, J=8 Hz and 1.2 Hz), of 6.20 (s, 2H), 6,09 (d, 1H, J=a 16.4 Hz), 6,01 (d, 1H, J=9.6 Hz), of 3.05 (m, 4H), 2,47 (m, 4H), 2,34 (m, 4H), of 1.51 (m, 4H).

Stage 2: Connecting the above step 1 (100 mg, 0.2 mmol) contribute in a sealed test tube with 2 ml of a 2 M solution of dimethylamine in MeOH at ambient temperature for 3 h. the Entire volume evaporated to dryness and the residue triturated with isopropanol - HCl, hydrochloride bring in iPr₂O and filtered. MS, EMI, m/z=557 (MH+);¹H NMR (DMSO) hydrochloride: 10,10 (s, 1H), 8,23 (s, 1H), 7,22 (m, 2H), 6,78 (m, 3H), 6,21 (s, 2H), score of 3.77 (m, 2H), 3,68 (m, 2H), 3,55 (m, 2H), 3.45 m (m, 2H), 3,13 (m, 6H), to 2.76 (s, 6H), is 2.40 (m, 2H), of 1.74 (m, 2H), a 1.55 (m, 2H).

Example 24: 2-Methoxyethanol acid(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-amide

Example 25: 7-{4-[4-(1H-Indol-4-yl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he

By the same sequence of reactions that described in Example 16, but using 4-indolylbutyric, get 7-{4-[4-(1 H-indol-4-yl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-it, PL º C=177 to 179; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄30-70-6,8 g/l, pH 4, r.t.=9,69 min;

MS, EMI, m/z=446 (MH⁺);¹H NMR (DMSO): 11,0 (s, 1H), 9,51 (s, 1H), 8,18 (s, 1H), to 7.33 (s, 1H), 7.23 percent (m, 2H), 7.00 x (d, 1H, J=8 Hz), 6.94 per (t, 1H, J=7,2 Hz), to 6.42 (d, 1H, J=7,2 Hz), system 6.34 (s, 1H), 6,20 (s, 2H), 3,09 (m, 4H), of 2.57 (m, 4H), 2,37 (m, 4H), of 1.51 (m, 4H).

Hydrochloride: Analysis of C₂₆H₂₇N₃O₄, HCl=481,98+0,54% H₂O calculated C% 64,79, H% 5,86, N% 8,72 detected% 63,78, N% 5,70, N% is 8.46.

Example 26: 3-{4-[4-(3-Triptoreline)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he

By the same sequence of reactions as in stages 2 and 3 of Example 16, but using 6-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)-hexane-1-he obtained in stage 2 of Example 1, get 3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-6,7-dimethoxy�Myung-4-it is in the form of a salt with 1.5 equivalents of fumaric acid. T. PL. ° C=220; TLC: SiO₂elution CHCl₃-MeOH 90-10, Rf=0,56; Analysis of C₂₆H₂₉F₃N₂O₄, C₆H₆O₆=664,63 calculated C% 57,82, H% 5,30, N% 4,21, F% to 8.57 found C% 57,71, H% 5,24, N% 4,30, F% 8,80%.

Example 27: 6-Methoxy-3-[4-(4-phenylpiperazin-1-yl)-butyl]-chromen-4-he

By the same sequence of reactions as in stages 2 and 3 of Example 16, but using 6-bromo-1-(2-hydroxy-4-methoxyphenyl)-hexane-1-he obtained in accordance with stage 1 of Example 1 and using 1,4-dimethoxybenzene is 1,2,4-trimethoxybenzene, or using 4-methoxyphenol as starting substances in accordance with the same method as in step 1 of Example 16, get 6-methoxy-3-[4-(4-phenylpiperazin-1-yl)-butyl]-chromen-4-it is obtained in the form of white crystals of the hydrochloride. T. PL. ºC=198; TLC: SiO₂elution CHCl₃-MeOH-NH₄OH 95-4,5-0,5, Rf=0,45; Analysis of C₂₄H₂₉ClN₂O₃=428,94 calculated% 67,20, N% 6,81, N% A 6.53, Cl% 8,26 detected% Up 66,78, H% About 6,82, N% 6,47, Cl% to 7.95%.

