Acylbenzoxazines for enhancing synaptic response(s)

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

 

The present invention relates to the prevention and treatment of cerebral insufficiency, including enhancement of the action of the receptor neurotransmission in the brain mesh structures responsible for the actions of the highest order. In a particular aspect, the present invention relates to methods of using the compounds disclosed therein, and to methods for the latter.

The glutamate in the synapses in many areas of the front of the mammalian brain stimulates two classes of postsynaptic ionotropic receptors. These classes are usually referred to as AMPA receptors/quisqualate and N-methyl-D-aspartic acid (NMDA). AMPA/quisqualate receptors serve as a link for potentialization postsynaptic current fast excitation (fast epsc), whereas NMDA receptors generate potentsialzavisimye current slow excitation. Research conducted on sections Amanova horns or cortex, indicate that mediated AMPA receptor postsynaptic current fast excitation is the dominant component in most glutamatergic synapses in most cases.

AMPA receptors are unevenly distributed in the brain, but to a large extent limited by the finite brain and cerebellum.

These receptors are found in high concentrations in the surface layers of the neocortex, in CA the DOI of the main synaptic zones Amanova horns and veins in the complex, according to Monaghan with collaborators in Brain Research 324:160-164(1984). Studies on animals and humans show that these structures organize perceptual-motor processes and provide the substrates for the reactions of the highest order. Thus, AMPA receptors mediate the transfer of those mesh structures of the brain that are responsible for cognitive actions of the owner.

For the above reasons, drugs that enhance the functioning of AMPA receptors, can have a significant impact on cognitive ability. Such drugs would also enhance the encoding of memory. Experimental work, as those published Arai and Lynch, Brain Research, 598:173-184(1992)show that the magnitude of the mediated AMPA receptor synaptic response(s) enhances the induction of long-term potential (LTP). Long-term potential LTP is a steady increase in the intensity of synaptic contacts, followed by repeating the physiological activity of this type, which takes place in the brain in the learning process. Compounds that enhance the activity of AMPA receptors form of glutamate, facilitate the induction of LTP and the acquisition of skills for learning, as measured by a number of paradigms. Granger et. al., Synapse 15:326-329 (1993); Staubli et. al., PNAS 91:777-781 (1994); Arai et. al., Brain Research, 638:343-346 (1994); Staubli et. al., PNAS 91:11158-1162 (199); Shors et. al., Neurosci. Let. 186:153-156 (1995); Larson et. al., J. Neurosci. 15:8023-8030 (1995); Granger 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); Lynch et. al., Exp. Neurology 145:89-92(1997); Ingvar et. al., Exp. Neurology 146:553-559(1997); Hampson et. al., J. Neurosci., 18:2740-2747 (1998); Hampson et. al., J. Neurosci., 18:2748-2763(1998) and publication of international patent application no WO 94/02475 (PCT/US93/06916) (Lynch and Rogers, Regents of the University of California).

There is a lot of evidence that long-term potentiation LTP is a substrate of memory. For example, compounds that block LTP, prevent the formation of memory in animals, and some drugs that disrupt learning in humans, are antagonists stabilization of LTP, as evidenced by the data of del Cerro and Lynch, Neuroscience 49:1-6 (1992). A possible prototype of a compound that selectively facilitates AMPA receptor, revealed Ito and co-authors, J. Physiol. 424:533-543 (1990). These authors found that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) increases the currents mediated brain AMPA receptors expressed in Xenopus oocytes, without compromising the answers through receptors γ-aminobutyric acid (GABA), kainic acid (KA) or NMDA. It was also shown that infusion of aniracetam in slices of hippocampus leads to a significant increase of the values of fast synaptic potentials without changing other properties of the membrane. Since the EOS obtained evidence, that aniracetam enhances synaptic responses in several regions of the hippocampus and that it does not affect mediated NMDA receptor potentials. See, for example, Staubli with co-authors in Psychobioiogy 18:377-381(1990) and Xiao and co-authors. Hippocampus 1:373-380 (1991). It was also found that aniracetam has an extremely rapid onset of prolapse of the action of the stimulus and the washing and can be re-applied without apparent long-term effects; it is a valuable strokes for behavior-relevant drugs. Unfortunately, the peripheral introduction of aniracetam probably does not affect brain receptors. The drug works only at high concentrations (~1.0 mm), and according to Guenzi and Zanetti, J. Chromatogr. 530:397-406 (1990), about 80% of the drug is hydrolyzed to anisoyl-GABA after peripheral injection into the body. It was found that the metabolite, anisoyl-GABA, has weak effects similar to aniracetam.

