Derivatives benzofurazan or benzo-2,1,3-thiadiazole and method of treatment

 

(57) Abstract:

The invention relates to a derivative benzofurazan or benzo-2,1,3-thiadiazole of the formula I, in which R1represents oxygen or sulfur, R2and R3independently selected from the group consisting of-CR=, M is =CR4- where R4independently represents R, R8is hydrogen, R5selected from the group consisting of-CR=CR1-, -CR=CX-, -(RR1)n-, R7selected from the group consisting of -(CRR1)n-, -C(O)-, -CRX-, -CXX1-, R6selected from the group consisting of -(CRR1)m-, -C(O)-, -CRX -, -CXX1-, -S - and-O-. The compounds possess enhancing AMPA receptor properties. These compounds can be used for such therapeutic purposes as facilitating learning behavior, and to treat conditions such as memory impairment due to the reduction in the number or effectiveness of AMPA receptors or synapses that use these receptors. Also described is a method of treatment using the claimed compounds. 2 C. and 28 C.p. f-crystals, 3 ill., 1 PL.

The scope of the invention

The invention relates to the prevention and treatment of cerebral insufficiency, including enhancement of the functioning of the receptors in the x abilities, related memory disorders, such as are observed in the various forms of dementia and disorders of neural activity between different parts of the brain that is expected from such diseases as schizophrenia. More specifically, the present invention relates to compounds that can be used for treatment of these conditions and to methods of using these compounds for such treatment.

Background of the invention

The glutamate at synapses in many points the front of the mammalian brain stimulates two classes of postsynaptic receptors. Usually these classes are called receptors AMPA/quisqualate and N-methyl-O-aspartic acid (NMDA). AMPA/quisqualate receptors mediate independent voltage fast excitatory postsynaptic current (fast EPSC), whereas NMDA receptors create depends on the voltage, slow excitatory current. Research conducted on sections of the hippocampus or cortex, show that AMPA receptor, mediating fast EPSC, is usually the dominant component of most gluta-metalicheskoj synapses.

AMPA receptors are not evenly distributed across the brain, but rather and primarily limited is neocortex, in each of the major synaptic zones of the hippocampus and veins in the complex, as reported by Monaghan et al. in Brain Research, 324:160-164 (1984). Studies on animals and humans show that these structures organize complex continuous motor processes and provide a framework for the conduct of the highest order. Thus, AMPA receptors mediate the transmission in the networks of the brain responsible for cognitive activity of the individual.

For these reasons, drugs that enhance the functioning of AMPA receptors, can have a significant beneficial effect on intellectual performance. These drugs should also facilitate the encoding of memory. Experimental studies such as those reported by Aria and Lynch, Brain Research, 598:173-184 (1992) show that an increase in the intensity of AMPA receptor oposredstvovanii synaptic reactions enhances the induction of long-term potentiation (LTP). LTP steadily increases the strength of synaptic contacts that occur after repeated physiological activity of this type, which is known to occur in the brain during learning.

Compounds that enhance the functioning of AMPA forms of glutamate, receptor is t al., Synapse, 15:326-329 (1993); Staubli et al., PNAS, 91:777-781 (1994); Arai et al., Brain Res. , 638:343-346 (1994); Staubli et al., PNAS, 91:11158-11162 (1994); Shors et al. , Neurosci., 186:153-156 (1995); Larson et al., J. Neurosci., 15:8023-8030 (1995); Grang er et al., Synapse, 22:332-337 (1996); Arai et al., JPET, 278: 627-638 (1996); Lynch et al., Internat. Clin. Psychopharm., 11:13-19 (1996); and Lynch and Rogers, PCT Pubn. N WO 94/02475. There is a significant amount of evidence showing that LTP are the basis of memory. For example, compounds that block LTP, violate the formation of memory in animals, and some drugs that disrupt learning in humans, preventing the stabilization of LTP, as reported by Sergo and Lynch, Neuroscience, 49:1-6 (1992).

A possible prototype of a compound that selectively enhances AMPA receptor was described lto et al., J. Physiol., 424:533-543 (1990). These authors found that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) enhances currents mediated AMPA receptors in the brain, expressed in Xenopus oocytes, without violating the reactions induced by gamma - aminobutyric acid (GABA), kainic acid (KA) or NMDA receptors. It was also shown that infusion of aniracetam in slices of hippocampus increases the value of the fast synaptic potentials without changing the properties at rest membranes. Since then, they have received confirmation that aniracetam peloritani potentials. Cm. for example, Staubii et al., Psychobiology, 18:377-381 (1990) and Xiao et al., Hippocampus, 1: 373-380 (1991).

It was found that aniracetam acts quickly and rapidly excreted and can be used repeatedly without apparent long-term effects, which is a very desirable property for drug-related behavior. However, aniracetam there are a few drawbacks. Peripheral injection of aniracetam, apparently, has no effect on the receptors in the brain. The medicine works only at high concentrations (approximately 1.0 mm) and about 80% of the drug is converted into anisoyl-GABA after peripheral injection (Guenzi and Zanetti, J. Chromatogr., 530:397-406 (1990). It was found that this metabolite, anisoyl-GABA has a lower activity than aniracetam,

Was described class of compounds that enhance AMPA receptors, which did not show characteristics of low efficiency and instability inherent in aniracetam (Lynch and Rogers. PCT publication WO 94/02475). These compounds, called "AMPAKINES"TMrepresent benzamide, which include, for example, 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine. They are chemically more stable than aniracetam, and have increased bioavailability according to the experiments conducted with recently discovered, another class of ampakines, benzoxazines, has a very high activity in models in vitro and in vivo to assess the probability of achieving improvements in cognitive abilities, as disclosed in PCT WO 97/36907 "Benzoxazines to enhance synaptic reactions" Rogers and Lynch. Some, but not all, of these compounds demonstrate activity in models in rats in relation to human illness - schizophrenia (Larson et al., Brain Res., 728:353-356 (1996).

It was discovered that certain substituted benzofurazan and benzothiadiazole are significantly and unexpectedly more effective in models of schizophrenia in animals than compounds previously reported, and are also more effective in improving cognitive abilities. These compounds are disclosed in the present invention.

Summary of the invention

The present invention includes, in one aspect of the compounds, which are listed and described in section II of the subsequent detailed description. These compounds effectively enhance AMPA receptor mediated reactions and is therefore useful for different purposes. These include facilitating the study of behavior, dependent on AMPA receptors, treat the condition in which reduced RH excitatory synapses to restore the disturbed balance between subcatname brain. In the invention, a method for treating mammals suffering from hypoglutamatergic state or from a deficiency in the number or effectiveness of excitatory synapses or in the number of AMPA receptors, such that impaired memory or other cognitive functions. Such States may also be a cause of kortiko/veins of imbalance, leading to schizophrenia or schizophrenic behavior.

In accordance with the method of the present invention the patient is treated with an effective amount of a compound as disclosed in section II of the detailed description, in a pharmaceutically acceptable carrier. As demonstrated hereinafter, these compounds are much more effective than the previously described connections, in terms of enhancing the function of AMPA receptors in hippocampal slices of rats in a model of schizophrenia and depression in animals and in terms of improving the characteristics of cognitive abilities, such as behavior in the maze with 8 radial paths.

These and other objects and features of the invention will become more apparent after reading the subsequent detailed description of the invention with reference to the accompanying drawings.

Brief description of drawings

Fig. 1 represents the tetracyclic compounds, which constitute one of the embodiments of the present invention; and

Fig.3 represents a selection of compounds suitable for use in the practice of the method of the present invention.

Detailed description of the invention

I. Definitions

The following terms have the following meanings, unless otherwise indicated.

"Alkyl" refers to a fully saturated the monovalent radical containing carbon and hydrogen, which can be cyclic, branched or unbranched chain. Examples of alkyl groups are methyl, ethyl, n-butyl, n-heptyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl and cyclohexyl.