Example 28: 6-Methoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

Identical to the above example, but using the appropriate initial substance, get 6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-it's in the form of white crystals of the hydrochloride. T. PL. ° C=191;

TLC: SiO₂elution HCl ₃-MeOH-NH₄OH 95-4,5-0,5, Rf=0,67; Analysis of C₂₅H₃₁ClN₂O₄=458,97 calculated% 65,42, N% 6,81, N% 6,10, Cl% 7,72 detected% 66,28, N% To 6.88, N% 6,08, Cl% of 7.64%.

Example 29: 6-Methoxy-3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-chromen-4-he

Identical to the above example, but using the appropriate initial substance, get 6-methoxy-3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-chromen-4-it's in the form of white crystals of the hydrochloride. T. PL. ° C=180; TLC: SiO₂elution CHCl₃-MeOH-NH₄OH 95-4,5-0,5, Rf=0,56;

Analysis of C₂₅H₂₈ClF₃N₂O₃=496,45 calculated% 60,42, N% Of 5.68, N% 5,64, Cl% 7,13, F% 11,48 detected% 60,23, N% 5,63, N% 5,63, Cl% 6,97%, F% 11,28.

Example 30: 7-{4-[4-(2,3-Dichlorophenyl)piperazine-1-yl-]-butyl}-6-methyl-[1,3]dioxolo[4,5-g]chromen-8-he

6-[4-(2,3-Dichlorophenyl)-piperazine-1-yl]-1-(6-hydroxybenzo[1,3]dioxol-5-yl)-hexane-1-he (200 mg, 0.43 mmol) obtained in step 2 of Example 16 is introduced into the vessel for microwave reactions with 1 ml of dimethylacetamide dimethylacetal and heated at 160º for 5 min the Mixture was thrown into water and then extracted with AcOEt. The organic phase is separated, dried over MgSO₄, filtered and evaporated. Flash chromatography on SiO₂the elution gradient from CH₂Cl₂until CH₂Cl₂-MeOH 90-10 allows you to get after cypriani� and rubbing with iPr ₂O 30 mg (yield 14%) of beige crystals. T. PL. ° C=153-155; analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₂CN-H₂O, KH₂PO₄40-60-6,8 g/l, pH 4, r.t.=written: 11.09 min; MS, EMI, m/z=489-491 (MH⁺);¹H NMR (DMSO): 7,29 (m, 3H), made 7.16 interest (m, 2H), 6.18 of (s, 2H), 2,96 (m, 4H), of 2.45 (m, 6H), is 2.40 (s, 3H), of 2.35 (m, 2H), 1.46 in (m, 4H).

Example 31: 6/7-Methoxy-7/6-hydroxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he

This compound is prepared by the same sequence of reactions as for Example 1, stage 3 and 4, but using as starting substances 6-bromo-1-(2,4-dihydro-5-methoxyphenyl)hexane-1-he obtained as a secondary product in stage 2 demethylation of Example 1. Analytical HPLC Xbridge C8, a 4.6×250 mm, 5 μm, eluent: CH₃CN-H₂O, KH₂PO₄25-75-6,8 g/l, pH 4, r.t.=11,27 min; MS, EMI, m/z=439 (MH⁺).

Example 32: 7-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-3H-benzoxazol-2-he

Similarly to example 1, stage 4, but using 7-piperazine-1-yl-3H-benzoxazol-1-he described in Bioorg. Med. Chem. Let. 2001, 11, 2345, get 7-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-3H-benzoxazol-2-it.

Example 33: 4-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1,3-dehydrobenzperidol-2-he

Similarly to example 1, step 4, but using the derived experimental data showed 4-benzylpiperazine-1-�l)-1,3-dehydrobenzperidol-2-one, described in Bioorg. Med. Chem. Let. 1998, 8, 2675, get 4-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1,3-dehydrobenzperidol-2-it.