Was recently discovered class of compounds, which shows low efficiency and inherent hydrolytic instability characteristic of aniracetam. These compounds, called "Ampakine", disclosed in published international patent application WO 94/02475 (PCT/US93/06916) (Lynch and Rogers, Regents of the University of California). Ampakine are usually substituted benzamide and chemically more stable than aniracetam, and have improved the bioavailability, as evidenced by the experiments conducted by means of positron emission tomography (PET) [see, for example, Staubli al. in PNAS 91:11158-11162 (1994)]. Also found additional ampakine in the form of benzoylpiperidine and pyrrolidino, and they are subject are in the process of simultaneous processing of patent applications in the United States 08/458967, filed June 2, 1995. Recently it was discovered that a new class of ampakines, benzoxazines, has unexpectedly high activity in models in vitro and in vivo to assess the probability of achieving cognitive gain [Rogers and Lynch Benzoxazines for Enhancing Synaptic Response", U.S. Patent No 5736543, issued April 7, 1998.]. Further developments in the field dependence of the activity of the compounds on their structure allowed us to open a new series of compounds, acylresorcinol, which give a strong responses in vitro by activation of AMPA receptors and show a greater biostability compared to the isomeric benzoxazines. These compounds are disclosed in this application.

The authors of the present invention found that the synaptic responses mediated by AMPA receptors, increase with the introduction of a new class of derivative elvenskin. The ability of the new compound of the present invention to enhance mediated AMPA receptor responses determine the possibility of using this is x connections for different purposes, including silvania reactions learning-dependent AMPA receptors, as well as therapeutic drugs in cases where AMPA receptors or synapses that use these receptors are fewer or reduced efficiency, or in those cases when it would be useful reinforced excitatory synaptic activity. Unexpectedly it was found that the compounds of the present invention exhibit increased bioavailability and increased metabolic stability compared to known compounds. In addition, the compounds of the present invention that the initial assumptions would have to be completely inactive or exhibit significantly reduced activity compared with the known compounds, unexpectedly showed increased activity compared to known compounds.

In the following, the examples show that the compounds of the present invention have unexpectedly high biological activity, as evidenced by their ability to enhance the function of AMPA receptors in hippocampal slices of rats are much more metabolically stable in comparison with structurally related ampakine and accelerate the implementation of the relevant tasks on memorizing, such as behavior in vosmikova radial maze. the ti and other aspects and advantages of the present invention will be apparent from further description.

A detailed description of the invention and the preferred variants of its implementation

Compounds of the present invention are etilbenzimidazola having the following formula:

where the radicals R1and R2are either separate monovalent residues, or, United together, they form one of the bivalent residue. As the monovalent residue of the radicals R1and R2have either the same or different values and represent each a hydrogen atom, CH2OR4or or4provided that at least one of the radicals R1and R2is not a hydrogen atom, and in which the radical R4represents either a hydrogen atom, a C1-C6alkyl, C1-C6foralkyl, C7-C12arylalkyl or3-C10heteroallyl. As a single divalent residue of the radicals R1and R2together form a group selected from the following groups:

in which the radical R5means (CR2)m, CR2CR2or CR=CR, the radical R represents a hydrogen atom, halogen atom, cyano, C1-C6alkyl, C1-C6haloalkyl, C7-C12arylalkyl or3-C10heteroallyl and is the same is or are different in any radical R 5;

the radical R6means a hydrogen atom, cyano, HE, C1-C6alkyl, C1-C6foralkyl, C7-C12arylalkyl or3-C10heteroallyl,3-C10heteroaromatic or or4and R4has the same meaning given above;

the radical R7represents a hydrogen atom, a C1-C6alkyl or C1-C6foralkyl, C7-C12arylalkyl or3-C10heteroaromatic;

the radical R3represents a hydrogen atom, a C1-C6alkyl or C1-C6foralkyl;

the radical Q is a substituted or unsubstituted lower alkylene, pilooski, aryl, arylalkyl or heteroaromatic;

the radicals X and Y both independently from each other represent a hydrogen atom or together they form a covalent bond or (CH2)nconnecting Q with a benzoxazine ring;

m is 1 or 2; and n is 1 or 2.