"Aryl" refers to a substituted or unsubstituted monovalent aromatic radical containing a single ring (e.g. benzene) or multiple condensed rings (e.g., naphthyl). Other examples include heterocyclic aromatic ring system containing in the ring one or more nitrogen atoms, oxygen or sulfur, such as imidazole, furyl, pyrrole, pyridyl and indole.

The term "effective amount" refers to the number of selected compounds of formula I, to the activity. Need the exact amount will vary depending on the specific compound, the age and weight of the patient, the route of administration, etc. but it can easily be determined by ordinary experimentation.

The term "pharmaceutically acceptable carrier" refers to a carrier or excipient that is not toxic to the patient, which it is introduced. Pharmaceutically acceptable excipients are described in detail, T. W. Martin "Remington''s Pharmaceutical Science.

II. Compounds that enhance AMPA receptor

The present invention in one aspect is directed to compounds having the properties to enhance AMPA receptor. These compounds have the structural formula I below

< / BR>
where R1represents oxygen or sulfur;

R2and R3independently selected from the group consisting of-N=, -CR - and-CX=;

M is =N - or =CR4- where R4and R8independently represent R or together form a simple binding fragment linking M with the top of the ring 2', and binding fragment selected from the group consisting of simple communication, -CRR; -CR=CR'-, -C(O)-, -O-, -S(O)y-, -NR -, or-N=; and

R5and R7independently selected from the group consisting of

-(CRR')CXX'-, -S - and-O-;

where X and X' independently are selected from-Br, -Cl, -F, -CN, -NO2, -OR, -SR, -NRR', -C(O)R-, -CO2R or-CONRR', where two groups R or R' is the same or different X groups may together form a ring;

R and R' independently are selected from (i) hydrogen, (ii) C1-C6branched or unbranched alkyl which may be unsubstituted or may be substituted by one or more functional groups selected from halogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide, and where two such alkyl groups from one carbon atom or adjacent carbon atoms may together form a ring, and (iii) aryl, which may be unsubstituted or may be substituted by one or more functional group selected from hydrogen, nitro, alkoxy, hydroxy, aryloxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide;

m and p are independently 0 or 1;

n and y are independently 0, 1 or 2.

A preferred group of compounds covered by formula I, include those in which p=0, those in which R2and R3present-CR=, a M is = CR45and R7represent -(CRR')n-, a R6is -(CRR')m-; that is, some derivatives of 5-carboxamidotryptamine containing different amount of saturated heterocyclic rings associated with the carbonyl group. The preferred compounds of this group are those in which R and R' are selected from (i) hydrogen or (ii) alkyl, as described above. The most preferred compound of this group is 1-(benzofurazan-5-ylcarbonyl) piperidine, denoted here as compound 2. Preferred is also a corresponding compound in which R1is sulfur, that is, 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, denoted here as the connection 1. Other examples of compounds containing rings of various sizes (where n=1, a m is 0 or 2, respectively) include 1-(benzofurazan-5-ylcarbonyl) pyrrolidin (11) and 1-(benzofurazan-5-ylcarbonyl) hexamethylenimine (14).

A second preferred group of compounds of formula I are compounds in which R= 0, R4and R8both represent hydrogen, R6is -(CRR')m-, R7is -(CRR'what they preferred class of this second group is the same in which m is 0. Particularly preferred examples of this class are compounds in which R1represents oxygen, n=1, and R and R' represent hydrogen, that is, 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine, denoted here as the connection 3, and 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydro-4-herperidin, denoted here as the connection 6. Another example of compounds containing 5-membered ring (both m and n equal 0) is 1-(benzofurazan-5-ylcarbonyl)pyrrolin (12).

A third preferred group of compounds of formula I includes compounds in which R=0, R1represents oxygen, R4and R8both represent hydrogen, R5and R7represent -(CRR')n-, a R6represents-C(O)-, -CRX-, SHH'-, -O - or-S-. Another preferred class of compounds of this third group are those in which R6is-CRX - or-SHH'-, where R and X are each selected from the groups defined previously, a n=1. The two most preferred examples of this class are 1-(benzofurazan-5-ylcarbonyl)-4'-cyanopiperidine (compound 8) and 1-(benzofurazan-5-ylcarbonyl)-4'-hydroxypiperidine (compound 9). Preferred are also those in which X represents fluorine, and R and R' prticipation, denoted here as compounds 4 and 5, respectively. Other examples include the corresponding 4-methylpiperidine and 4-methoxypiperidine derivatives (13 and 17, respectively).

When any one of R5, R6and R7is SHH', two groups X and X' may form a ring with the same or with the adjacent carbon atom, as described above. An example is 1-(benzofurazan-5-ylcarbonyl)-1,4-dioxa-8 azaspiro[4,5]decane (15).

Another preferred class of this third group of compounds are those in which n=1, R and R' represent hydrogen, and R6represents oxygen or sulphur. This class includes morpholino and thiomorpholine benzofurazan, i.e., N-(benzofurazan-5-ylcarbonyl)morpholine (7) and N-(benzofurazan-5-ylcarbonyl)thiomorpholine (10). In compound 16 was obtained from 4-pyridinone, R6represents-C(O)-.

A fourth preferred group of compounds of formula I are those in which M is = CR4- where R4and R8together form one binding fragment linking M with the top of the ring 2'. This binding fragment selected from the group consisting of simple communication, -CRR'-, -CR=CR'-, -C(O)-, -O-, -S-, -NR -, and-N=. Preferred compounds of this fourth GRU is predstavlyaet-CR=, where R has the above values. The most preferred compounds are those in which all of these definitions; that is, some tetracyclic benzofurazan amides, such as those shown in Fig.2. A preferred group of these compounds includes those in which binding fragment selected from-CRR'-, -O-, -S - and-N=. Preferably, R5and R7represent -(CRR')n-, and R6is -(CRR')m-. More preferably in this case, n=1, a m=0 or 1, which leads to a 5-membered or 6-membered heterocyclic ring, respectively, as the right of the condensed ring. The preferred binder is particularly preferred fragments-CRR'-, oxygen, sulfur, or-N=, oxygen and imino (-N=), and the most preferred oxygen.

III. Receiving target compounds

Compounds of the present invention can be obtained in various ways, including conventional chemical methods of synthesis. Methods for obtaining compounds of the present invention is as follows.

Compounds of the invention in which R4and R8do not form binding fragment, usually obtained as shown in Fig.1, activating carboxyl gnuoy, piridincarbonova or pyrimidinecarboxylic acid, using carbonyldiimidazole or other activating group, for example, thionyl chloride, in an anhydrous solvent such as dichloromethane, chloroform, tetrahydrofuran or ethyl acetate. Then the cyclic amine is subjected to interaction with the activated carboxyl group. Cyclic amine preferably includes, in accordance with the above-described preferred structures, optionally substituted piperidine derivative. The ring may be unsaturated or include atoms of oxygen or sulfur, and are also considered larger or smaller sizes of rings. Commercially available large selection of such amines; in another embodiment they can be obtained using known methods of synthesis.

In examples 1-20 describes the obtaining of representative compounds of the present invention, referred to here as compounds 1-18, in accordance with the above described methods.

Compounds of the present invention, in which R4and R8form binding fragment can be obtained in accordance with the methods shown in Fig.2A-2D.

Although illustrative ways of getting use is etenia, for example, the relevant benzothiadiazole and other nitrogen-containing heteroaromatic systems.

As is shown in Fig.2A, after activation of the carboxyl group appropriately substituted salicylic acid carbonyl diimidazol in anhydrous solvent such as dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, or similar, should attach appropriate aminoalkylsilane. The resulting imidazenil subjected to interaction with a strong acid, such as alkyl - or arylsulfonic acid, or with triperoxonane acid to slightly basic solvent, such as dichloromethane, to effect the cleavage of the acetal and cyclization in the tetracyclic substituted benzoxazin, as presented, in which binding fragment formed by R4and R8is oxygen. In an alternative method of obtaining, shown in Fig. 2B, activated salicylate reacts with cyclic Eminem, such as 1-pyrrolin or 2,3,4,5-tetrahydropyridine.