The research Protocol in vivo

Introduction

Phencyclidine (PCP, phencyclidine), a noncompetitive antagonist at glutamate receptor subtype N-methyl-D-aspartate (NMDA, N-methyl-D-aspartate), the anesthetic agent is characterized by the presence of psychotomimetic properties in relation to the person (Javitt and Zukin, 1991). PCP induces a state of sensory deprivation, apparent intoxication and hallucinations, often followed by a sense of depersonalization at abusing (Snyder, 1980), and symptoms similar to schizophrenia, in healthy volunteers (Jentsch and Roth, 1999;. Luby et al., 1959). PCP also accelerates the development of psychosis in patients with schizophrenia (Ital et al., 1967). Psychotic symptoms caused by your PCP or pharmacologically related compound ketamine, and include positive (hallucinations, delusions) and negative symptoms (disorder formal thinking, social withdrawal), and cognitive dysfunction. Thus, the effects of uncompetitive NMDA receptor antagonist can be used as a convincing drug induced model of schizophrenia (Javitt, Zukin, 1991; Snyder, 1988). In animals, PCP or MK-801, another non-competitive antagonist of the receptor MDA (Wong et al., 1986), causes behavioral abnormalities, including hyperactivity, disruption of sensorimotor Gating deficit and social interactions that counteract antipsychotic drugs (Jentsch, Roth, 1999;. Leriche et al., 2003).

Among the neurotransmitter systems involved in induced by MK-801 behavioral deviations, the crucial role played by glutamate system (Jentsch, Roth, 1999; Moghaddam, Jackson, 2003; Moghaddam, 2003). This is a direct consequence of the mechanism of action of MK-801. Therefore, many drugs that modulate glutamatergic neurotransmission (including but not limited to, compounds which act against dopaminergic D3 (Sokoloff, 2012)) has been shown to modulate MK-801-induced responses (Jentsch and Roth, 1999; Moghaddam and Jackson, 2003; Moghaddam, 2003, Ieriche et al., 2003, Sokoloff et al., 2012).

Finally, since all antipsychotic drugs are able to inhibit MK-801-induced hyperactivity, this simple test, as usually considered, is a valuable predictive validity for the study of the possible characteristics of antipsychotic drug candidates (Jentsch, Roth, 1999; Leriche et al., 2003; Bradford et al., 2010).

The inventors investigated the effects of different antipsychotic drugs and some typical compounds of the current patent exerted on MK-801-induced locomotor hyperactivity in mice, to buffet 1) to estimate the model using reference antipsychotic drugs and 2) to register the potential effect F17779, such an antipsychotic.

Materials and methods

Animals

Animals were maintained and tested within the system, accredited by the Association for Assessment and Accreditation of care for laboratory animals (AAALAC (Association for the Assessment and Accreditation of Laboratory Animal Care). They were placed, they were treated and cared for in accordance with the Guide for the care and use of laboratory animals (national Research Council) and with the European Directive N° 86/609, and the experimental Protocol was carried out in strict accordance with all applicable regulations and local institutional standards of animal research Ethics Committee.

Male house mice (20-22 g body weight upon arrival) were housed in groups of 8 birds per cage (polycarbonate cage Type III, length 375 mm, width - 215 mm, height 149 mm; area of the floor surface 806 cm²coating of sawdust). Mice were kept in quarantine for at least 4 days before use in experiments. All mice were housed in an air-conditioned room (temperature 21±1°C; humidity, 55±5% and with the lights on from 7:00 to 19:00 h). Mice had free access to standard dry laboratory feed (a; SAFE, Augy, France) and water (filtered through 0.22 μm filter) at all stages of the placement and quarantine. On the day of the experiment at home�of cells with mice moved into the room with actimeter and placed in a ventilated closed shelving ("enceintes"). The environmental conditions in the experimental room were identical to those in the housing. All experiments were performed between 09:00 and 17:00 hours. Food and water were not available at the time of the individual test sessions inside actimetry (length=90 min). At the end of the day, after everything was done observing the behavior, the animals were euthanized by inhalation of 70% CO₂.

Drugs.