In the description of the present invention will be used the following terms.

Used in the text, the term "alkyl" includes remotemachine, branched and cycloalkyl residues. Used in the text the term "foralkyl" includes substituted by one or more fluorine atoms residues, of which preferred are perfluorinated C1-C3the mod is I. The term "aryl" includes substituted and unsubstituted carbocyclic and heterocyclic aromatic residues, such as phenyl, tolyl, pyridyl, imidazolyl, alkylenedioxy etc.

Thus, for those compounds in which the radicals R1and R2are separate monovalent residues, the preferred compounds are those in which one of these two residues is a hydrogen atom and the other represents OR4where R4means either C1-C6alkyl or C1-C3foralkyl, where the preferred values for R4are C1-C3alkyl or C1-C2foralkyl, even more preferred is-CH(CH3)2or CF3and the most preferred CH(CH3)2. The radical R3preferably represents a hydrogen atom and the radical Q preferably represents a lower alkylene, and the radicals X and Y together form a covalent bond.

The term "effective amount" or "therapeutically effective amount" is used throughout this application to describe the quantity or concentration of one or more compounds of the present invention, which is used to achieve the desired effect, or to create a specific condition in a patient or subject. With the organisations of the present invention can be used to enhance the action of the patient's sensorimotor problems, to facilitate the actions of subjects, including cognitive tasks that depend on the mesh structures of the brain, using AMPA receptors, to improve the strength of the encoding memory or to improve the functioning of the brain in subjects with nedostatocnosti in exitronix synapses or AMPA receptors. These compounds can also be used in effective amounts to reduce the time necessary for the subject to study cognitive, motor or perceptual task, or to reduce the number and/or severity of errors made by the subject during playback of cognitive, motor or perceptual task. These connections are also used for the treatment of subjects with the aim of speeding up the synaptic response mediated by AMPA receptors. In addition, these compounds may be used for the treatment of schizophrenia, schizophrenia-like psychosis behavior or depression in patients (people or entities. In each case, when using this connection, it is used in a quantity or concentration that is effective to achieve the desired effect or to treat a specific condition of the patient.

The term "patient" or "subject" used in the description of the application to describe an animal, including humans, for which it was intended treatment or the use of the compounds or compositions according to the present invention. In the treatment or use and/or those conditions or disease States which are specific for a specific animal (especially, for example, a human subject or patient), the term patient or subject refers to that specific animal.

The term "sensorimotor problems" is used to describe problems that arise in a patient or subject due to the inability to integrate the information received through the five known senses, therefore, to direct the appropriate physical responses, including movement and action.

The term "cognitive task" is used to describe the attempts of the patient or subject, which include thinking or knowledge. The various functions of the associative areas of the cerebral cortex in the parietal, temporal and frontal lobe, which account for approximately 75% of all brain tissue of the person responsible for the processing of much of the information that occurs between sensory input and motor response. The various functions of the associative areas of the cerebral cortex is often called knowledge, which literally means the process by which we understand the world. Selective response to specific stimuli, recognition and identification of these signs of significant incentives and planning and ispitivanje on the experience of the answer to depict ablaut some processes or abilities mediated by the human brain associated with cognition.

The term "lattice structure of the brain" used to describe the various anatomical parts of the brain that communicatively each other through synaptic activity of nerve cells.

The term "AMPA receptor" refers to a collection of proteins found in some membranes, which allows positive ions to cross the membrane in response to the binding of glutamate or AMPA (DL-α-amino-3-hydroxy-5-methyl-4-isoxazolidinone acid), but not NMDA.