In Fig. 2C presents the reaction of the appropriately substituted anthranilate of ester with a cyclic palominos, such as 2-chloro - or 2-bromamide, to obtain the tetracyclic compounds, in which St is th for example, catalytic hydrogenation, getting aminophenoxy fragment.

In Fig. 2D presents the reaction of the appropriately substituted homophthalic anhydride with cyclic Eminem, such as 1-pyrrolin or 2,3,4,5-tetrahydropyridine, followed by decarboxylation to obtain the tetracyclic compounds, in which binding fragments, educated R4and R8are-CH2- or-CRR'- group (see, e.g., Cushman et al., J. Org. Chem. , 45:5067-5073 (1980) and Smith et al., J. Heterocyclic Chem., 28:1813-1815 (1991)).

IV treatment

In accordance with the following aspect of the present invention the compositions of the present invention can be used for the treatment of schizophrenia or schizophrenic behavior in mammals, or for the treatment of memory problems or other cognitive functions. Such diseases are symptoms of hypoglutamatergic state or of insufficient quantity or efficiency of excitatory synapses or in the number of AMPA receptors. As treatment of the subject compositions of the present invention increases the activity of AMPA receptors, such treatment can be used to help develop skills that are dependent on AMPA receptors. The method of treatment you

< / BR>
where R1represents oxygen or sulfur;

R2and R3independently selected from the group consisting of-N=, -CR=- CX=;

M is =N - or =CR4- where R4and R8independently represent R or together form one binding fragment linking M with the top of the ring 2', and binding fragment selected from the group consisting of simple communication, -CRR'-, -CR=CR'-, -C (O)-, -O-, -S(O)y-, -NR -, or-N=; and

R5and R7independently selected from the group consisting of -(CRR')n-, -C(O)-, -CR=CR'-, -CR=CX-, -CRX-, -CXX'-, -S - and-O-; and

R6selected from the group consisting of -(CRR')m-, -C(O)-, -CR=CR'-, -CRX-, -CXX'-, -S - and-O-;

where X and X' independently are selected from-Br, -Cl, -F, -CN, -NO2, -OR, -SR, -NRR', -C(O)R-, -CO2R or-CONRR', where the two R and R' groups are the same or different X groups can be taken together to form a ring;

R and R' independently are selected from (i) hydrogen, (ii) C1-C6branched or unbranched alkyl which may be unsubstituted or may be substituted by one or more of the functional groups selected from halogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide, and where two such alkyl grey may be unsubstituted or may be substituted by one or more of the functional groups, selected from hydrogen, nitro, alkoxy, hydroxy, aryloxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide;

m and p are independently 0 or 1;

n and y are independently 0, 1 or 2.

Compounds introduced in accordance with the specified method, preferred groups include those described in section II above. Especially preferred compounds, designated as compounds 1-9, with the most preferred compounds 2, 7, 8 and 9.

As was discovered, connections, introduced in accordance with the method of the present invention, more effective than the previously described connections, in terms of increasing the activity of AMPA receptors, as shown in in vitro and in vivo tests described below.

V. Biological activity

A. the Enhancement of AMPA receptor function

Synaptic responses mediated AMPA receptors are amplified in accordance with the method of the present invention, using the compounds described herein. These compounds, as demonstrated in the examples that follow are much more effective than the previously described connections, in terms of enhancing AMPA receptor(excitatory postsynaptic potential), recorded in field CA1 after stimulation SA axons, known to be mediated by AMPA receptors, which are present in synapses (Kessler et al., Brain Res., 560: 337-341 (1991)). Drugs that selectively block this receptor, selectively block the field EPSP (Muller et al., Science, see earlier). Aniracetam, which, as shown, increases the mean open time of the channel AMPA receptors, increases the amplitude of the synaptic current and prolong its duration (Tang et al., Science, see earlier). These effects are reflected on the field EPSP (for example, Staubli et al., Psychobiology previously; Xiao et al., Hippocampus previously; Staubli et al., Hippocampus, 2:4958 (1992)). Similar results were reported for the previously open stable benzamide analogues aniracetam (Lynch and Rogers, PCT WO 94/02475).

To obtain the data presented in the table, bipolar nichrome stimulating electrode placed in the dendritic layer (stratum radiatum) of hippocampal subpos CA1 near the border subpos SA as described in example 21. The current pulse (0.1 μs) through the stimulating electrode activates population Schaffer-connective fibers (SC) that extend from neurons in cobrastyle SA and terminate at synapses on the dendrites of CA1 neurons. Activation of these synapses causes them to allocate transmitters glutamate. Gluta is their ion channels and enable the flow of sodium to penetrate into the postsynaptic cell. This current creates a voltage in the extracellular space (field EPSP), which is written to the recording electrode with high resistance, located in the middle of stratum radiatum CA1.

The intensity of the stimulating current install to get half maximum values of EPSP (usually about 1.5-2.0 mvolt). Paired stimulus pulse is served every 40 seconds with maineline intervals of 200 μs, as described later in example 21.

Slices of the hippocampus support in registering the camera, which continuously serves artificial cerebrospinal fluid (ACSF). In 15-30 minute intervals perfusion medium replaced with medium containing different concentrations of test compounds. Reactions registered immediately before or at the end of perfusion drugs pose to calculate the percentage increase in EPSP amplitude.

Compounds of the invention 1-9, as shown in Fig.3 and in the following table, as well as comparative compound SH (1-(cinoxacin-6-ylcarbonyl)piperidine), disclosed in PCT WO 94/02475, analyze in the above-described physiological test system. Results in the first column of the table demonstrate the assessment of the concentration of each of castilloa value.

< / BR>
As the results of table compounds of the present invention provide a dose-dependent increase in the amplitude of the EPSP and be effective in concentrations as low as 3 microns. Most of the tested compounds proved to be equally or more effective, up to a factor of 50 compared with the comparative compound SH, the increase in AMPA receptor function. Compounds 2, 4 and 6-9 proved to be particularly effective.

Studies that compared the effects of AMPA modulators monosynaptic (as reported here) and polysynaptic responses, demonstrated that a 10% increase in the amplitude monosynaptic field EPSP increases by 300% trisynaptic reaction (Strvio et al., Neuroscience, 74: 1025-1035 (1996)). In addition, as has been shown, the concentration of the modulator, which causes these reactions, there is a plasma derived from behavioral relevant doses (Graner et al., Synapse previously). So, a 10% increase in the amplitude monosynaptic field EPSP, as can be seen from the table, apparently represents behavioral corresponding plasma concentration.

C. Behavioral test

Compounds of the present invention is also effective when tested in animal models with the positive abilities, such as features in the maze with 8 radial paths.

The results in the second column of the table show the minimum effective dose (MED= MEDsfor activity in rat models using methamphetamine, which proved to be applicable for evaluating the effectiveness of antipsychotic drugs to treat schizophrenia (Larson et al., Brain Res., previously). Recorded doses that reduce hyperactivity and/or stereotypically activity induced by acute injection of 2 mg/kg of methamphetamine to rats as described in example 22.

All tested compounds proved to be significantly more effective than the comparative compound as shown in the table that provided a 10-fold or more reduction in the dose that causes an equivalent effect. Compound 2 was found to be equally effective at a dose 100 times lower.