In cases where it was possible, reference antipsychotics were purchased from commercial suppliers; the rest were synthesized at the Department of medical chemistry Research Institute. Pierre Fabre. (+)-dizocilpine maleate (MK-801) was obtained from Sigma. Typical compounds were synthesized at the Department of medical chemistry Research Institute. Pierre Fabre. Each compound was dissolved in a suitable environment. All solutions were prepared fresh daily and i entered.p. (i.p., - intraperitoneally, intraperitoneal) in a volume of 10 ml/kg of Sterile 0.9% NaCl solution (saline, Sal (saline) or a suitable medium was used as control. Doses are expressed in mg/kg free base.

Treatment drugs.

For the induction of hyperactivity used a fixed dose of MK-801 equal to 0.14 mg/kg i.p., as, on the basis of the results obtained in the studies conducted�'s for internal purposes in accordance with the same experimental Protocol and in accordance with the literature (Leriche et al., 2003) this dose is fitted as standard load for the induction of hyperactivity.

Observing behavior

The experiments were performed in accordance with the procedures described Leriche et al. (Neuropharmacology, 2003, 45: 174-81), to assess the effect of compounds on the hyperactivity caused by MK-801.

Mice were injected i.p., containing compound or saline (control group) and measured physical activity for 30 minutes (phase habituation phase, the effect of a compound on spontaneous activity). Then the mice were injected i.p. saline (negative control) or MK-801 and activity was recorded during the additional period of 1 hour to measure the effect of the induced connection on MK-801 hyperactivity.

All experiments were performed between 09:00 and 17:00 hours. First, the wait staff care for the animals endured mice in a test room at 08:00 hours and they get used to the testing room for at least 1 h prior to any manipulation. Locomotor activity was measured in altimeter, which consisted of 16 individual cells to assess General activity activity (model 2150, Tecniplast, internal dimensions: 190×305×190 mm W×D×V, the surface area of the floor - 580 cm²with sawdust on the floor) crossed infrared �uchami (Imetronic, Pessac, France). Points for pointing forward horizontal activity is increased every time an animal is moved from one half cell to another, which corresponds to the interruption of two crossed parallel light beams 14 cm from each other. Vertical activity (pripodnimanie) was also recorded.

Statistical analysis

Differences between groups were analyzed using one-factor analysis of variance (ANOVA, analysis of variance) and retrospective analysis is less significant differences (LSD, least significance difference). Statistical analysis was performed using the software SigmaStat 3.5.

The calculation of the ED₅₀

The inhibition of MK-801-induced hyperactivity was calculated by the formula:

%inhib.^MK=100·[(M_Saline+MK- M_{Drug_dose+MK})/(M_Saline+MK- M_{Saline+Saline})]

Where M_Saline+MKis the average activity ranging from 30 min to 90 min in the group pretreated with saline and then treated MK-801, M_{Drug_dose+MK}is the average activity ranging from 30 min to 90 min in the group previously treated with a dose of the drug and then processed MK-801, and M_{Saline+Saline}this is the average activity ranging from 30 min to 90 min in the group pretreated with saline and then treated saline�M.

Effective dose causing 50% inhibition of MK-801 - induced hyperactivity ED₅₀(MK-801) were calculated using non-linear regression (sigmoidal curve dose-effect with or without variable slope using the most appropriate model given the corrected information criterion Akaka (AICC, Akaike''s Information Criterion Corrected)) % inhibition = f(log[dose]). These calculations were performed using the software GraphPad Prism 4.0.

The results in Table 2

The following Table 2 shows the values of the ED₅₀some examples of compounds of formula 1, comprising 0.01 to 6 mg/kg, together with other antipsychotic drug reference. These values were obtained by testing on the hyperactivity induced by MK-801 (L. Leriche et al., Neuropharmacology 2003, 45, 174).

And, as shown in Figure 1, MK-801 induced a strong and significant hyperactivity compared with animals pretreated with saline and then treated with saline. These stimulatory effects are dose-dependent ingibirovalis antipsychotic agent with haloperidol, dose dependently inhibited by the antipsychotics haloperidol, with ED₅₀equal to 0.05 mg/kg i.p. Connection example 25 was tested in the� same conditions, and it also dose-dependently inhibited induced by MK-801 hyperactivity calculated with EDso equal to 0.12 mg/kg, i.p.