The results in the third column show EDR for efficiency to improve performance in the task, a maze with 8 radial paths, in which test the improvement of memory and cognitive abilities (HONEYwith). This task was described previously (Staubli et al., PNAS, 91:777-781 (1994) and Lynch and Rogers, PCT WO 94/02475). And again, all the tested compounds (2 and 7-9) of acatalasemia HONEY, which cause statistically significant improvement in behavior in models of depression in animals (HONEYdas described Malatynska and Kostowski, Pol. J. Pharmacol., 40, 357-364 (1984).

Compounds 2 and 9 were tested and again proved to be more effective (about 500 times) in comparison with the comparative compound.

VI. The routes of administration, dose and composition

As indicated above, the compounds and method of the invention increases AMPA receptor-mediated reaction and can be used to treat hypoglutamatergic States. They can also be used to treat conditions such as memory impairment or other cognitive functions caused by a deficiency in the number or effectiveness of excitatory synapses or in the number of AMPA receptors. They can also be used for treatment of schizophrenia or schizophrenic behavior arising from cortical/industrial imbalance, and to facilitate the study of behavior, dependent on AMPA receptors.

Typically, doses and routes of administration of the compounds is determined in accordance with the weight and condition of the patient, in accordance with standard pharmaceutical practice. The levels used doses may vary widely and can easily op the patient in various ways, for example, oral, transdermal, perineurally or parenterally, i.e., via intravenous, subcutaneous, intraperitoneal or intramuscular injection. Subjects who can be treated in accordance with the method of the present invention include humans, domestic animals, laboratory animals, etc.

Compositions containing compounds of the present invention may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as tablets, capsules, powders, compositions with delayed allocation, solutions, suspensions, emulsions, suppositories, creams, ointments, lotions, aerosols or similar, preferably in unit dosage forms suitable for simple introduction of an accurate dose.

The compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvant, etc., it is Preferable that the composition contain from about 0.5 to 75% by weight of the compound or compounds of the invention, and the rest are pharmaceutical excipients. For oral administration such excipients include pharmaceutical grades mannitol, lactose, brahmaji composition may also contain minor amounts of nontoxic auxiliary substances, such as wetting agents, emulsifying agents or buffers.

Liquid compositions can be prepared by dissolving or dispersive connection (from about 0.5% to about 20%) and optional pharmaceutical adjuvant in the media, such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension. For use in preparations for oral administration, the composition can be prepared in the form of a solution, suspension, emulsion or syrup, supplied either in the form of liquid or in dry form suitable for dissolution in water or normal saline solution.

If the composition is used in the form of solid preparations for oral administration, these drugs can be tablets, granules, powders, capsules or similar To compositions in the form of tablets composition is usually prepared with additives such as excipients, such as sugar or cellulose, a binder such as starch paste or methyl cellulose, fillers, disintegrating agents and other additives that are typically used in the manufacture of medical products. Compositions for injection for parenteral administration typically contain a link the notice may also be prepared in the form of a suspension in a lipid or phospholipid, in liposomal suspension or in aqueous emulsion.

Methods for such dosage forms are known or will be apparent to specialists; see, for example, "Remington''s Pharmaceutical Sciences" (17thEd. , Mack. Pub. Co., 1985). Composition intended for the introduction must contain the number of selected compounds in a pharmaceutically effective amount for implementation enhance AMPA receptor currents in the patient.

EXAMPLES

The following examples are only illustrative of the invention but in no way limit it.

Unless otherwise indicated, all temperatures are given inoC.

All spectra1H NMR obtained in the solvent deuterium chloroform using as an internal standard tetramethylsilane. Infrared spectra (IR) were recorded with films on Fresnel crystal mode ATI Mattson Gemini FTIR.

Note: the Distillation of any of the following connections should be made with caution. The risk allocation of the gaseous products of decomposition increases with the scale of the reaction. An alternative method of treatment using activated carbon described in example 2, in the way In the next.

EXAMPLE 1: 1-(Benzo-2,1,3-thiadiazole-5-ylcarbonyl) piperidin (0.55 g, 6.6 mmol) and methyl benzo-2,1,3-thiadiazole-5-carboxylate (1,16 g, 6,00 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to half volume in a rotary evaporator. Add dry toluene (25 ml) and the reaction solution is heated to 80oC for 1 hour. Add additional piperidine (about 0.2 g) and the temperature was raised to 100oC for 1 hour. The solution is allowed to cool to room temperature and stirred overnight, then the reaction is quenched with 10% citric acid and hydrochloric acid. This solution is diluted with ethyl acetate and sequentially washed with 10% citric acid, saturated solution of the secondary acid phosphate of sodium and saturated sodium chloride solution and then dried over anhydrous sodium sulfate. This solution was concentrated on silica and the product elute with a mixture of hexane/ethyl acetate (3: 1). In the purification by distillation in a round bottom flask (kugelrohr) at 180oC and a pressure of 0.5 mm RT.art., get 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine (1) (1.29 g, 87%) as oil is pale yellow in color.

IR: 2920, 2855, 1633, 1478, 1439, 1280, 1223, 1001, 816 and 748 cm-1.

1H NMR (500 MHz) : of 8.06 (1H, d, J=9, 1 Hz); 8,02 (1H, s); 7,63 (1H, t, J= 9.0 and 1.5 Hz); of 3.77 (2H, Chi (2)

Method a:

Benzofurazan-5-carboxylic acid (2.0 g, 12.2 mmol) is suspended in 10 ml of dichloromethane. Add carbonyldiimidazole (2.0 g, 12.3 mmol), which leads to the dissolution of the emitting gas. The obtained yellow solution is stirred for 40 min at room temperature, then added piperidine (1.2 g, 14.1 mmol). The resulting solution is stirred overnight and concentrated on silica. Product elute with a mixture of hexane/ethyl acetate (2: 1) and purified by distillation in a round bottom flask (kugelrohr) at 155-170oC and a pressure of 0.5 mm RT.article 1-(Benzofurazan-5-ylcarbonyl)piperidine (2) (2,78 g, 99%), representing the first oil is pale-yellow, crystallizes upon cooling. So pl. 88,5-90,5oC.

IR: 2938, 2857, 1630, 1519, 1439, 1266, 1223, 996, 881, 816 and 740 cm-1< / BR>
1H NMR (500 MHz) : of 7.90 (1H, d, J=9, 17 Hz); to 7.84 (1H, s); 7,44 (1H, DD, J=9,0 and 1.4 Hz); 3,74 (2H, Shir. C); 3,39 (2H, Shir. C); 1,72 (4H, Shir. C) and 1.57 million D. (2H, Shir. C).

Method:

A 5-liter flask is charged with ethyl acetate (2.3 l) and carbonyldiimidazole (500.0 g, 2.48 mol), to this add 4-chloro-3-nitrobenzoic acid (402,5 g, 2.48 mol) in portions over 1 hour. The solution is stirred for another 1.5 hours. Within 2 hours added dropwise piperidine (to 222.2 g, 2,60 mol) and receive. The CL solution (600 ml), twice with saturated sodium bicarbonate solution (250 ml) and finally saturated NaCl solution (250 ml). The organic solution is dried over anhydrous sodium sulfate and filtered, and the solvent is removed in vacuum, obtaining 646 g (97%) of 4-chloro-3-nitrobenzoyl-piperidine in the form of a crystalline solid yellow with so pl. 76-77oC.

IR: 1633, 1535, and 1440 cm-1.

1H NMR (500 MHz, CDCl3) : a 7.92 (1H, d, J=1.5 Hz); of 7.60 (1H, d, J=8.1 Hz); 7,56 (1H, DD, J=8.1 and 1.5 Hz); 3,70 (2H, Shir. C); 3, 35 (2H, Shir. C); and 1.0 (4H, Shir. C) and 1.56 million D. (2H, Shir.C ).

4-Chloro-3-nitrobenzonitrile (539,2 g, a 2.00 mol) dissolved in 2,93 l of ethylene glycol in a five-liter flask with stirring and heated to 50oC. To this solution in portions over 40 min add sodium azide (137,0 g, 2,10 moles). After complete addition the temperature was raised to 120oC for 2.5 hours and maintain at this temperature for 3 hours. The solution is allowed to cool to 50oAnd at this time, for 5 minutes, add additional sodium azide (65,2 g, 1.00 mol). The temperature was raised to 120oC for 2.5 hours and maintain this temperature for 4.5 hours until the evolution of gas ceases. The solution is allowed to cool to room temperatureto (300 ml). The combined organic phases are washed with 30 ml of water, twice with saturated NaCl solution (200 ml) and finally dried over anhydrous sodium sulfate. The filtered solution is evaporated, getting 345,5 g crude 1-(benzofurazan-5-ylcarbonyl)piperidine.

Untreated (raw)) 1-(benzofurazan-5-ylcarbonyl)piperidine (22 g) was dissolved in 200 ml of ethyl acetate under stirring. To the solution was added activated carbon (11,0 g) and the resulting suspension is heated to boiling under reflux, allow to cool to 60oAnd finally filtered on celite. Remaining on the filter, activated carbon again suspended in 200 ml of ethyl acetate, heated to boiling under reflux and again filtered on celite. The filtered cake washed twice with ethyl acetate (50 ml) and the resulting filtrate concentrated in a rotary evaporator, getting 19,0 g butter, orange color, which solidifies upon standing. Discolored product is washed with 20 ml ice ethanol, getting to 13.1 g of pale yellow crystals (2), so melting 91,0-93,0oC.

EXAMPLE 3: 1-(Benzofuroxan-5-ylcarbonyl) piperidine (1)

Benzofuroxan-5-carboxylic acid (1 g, 5.6 mmol) is suspended with stirring in 15 ml of dihormati mesilat for 40 min, and at this time added under stirring piperidine (0.5 g, 5.9 mmol). The reaction solution was concentrated on silica and the product elute with a mixture of hexane/ethyl acetate (3:1). As a result of recrystallization from a mixture of 2-propanol/hexane (1:10) to obtain 1-(benzofuroxan-5-ylcarbonyl)piperidine (0,94 g, 69%) as a solid yellow color with so pl. 94,5-96,5oC.

IR: 2938, 2855, 1620, 1612, 1528, 1487, 1435, 1257, 1233, 1018, 1000, 852, 811 and 747 cm-1.

1H NMR (500 MHz) : 7,10-7,80 (3H, Shir. C), and 3.72 (2H, Shir. C); 3,39 (2H, Shir. C); 1,72 (4H, Shir. C) and 1.54 million D. (2H, Shir. C).

EXAMPLE 4: Obtaining 4-foreveryday and 1,2,3,4-tetrahydropyridine

N-TRIFLUOROACETYL-4-hydroxypiperidine (7, 92 g, 40 mmol ) is suspended in 10 ml of dichloromethane and cooled to -78oC. Add TRIFLUORIDE dimethylaminoethyl (6.8 g, 42 mmol) and the suspension allowed to warm to room temperature over night. Then the reaction mixture was diluted with 125 ml of dichloromethane and washed with saturated sodium bicarbonate solution, which leads to intense bubbling. The dichloromethane solution is then dried by washing with a saturated solution of sodium chloride, and then treated with anhydrous magnesium sulfate. The solvent is removed in vacuo and the resulting oil reagiruut ether and dried over anhydrous magnesium sulfate. The solution is filtered and the ether removed by distillation at atmospheric pressure. Amines distilled at 95oWith, the result is 0.7 g of colorless oil, which consists of a mixture of 4-foreveryday/1,2,3,6-tetrahydropyridine.

IR: 3317, 3293, 2968, 2955, 2943, 2929, 1451, 1427, 1418, 1377, 1279 and 1023 cm-1.

EXAMPLE 5: 1-(Benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (3) and 1-(benzofurazan-5-ylcarbonyl)-4-foreperiod (4)

Benzofurazan-5-carboxylic acid (0.75 g, 4.6 mmol) is suspended in 15 ml of dichloromethane. To this suspension add carbonyldiimidazole (0.75 g, 4.6 mmol), causing the conversion of the reaction mixture in yellow color as the evolution of a gas. The solution is stirred for 30 minutes, then add a mixture of 4-foreveryday and 1,2,3,6-tetrahydropyridine (0.7 g, about 7 mmol), obtained as described in example 4. The solution is stirred for 2 hours at room temperature, after which the reaction mixture was concentrated on silica and products elute with a mixture of hexane/ethyl acetate (3:1). There are three component, 100 mg, 200 mg and 300 mg, respectively. Connection released the second solidifies upon standing and identified as 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine, (3) according to NMR data. So plavini is, =9,0 Hz); 7,88 (1H, s); 7,47 (1H, d, J= 9,0); 5,57-5,95 (2H, m); 4, 23 (1H, Shir. C); 3,90-of 3.97 (2H, m); of 3.53 (1H, Shir. C); 2,33 (1H, Shir. C) and 2,22 million (1H, Shir. C).

Component, which came third, is recrystallized from a mixture of ethyl acetate/hexane (1:30), receiving 200 mg of white crystals with tons of melting point 124-125,5oWith, and identified as 1-(benzofuroxan-5-ylcarbonyl)-4'-foreperiod (4) according to NMR data.

IR: 1633, 1439, 1274, 1231, 1034, 923, 881 and 742 cm-1.

1H NMR (500 MHz) : to 7.93 (1H, d, J=9.0 Hz); 7,87 (1H, s); 7,44 (1H, d, J= 9.0 Hz); 4,9-5,1 (1H, m); 4,0-4,2 (1H, Shir. with); to 3.5-3.7 (2H, m); 3,4-3,5 (1H, Shir. C); 1,72-2.1 million (4H, m).

EXAMPLE 6: 1-(Benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (3)

An alternative way

A more direct way to obtain 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (3) was carried out according to the method of example 2, method A, as described earlier, based on net tetrahydropyridine. The crude product (yield 94%) was purified using chromatographic processing on silica gel (hexane/ethyl acetate (1: 3)), resulting in the get with the yield 74% crystals pale yellow color with tons of melting point 82-83,5oC. Presumably other crystalline isomorph obtained earlier.

EXAMPLE 7: Getting 4,4-ceftobiprole/1,2,3,6-tetrahydro-4-foreplay diethylaminosulfur (9,1 g, of 56.5 mmol). The reaction initially proceeds slowly, but after a few minutes the mixture rapidly to boiling. To reduce the intensity of the boil, carry out cooling. The mixture is stirred over night, diluted with 125 ml of dichloromethane and washed with saturated sodium bicarbonate solution, after which there is rapid formation of bubbles. Then dichloromethane is dried with saturated sodium chloride solution and then anhydrous magnesium sulfate. The solvent is removed in vacuum and the resulting orange oil was stirred with 7.5 M KOH solution for 1 hour at room temperature. The product is extracted with ether, the resulting solution was dried over anhydrous magnesium sulfate and filtered. The ether is distilled off at atmospheric pressure and the product distilled at 105-125oWith, receiving 4.5 g of pale yellow oil consisting of a mixture of 4,4-ceftobiprole/1,2,3,6-tetrahydro-4-foreveryday.

IR: 2960, 1357, 1265, 1146, 1117, 987, 952, 814 and 792 cm-1.

EXAMPLE 8: 1-(Benzofurazan-5-ylcarbonyl)-4,4-ceftobiprole (5) and 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydro-4-herperidin (6)

Benzofurazan-5-carboxylic acid (0.75 g, 4.6 mmol) activate in 15 ml of dichloromethane carbonyl diimidazol, according to the method of example 4. A mixture of 4,4-debtor the CT elute with a mixture of hexane/ethyl acetate (3:1), getting two components. Component suirvey first, is recrystallized from a mixture of ethyl acetate/hexane (1:5) to give 480 mg of a solid product with so pl. 148-149oWith, and identified as 1-(benzofurazan-5-ylcarbonyl)-4,4'-ceftobiprole (5).