Brief description of graphic materials

Figure 1 shows the comparison between the compound according to Example 25 and haloperidol (reference antipsychotic agent), in the test for hyperactivity caused by MK-801.

Haloperidol (A) or Example 25 (b) dose-dependent manner inhibited spontaneous horizontal locomotor activity with a significant effect at doses of 0.16 and 0.63 mg/kg i.p. for haloperidol, or 0.04, 0.63 and 2.5 mg/kg i.p. for Example 25. Haloperidol (0.01 to 0,63 mg/kg, i.p.), Example 25 (0.01-2.5 mg/kg i.p.) or saline (Sal) was injected to animals and put them in actimeter. Thirty minutes later were injected with MK-801 (0.14 mg/kg, i.p., MK) or Sal and recorded locomotor activity during the follow-up period of 1 hour. The results represent the mean ± S. E. M. for N=20 animals (A) and N=9-20 animals (). * P<0,05, ** P<0.01 and *** P<0.001 compared to Sal+Sal (In) and^##P<0.01 and^###P<0,005 compared to MC(b); calculated using ANOVA with subsequent retrospective LSD test.

1. The compound of the General formula 1

where:
- R1 is one or more than one identical or different substituents on the benzene ring, each of which independently represents with�fight a hydrogen atom or a halogen atom, or C_1-4alkoxy group, or is IT a group or a group-O(CH₂)_nO-, in which n=1 or 2
- R2 represents a hydrogen atom or a C_1-4alkyl group,
A and b independently represents either a nitrogen atom or a carbon atom,
- R3 represents a hydrogen atom or one or more than one identical or different substituents selected from the group consisting of: halogen atom, a C_1-4alkyl group, a C_1-4alkoxygroup, groups,- O(CH₂)_nO-, in which n=1 or 2, group NO₂group NHSO₂R4, NHR5 group, Oh group, a C_1-4halogenoalkanes group, CN group,
or R3 is a ring condensed with a benzene ring, a carrier selected from the group consisting of indole, benzimidazole, barbastella, benzoxazolone and benzimidazolone,
- R4 represents a C_1-4alkyl group, or C_1-4dialkylamino, or C_1-4alkoxyalkyl group, or C_1-4dialkylaminoalkyl group;
R5 represents a hydrogen atom or a C_1-4alkylcarboxylic group, or C_1-4alkoxycarbonyl group, as well as its pharmaceutically acceptable salt.

2. The compound according to claim 1, characterized in that R1 represents one or more than one identical or different substituents selected from the group consisting of C_1-4alcox� group, HE group-O(CH₂)_nO-, in which n=1 or 2.

3. The compound according to claim 1, characterized in that R2 represents a hydrogen atom.

4. The compound according to claim 1, characterized in that R3 represents a hydrogen atom, when A and/or b represents a nitrogen atom.

5. The compound according to claim 1, characterized in that A and b simultaneously represent a carbon atom.

6. The compound according to claim 1, characterized in that R3 represents one or more than one identical or different substituents selected from the group consisting of: halogen atom, a C_1-4alkoxy groups,- O(CH₂)_nO-, in which n=1 or 2, groups NHSO₂R4, Oh groups and CN groups.

7. The compound according to claim 1, characterized in that R3 together with the benzene ring, a carrier, is an indole group, or benzimidazolyl group, or carboncillo group.