IR: 1642, 1440, 1365, 1266, 1123, 1086, 936, 822, 817, 737 and 607 cm-1.

1H NMR (500 MHz) : of 7.96 (1H, d, J=9, 5 Hz); of 7.90 (1H, s); coefficient 7.45 (1H, t, J= 8.8 and 1.1 Hz); of 3.8-4.1 (2H, Shir. with); to 3.5-3.7 (2H, Shir. C) and 1.9-2.2 million (4H, Shir. d).

Component borovany second, is recrystallized from a mixture of ethyl acetate/hexane (1: 10) to give 180 mg of the solid product with so melting 102-105oWith, and identified as 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydro-4-herperidin (6).

IR: 1639, 1436, 1361, 1241, 1146, 1007, 828, 817, 742 and 605 cm-1.

1H NMR (500 MHz) : 7,94 (1H, d, J=9.0 Hz); of 7.90 (1H, s); 7,46 (1H, d, J= 9.0 Hz); of 5.1 and 5.4 (1H, m); 4,3 (1H, Shir. C); 4,0 (2H, Shir. C); the 3.65 (1H, Shir. C) and of 2.30-2.55 million D. (2H, Shir. d).

EXAMPLE 9: 4-(Benzofurazan-5-ylcarbonyl)morpholine (7)

4-(Benzofurazan-5-ylcarbonyl)morpholine receive according to the method of example 2 (method A), using morpholine instead of piperidine. The product is obtained with a yield of 65% in the form of a pale crystalline solid with tons of melting point 148-150oC.

IR: 1638, 1522, 1439, 1276, 1108, 1003 and 6

EXAMPLE 10: 1-(Benzofurazan-5-ylcarbonyl)-4-cyanopiperidine (8)

Method AND

1-(Benzofurazan-5-ylcarbonyl)-4-cyanopiperidine receive according to the method of example 2 (Method A), using 4-cyanopiperidine instead of piperidine. The product is obtained with a yield of 74%, so the melting point 190-192oAfter chromatographic purification on silica gel, using as eluent a mixture of ethyl acetate/methanol (95:5).

IR: 1675, 1611, 1431, 1261 and 1226 cm-1.

1H NMR (500 MHz) : to 7.93 (1H, d, J=9,2 Hz); 7,88 (1H, s); 7,46 (1H, d, J= 9,1); AND 5.30-OF 5.50 (2H, m); 4,60-4,70 (1H, m); 3.75 to of 3.85 (1H, m); 2,90-of 3.25 (2H, m); 2.40 a-2,50 (1H, m) and 1.60-2,10 million (4H, m).

The way IN

1-(Benzofurazan-5-ylcarbonyl)-4-carboxamidotryptamine (2.50 g, 9,11 mmol) dissolved in SNS3(90 ml) and treated with thionyl chloride (1.65 g, of 13.8 mmol). The reaction mixture is heated to boiling under reflux for 30 minutes and during this time the solution becomes turbid. Add additional thionyl chloride (1.52 g, 12.8 mmol) and the reaction mixture is heated additional 1.5 hours. After the solution is cooled to room temperature, it was diluted with CH2Cl2, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. The product is concentrated on silica gel and elute with a mixture of Gex is razan-5-ylcarbonyl)-4-cyanopiperidine (0,570 g, 24%) (51%, based on the selected source material) in the form of an oil which crystallizes upon standing as a pale solid. So melting 104-107oC.

IR: 2240, 1735, 1633, 1435, 1271 and 1236 cm-1.

1H NMR (500 MHz) : of 7.96 (1H, DD, J=9.0 and 1.2 Hz); 7,88 (1H, DD, J=1.7 and 0.7 Hz); 7,44 (1H, DD, J=9.1 and 1,6 Hz); 3,60-4,00 (4H, m); 2.95 and was 3.05 (1H, m) 1,80-2,15 million (4H, m).

EXAMPLE 11: 1-(Benzofurazan-5-ylcarbonyl)-4-hydroxypiperidine (9)

1-(Benzofurazan-5-ylcarbonyl)-4-hydroxypiperidine receive according to the method of example 2 (method A), using 4-hydroxypiperidine instead of piperidine. The product is obtained with a yield of 45%, and so melting 132-136oAfter chromatographic purification on silica gel using ethyl acetate as eluent.

IR: 1614 and 1446 cm-1.

1H NMR (200 MHz) : to 7.95 (1H, d, J=9,3 Hz); 7,86 (1H, s); 7,44 (1H, DD, J= 9.2 and 1.3 Hz); 4,0-of 4.25 (2H, m) 3,1-4,0 (3H, m); 1,8-2,1 (2H, m) and of 1.5-1.8 (3H, m) M. D.

13With NMR (125 MHz) : 33,6, 34,5, 39,3, 44,6, 66,5, 114,6, 117,5, 130,6, 139,1, 148,5, 148,6 and 167.5 million D.

EXAMPLE 12: 1-(Benzofurazan-5-ylcarbonyl)thiomorpholine (10)

1-(Benzofurazan-5-ylcarbonyl)thiomorpholine receive according to the method of example 2 (method A), using thiomorpholine instead of piperidine. The product is obtained with a yield of 58%, and so the melting point 144-146oWith as tx2">

1H NMR (500 MHz) : 7,94 (1H, d, J=9.6 Hz); 7,86 (1H, s); 7,41 (1H, d, J=9,2 Hz); 4,06 (2H, Shir. with); to 3.73 (2H, Shir. C), 2,78 (2H, Shir. C) and 2,62 M. D. (2H, Shir. C).

EXAMPLE 13: 1-(Benzofurazan-5-ylcarbonyl)pyrrolidin (11)

1-(Benzofurazan-5-ylcarbonyl)pyrrolidin receive according to the method of example 2 (method A), using pyrrolidine instead of piperidine. The product is obtained with a yield of 61%, and so the melting of 97.8-99,3oC.

IR: 2957, 2878, 1632, 1619, 1514, 1471, 1432, 1194, 1009, 882, 822, 786 and 742 cm-1.

1H NMR (500 MHz) : of 7.96 (1H, s); to $ 7.91 (1H, d, J=9.0 Hz); 7,58 (1H, d, J= 9.5 Hz); of 3.69 (2H, t, J=6.6 Hz); 3,50 (2H, t, J=6.5 Hz); a 2.01 (2H, q, J= 6.6 Hz) and 1.96 M. D. (2H, t, J=6.5 Hz).

EXAMPLE 14: 1-(Benzofurazan-5-ylcarbonyl)-3-pyrrolin (12)

1-(Benzofurazan-5-ylcarbonyl)-3-pyrrolin receive according to the method of example 2 (method A), using 3-pyrrolin instead of piperidine. The product is obtained with a yield of 65%, and so the melting point 117-118oWith in the form of a pale crystalline substance.

IR: 3072, 2862, 1633, 1609, 1562, 1535, 1524, 1471, 1460, 1432, 1408, 1360, 1304, 1192, 1156, 1012, 882, 834, 822, 769, 744, 695 and 684 cm-1.

1H NMR (500 MHz) : 8,00 (1H, s) to 7.93 (1H, d, J=9.7 Hz); 7,58 (1H, d, J= 9,3 Hz); 5,97 (1H, m); 5,80 (1H, m); 4,50 (2N, C) and 4,30 million d (2N, C).

EXAMPLE 15: 1-(Benzofurazan-5-ylcarbonyl)-4-methylpiperidin (13)

1-(Benzofurazan-5-ylcarbonyl)-4-methylpiperidin Polo%, and so the melting point 86-87oC.

IR: 1633, 1441 and 1239 cm-1.

1H NMR (500 MHz) : a 7.92 (1H, d, J=9.5 Hz); of 7.90 (1H, s); 7,44 (1H, d, J= 9.0 Hz); 4,50-4,70 (1H, m); 3,65-of 3.80 (1H, m); 3,05 is 3.15 (1H, m); 2,80-2,90 (1H, m); 1,75-of 1.85 (1H, m); 1,60-1,75 (2H, m); 1,20-1,30 (1H, m); 1,05-1,20 (1H, m) and 1.00 million (3H, d, J=6 Hz).

EXAMPLE 16: 1-(Benzofurazan-5-ylcarbonyl)hexamethylenimine (14)

1-(Benzofurazan-5-ylcarbonyl)hexamethylenimine receive according to the method of example 2 (method A), using hexamethylenimine instead of piperidine. The product is obtained with a yield of 67%, and so the melting point 86-87oAfter chromatographic purification on silica gel, using as eluent a mixture of hexane/ethyl acetate (1: 1).

IR: 1631, 1428, 1273 and 743 cm-1.

1H NMR (500 MHz) : to $ 7.91 (1H, DD, J=8,6, 0.6 Hz); of 7.82 (1H, s); 7,44 (1H, DD, J= 9,2, 0.8 Hz); and 3.72 (2H, t, J=3,9 Hz); of 3.43 (2H, t, J=3,9 Hz); of 1.88 (2H, t, J=3,9 Hz; and 1,60-1,70 M. D. (6N, m).

EXAMPLE 17: 1-(Benzofurazan-5-ylcarbonyl)-1,4-dioxa-8 azaspiro[4,5]decane (15)

1-(Benzofurazan-5-ylcarbonyl)-1,4-dioxa-8 azaspiro[4,5] decane receive according to the method of example 2 (method A) using 1,4-dioxa-8 azaspiro[4,5]decane (atlantal 4-pyridone) instead of piperidine. The product is obtained with a yield of 54%, and so the melting point 88-90oC.

IR: 1638, 1440, 1268, 1120, 1081 and 742 cm-1.

1H NMR (500 MHz) : to $ 7.91 (1H, DD, J=9.0 and 1.0 G (2N, Shir. C).

EXAMPLE 18: 1-(Benzofurazan-5-ylcarbonyl)-4-piperidone (16)

1-(Benzofurazan-5-ylcarbonyl)-4-piperidone receive according to the method of example 2 (method A), using 4-piperidone instead of piperidine. The product is obtained in 30% yield, and so melting 136-139oC.

IR: 1715, 1637, 1433, 1270 and 1238 cm-1.

1H NMR (500 MHz) : of 7.96 (1H, DD, J=9,6, 1.0 Hz); 7,94 (1H, s); 7,49 (1H, d, J=9.6 Hz); 3,70-4,20 (4H, s) and 2,30-2,80 M. D. (4H, Shir. C).

EXAMPLE 19: 1-(Benzofurazan-5-ylcarbonyl)-4-methoxypiperidine (17)

1-(Benzofurazan-5-ylcarbonyl)-4-methoxypiperidine (840 mg, 3,40 mmol) dissolved in dimethylformamide (12 ml) and treated with 60% sodium hydride (150 mg, 3.75 mmol) for 30 minutes. Add methyliodide (650 mg, of 4.54 mmol) and 3 hours at room temperature the reaction mixture is treated with still the same amount of sodium hydride and under the conditions as before, and left to stand for 16 hours. The reaction solution was diluted with water and the product extracted with ethyl acetate. The organic solution is washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product is purified discoloring activated carbon in ethanol, double handle chromatography on silica gel, elwira a mixture of hexane/etilize is n-5-ylcarbonyl)-4-methoxypiperidine (269 mg, 30%) as a pale yellow oil.

IR: 1639, 1440, 1274, 1101 and 1089 cm-1.

1H NMR (500 MHz) : to $ 7.91 (1H, DM, J=9,2 Hz); a 7.85 (1H, t, J=1.1 Hz); the 7.43 (1H, DD, J= 9,2, 1.2 Hz); 3,90-of 4.05 (1H, m); 3,55-and 3.72 (2H, m); of 3.53 (1H, Sept, J= 3.5 Hz); to 3.38 (3H, s); 3,20-to 3.35 (1H, m); 1,90-2,02 (2H, m); 1,65-of 1.85 (2H, m) and 1,65 M. D. (1H, m).

EXAMPLE 20: 1-(Benzofurazan-5-ylcarbonyl)decodecharreferences (18)

Benzofurazan-5-carboxylic acid (0,9070 g 5,526 mmol) is suspended in 15 ml of methylene chloride, and to this solution add carbonyldiimidazole (0,9027 g 5,567 mmol). The reaction mixture becomes dark as the evolution of a gas. This solution is stirred for 30 minutes and at this point add piperidine-d11(0,5125 g 5,437 mmol). The reaction mixture is stirred for two hours at room temperature, concentrated on silica gel and elute with a mixture of hexane/ethyl acetate (2:1) to give 1-(benzofurazan-5-ylcarbonyl) decodecharreferences (911,1 mg, 69%) as a pale crystalline solid with tons of melting 88-89oC.

IR: 2213, 2113, 1624, 1517, 1416, 1233, 1103, 970, 930, 897, 881, 872, 772, 740 and 605 cm-1.

1H NMR (500 MHz) to $ 7.91 (1H, d, J=9.8 Hz); to 7.84 (1H, s) and 7,44 M. D. (1H, DD, J=9,4, 1,4 Hz).

EXAMPLE 21: In vitro physiological testing

Physiological action connect the giver reaction (field EPSP) measured in slices of hippocampus, located in the recording chamber, which is continuously serves artificial cerebrospinal fluid (ACSF). In 15-30 minute intervals perfusion medium replaced with medium containing various concentrations of test compounds. Reactions registered immediately before and at the end of perfusion drugs pose to calculate the percentage of increase in EPSP amplitude.

To conduct these tests, the hippocampus is removed from shot a two-month rat strain Sprague-Dole and prepare in vitro slices (thickness 400 μm), which is placed in the camera interface 35oWith using conventional methods (see , for example, Dunwiddie and Lynch, J. Physiol., 276:353-367 (1978)). The camera constantly served at a rate of 0.5 ml/min ACSF containing (in mm): NaCl 124, KCl 3, KN2RHO41,25, MgSO4of 2.5 CaCl23,4, Panso326, glucose 10, and L-ascorbate 2. Bipolar nichrome stimulating electrode placed in the dendritic layer (stratum radiatum) of hippocampal subpos CA1 near the border subpos SA.

The current pulse (0.1 μs) through the stimulating electrode activates population Schaffer-connective fibers (SC) that extend from neurons in subsection SA and terminate at synapses on the dendrites of CA1 neurons. Activate the MPA receptors which then briefly open the associated ion channels and enable the flow of sodium to penetrate into the postsynaptic cell. This current creates a voltage in the extracellular space (field EPSP), which is written to the recording electrode with high resistance, located in the middle of stratum radiatum CA1.

For experiments, summarized in the table, the intensity of the stimulating current install to get half maximum values; EPSP (usually about 1.5-2.0 mvolt). Paired stimulus pulse is served every 40 seconds with maineline intervals of 200 μs, see below. Field EPSP second reaction locations are digitized and analyzed to determine the amplitude. If the responses are found to be stable for at least 15-30 minutes (baseline), test compounds added to the perfusion line for about 15 minutes. Then the perfusion return to regular ACSF.

Use the paired stimulation pulses, as stimulation of the SC fibers partially activates interneuron that create inhibitory postsynaptic potential (IPSP for acquiring) in pyramidal cells of CA1. It moves forward typical values IPSP for acquiring normal values after EPSP reaches its Piiroinen compounds. One of the associated features of shift forward IPSP for acquiring is that it is not possible to reactivate within a few hundred milliseconds after stimulus pulse. This phenomenon can be used to advantage to eliminate IPSP for acquiring, feeding the pair of pulses separated by 200 milliseconds, and using the second ("praimirovanie") reaction for analysis of results.