8. The compound according to claim 1, characterized in that it is selected from the following group of compounds:
-6,7-dimethoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he
-3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-benzonitrile
-3-{4-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he
-3-{4-[4-(3-hydroxyphenyl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he
-6,7-dimethoxy-3-[4-(4-pyrimidine-2-yl-piperazine-1-yl)-butyl]-chromen-4-he
-6,7-dimethoxy-3-[4-(4-Piri�in-2-yl-piperazine-1-yl)-butyl]-chromen-4-he
-3-{4-[4-(2,3-differenl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he
-3-{4-[4-(1H-benzimidazol-4-yl)piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he
-3-{4-[4-(1H-indol-4-yl)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he
-5-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1H-quinolin-2-he
-6,7-dimethoxy-3-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}-chromen-4-he
-3-{4-[4-(3-the Dapsone base)-piperazine-1-yl-]-butyl}-6,7-dimethoxyfuran-4-he
N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide
-N-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-acetamide
-methyl-(3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-phenyl)-carbamate
-7-{4-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he
-7-{4-[4-(2,3-differenl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he
-7-{4-[4-(3-nitrophenyl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he
-7-{4-[4-(3-the Dapsone base)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he
-N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl-acetamide
-N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-methanesulfonamide
-N-(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-econsultant
-2-dimethylaminoethanol acid(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-Hairdryer�l)-amide
-2-methoxyethanol acid(3-{4-[4-(8-oxo-8H-[1,3]dioxolo[4,5-g]chromen-7-yl)-butyl]-piperazine-1-yl}-phenyl)-amide
-7-{4-[4-(1H-indol-4-yl)-piperazine-1-yl]-butyl}-[1,3]dioxolo[4,5-g]chromen-8-he
-3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-6,7-dimethoxyfuran-4-he
-6-methoxy-3-[4-(4-phenylpiperazin-1-yl)-butyl]-chromen-4-he
-6-methoxy-3-{4-[4-(2-methoxyphenyl)-piperazine-1-yl]-butyl}-chromen-4-he
-6-methoxy-3-{4-[4-(3-triptoreline)-piperazine-1-yl]-butyl}-chromen-4-he
-7-{4-[4-(2,3-dichlorophenyl)piperazine-1-yl-]-butyl}-6-methyl-[1,3]dioxolo[4,5-g]chromen-8-he
-7-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-3H-benzoxazol-2-he
4-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazine-1-yl}-1,3-dehydrobenzperidol-2-it.

9. A method of producing compounds of the General formula 1 according to any of claims. 1-8, characterized in that the receive maybe substituted chroman formula 4 (X=Cl, Br, I), which is subjected to interaction with a piperazine of formula 5,

wherein the radicals R1, R2, R3, A and b have the meanings given in claim 1.

10. A method of producing compounds of the General formula 1 according to any of claims.1-8, characterized in that the possibly substituted phenol derivative of formula 6 receive, from a compound of formula 3 (X=Cl, Br),

in the alkylation conditions in the presence of base in a solvent and the compound of formula 6 is then subjected�Ute interaction with DMF (dimethylformamide), or dimethylacetal DMF, or DMA (dimethylamine), where the values of the radicals R1, R3, A and b, as given in claim 1.

11. A method of producing compounds of the General formula 1 according to claim 10, characterized in that the substrate is chosen from the K₂CO₃Cs₂CO₃or NEt₃.

12. A method of producing compounds of the General formula 1 according to claim 10, characterized in that the solvent is selected from acetonitrile or methyl ethyl ketone.

13. Pharmaceutical composition containing at least one compound according to any of claims.1-8 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient, for the treatment of neurological or psychiatric conditions.

14. Pharmaceutical composition according to claim 13, wherein the neurological or psychiatric condition is selected from neurological or psychiatric disease or disorder, or erectile dysfunction, or dependence on drugs and substances causing addiction.

15. The compound according to claim 1 for use as a medicament for the treatment of neurological or psychiatric conditions, in particular for the treatment of neurological or psychiatric disease or disorder, or erectile dysfunction, or dependence on drugs and substances causing addiction.

16. The compound according to claim 15 for medicinal products for treatment n�urologicheskogo or psychiatric disease or disorder, or erectile dysfunction, or dependence on drugs and substances causing addiction.

17. The compound according to claim 16, wherein the neurological or psychiatric disease or disorder, or erectile dysfunction, or dependence on drugs and substances, addictive selected from the group consisting of: Parkinson's disease, psychosis, schizophrenia, dyskinesia associated with Parkinson's disease, cognitive deficits, possibly associated with age or with Alzheimer's disease, mood disorders, essential tremor, anxiety, depression, bipolar disorder, sexual impotence, premature ejaculation, alcoholism and nicotine addiction.