Results in the first column of the table shows the evaluation of the concentrations of each of the tested compounds, which will need to increase the amplitude of the field EPSP to a value of 10% above the baseline level. Values in most cases installed by interpolation, but in other cases by extrapolation from specific values.

EXAMPLE 22: Behavioral testing

The results in the second column of the table show the minimum effective dose (MED = MEDsfor activity in the model in rats using methamphetamine, to assess the effectiveness of antipsychotic drugs to treat schizophrenia (Larson et al., Brain Res., previously). Recorded doses that reduce hyperactivity and/or stereotypically activity induced by acute injection of 2 mg/kg of methamphetamine, two rats strain on the Right is Dr. detectors with the to the bottom row were detected movement, and the top row has detected behavior of the tail. Data are collected and stored in a personal computer for subsequent analysis.

Although the present invention has been described with reference to specific methods and embodiments, it should be understood that, without going beyond the scope and essence of the invention, it is possible to make various modifications.

1. Derivatives benzofurazan or benzo-2,1,3-thiadiazole of the General formula I

< / BR>
where R1represents oxygen or sulfur;

R2and R3independently selected from the group consisting of-N= , -CR=- CX= ;

M is = N - or = CR4- where R4and R8independently represent R or together form one binding fragment linking M with the top of the ring 2', and binding fragment selected from the group consisting of simple communication, -CRR'-, -CR= CR'-, -C(O)-, -O-, -S(O)y-, -NR -, or-N= ; and

R5and R7independently selected from the group consisting of -(CRR')n-, -C(O)-, -CR= CR'-, -CR= CX-, -CRX-, -CXX'-, -S - and-O-, and

R6selected from the group consisting of -(CRR')m-, -C(O)-, -CR= CR'-, -CRX-, -CXX'-, -S - and-O-; where X and X' independently are selected from-Br, -Cl, -F, -CN, -NO2, -OR, -SR, -NRR', -C(O)R-, -CO2R or-CONRR', where two groups R or R' in one is a, (ii) C1-C6branched or unbranched alkyl or C3-C5cycloalkyl, which may be unsubstituted or may be substituted by one or more functional groups selected from halogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide, and where two such alkyl groups from one carbon atom or adjacent carbon atoms may together form a ring, and (iii) aryl, which may be unsubstituted or may be substituted by one or more functional group selected from hydrogen, nitro, alkoxy, hydroxy, aryloxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide, m and p independently are 0 or 1, n and y are independently 0, 1 or 2, where "alkoxy" denotes alkyl ether, and alkylthio" denotes alkyl thioether, where alkyl contains from one to seven carbon atoms; "aryl" means substituted or unsubstituted monovalent aromatic radical containing one ring or multiple condensed rings, including heterocyclic aromatic ring system containing one or nasalcease" refers to aryl ether.

2. Connection on p. 1, where R and R' independently are selected from (i) hydrogen, (ii) C1-C6branched or unbranched alkyl or C3-C6cycloalkyl, which can be nezamechennym or may be substituted by one or more functional group selected from hydrogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, a complex ester of carboxylic acid or carboxylic acid amide, and where two such alkyl groups from one carbon atom or adjacent carbon atoms may together form a ring.

3. Connection on p. 1, where R2and R3present-CR-, a M is = CR4-.

4. Connection on p. 3, where R= 0, R1is oxygen, and R4and R8represent hydrogen.

5. Connection on p. 4, where R5and R7represent -(CRR')n-, and R6is -(CRR')m-.

6. Connection on p. 5, where R and R' represent hydrogen, and m= n= 1, and the specified compound is 1-(benzofurazan-5-ylcarbonyl)piperidine.

7. Connection on p. 3, where R= 0, R1is sulfur, R4, R8, R and R' represent hydrogen and m= n= 1, and the specified compound is 1-(benzo-2,1,3-testable -(CRR')m-, R7is -(CRR')n- and m= 0.

9. Connection on p. 8, where R and R' represent hydrogen.

10. Connection on p. 9, where X is fluorine, and n= 1, and the specified compound is 1-(benzofuran-5-ylcarbonyl)-4-fluoro-1,2,3,6-tetrahydropyridine.

11. Connection on p. 4, where R5represents-CR= CR'-, R6is -(CRR')m-, R7is -(CRR')n-, a m= 0.

12. Connection on p. 11, where R and R' represent hydrogen.

13. Connection on p. 12, where n= 1, and the specified compound is 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine.

14. Connection on p. 4, where R5and R7represent -(CRR')n-, and R6represents-C(O)-, -CRX-, SHH'-, -O - or-S-.

15. Connection on p. 14, where R6is-SHH'-, R and R' represent hydrogen, n= 1, X represents a fluorine, with the specified connection is 1-(benzofurazan-5-ylcarbonyl)-4', 4'-deformabilities.

16. Connection on p. 14, where R6is-CRX'-, R and R' represent hydrogen, and n= 1.

17. Connection on p. 16, where the specified compound selected from 1-(benzofurazan-5-ylcarbonyl)-4'-foreveryday, 1-(benzofurazan-5-ylcarbonyl)-4'-cyanopiperidine and is-O-, -S-or-C(O)-, n= 1, a R and R' represent hydrogen, and a specified compound selected from 4-(benzofurazan-5-ylcarbonyl)research, 4-(benzofurazan-5-ylcarbonyl)thiomorpholine and 4-(benzofurazan-5-ylcarbonyl)-4-piperidone.

19. Connection on p. 1, where M is = CR4- where R4and R8together form a separate binding fragment linking M with the top of the ring 2', and this binding fragment represents a simple bond, -CRR'-, -CR= CR'-, -C(O)-, -O-, -S-, -NR -, or-N= .

20. Connection on p. 19, where R2and R3present-CR= .

21. Connection on p. 20, where p= 0, R1represents oxygen, R5and R7represent -(CRR')n-, a R6is -(CRR')m-.

22. Connection on p. 21 where n= 1.

23. Connection on p. 21, where the connecting part is-CRR'-, -O-, -S - or-N= .

24. Connection on p. 23, where the connecting part is-O-.

25. The compound according to any one of paragraphs. 1-24 intended for use in conjunction with a pharmaceutically acceptable carrier to enhance AMG receptor function in a mammal.

26. A method of treatment of disorders of memory or other cognitive functions called hypoglutamatergic setlocale introduction to the subject, in need of such treatment, an effective amount of the compounds under item 1.

27. The method according to p. 26 for the treatment of schizophrenia or schizophrenic behavior arising from cortical/veins imbalance caused hypoglutamatergic condition or deficiency in the number or effectiveness of excitatory synapses or in the number of DMR receptors.

28. Connection on p. 25, used to facilitate the study of behavior, depending on the functioning of AMPA receptors.

29. The method according to p. 26, which is administered to the subject the compound according to any one of paragraphs. 2-18.

30. The method according to p. 26, where the specified connection selected from the group consisting of: 1-(benzofurazan-5-ylcarbonyl)piperidine, 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine, 1-(benzofurazan-5-ylcarbonyl)-4-fluoro-1,2,3,6-tetrahydropyridine, 1-(benzofurazan-5-ylcarbonyl)-4'-foreveryday, 1-(benzofurazan-5-ylcarbonyl)-4', 4'-deformability, 1-(benzofurazan-5-ylcarbonyl)-4'-cyanopiperidine, 1-(benzofurazan-5-ylcarbonyl)-4'-hydroxypiperidine, 4-(benzofurazan-5-ylcarbonyl)research, 4-(benzofurazan-5-ylcarbonyl)thiomorpholine and 4-(benzofurazan-5-ylcarbonyl)-4-piperidone.

 

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< / BR>
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< / BR>
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