The term "axilary synapse" is used to describe the connection of cells in which the separation of the chemical messenger in one cell causes depolarization of the outer membrane of another cell. Axilary synapse used to describe the postsynaptic neuron, which has a reverse potential is more positive than the threshold potential, and, respectively, then the synapse neuroparalytic increases the likelihood that there will be axilary postsynaptic potential (neuron will burn, forming an action potential). Reverse potentials and threshold potentials determine the postsynaptic excitation and inhibition. If the reverse potential postsynaptic potential ("SRP") is more positive than the threshold, the action potential, the effect of carrier vlaamsemusicals and accompanied by the emergence externado postsynaptic potential (EPSP") and the burning of the action potential of the neuron. If the reverse potential of the postsynaptic potential is more negative than the threshold, the action potential, the vector is an inhibitor and may generate inhibitory postsynaptic potentials (IPSP), thereby reducing the probability that the synapse will ignite the action potential. The General rule for postsynaptic action: If the return potential is more positive than the threshold, agitation; braking occurs when the reverse potential more negative than the threshold. See, for example. Chapter 7, NEUROSCIENCE, edited by Dale Purves, Sinauer Associates, Inc., Sunderland, MA, 1997.

The term "task to perform movements" is used to describe attempts by the patient or subject, which includes the movement or action.

The term "perceptual task" is used to describe the act of a patient or subject associated with attention to sensory inputs.

The term "synaptic response" is used to describe the biophysical reactions in a single cell due to the selection of chemical messengers by another cell with which it is in close contact.

The term "schizophrenia" is used to describe the state, which is a psychosis common type, characterized by a breakdown of thought processes, such as delirium and hallucinat what I and extensive care of the interests of the individual from other people and the outside world and immersion in his or her own world. Now schizophrenia is considered to be more of a group of mental disorders, and not a single entity, but a distinction is made between acute and continuous current schizophrenia. Used here, the term schizophrenia or schizophreniform covers all types of schizophrenia, including outpatient schizophrenia, catatonic schizophrenia, hebephrenia, latent schizophrenia, continuously current schizophrenia, pseudoneurotic schizophrenia, acute schizophrenia, simple schizophrenia and related psychotic disorders that are similar to schizophrenia, but that may not necessarily be diagnosed as schizophrenia per se. Schizophrenia and other psychotic disorders can be diagnosed using the guidelines defined, for example, in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Sections 293.81,293.82,295.10, 295.20, 295.30, 295.40, 295.60, 295.70, 295.90, 297.3, 298.8.

The term "brain function" is used to describe the combined tasks of perception, integration, filtering and response to external stimuli and internal processes of motivation.

Compounds of the present invention can be synthesized in various ways, using known methods of chemical synthesis. One method of preparing compounds of the present invention for Luchesa the following: obtain ortho-oxetanemethanol of benzylamine by reacting appropriately substituted phenol with oxymetholone inert solvent suitable for use a catalyst, such as aryl or alkylsulfonyl acid or another Lewis acid, known as the catalyst. Once released benzyl amine in the treatment with hydrazine in ethanol his acelerou suitable activated carboxylic acid and get amide. The closing of the cycle and the formation of elvenskin can be achieved by treatment with formaldehyde or an appropriately substituted higher aldehyde, resulting in the formation of the structure shown below type:

where each of the radicals R1and R2has the above meanings and, in addition, may be an aromatic carbocyclic, aromatic heterocyclic or benzyl group, each of which may contain structurally different substituents.

Another method of preparing compounds of the present invention lies in the interaction of benzylamine with an activated acid, which contains the starting aldehyde or ketone in the form of an acetal or Catala or oxidize alcohol. The aldehyde or ketone are formed and kataliziruetsa under the action of a strong acid in a solvent of low basicity for cyclization of the amide nitrogen and phenol, resulting in the formation of structures with limited rotation shown below type:

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where each of the radicals R1and R2matter above and, in addition, can additionally represent an aromatic carbocyclic, aromatic heterocyclic or benzyl group, each of which may contain structurally different substituents.

This application is related to U.S. patent No. 5736543, published on 7 April 1998, and patent application serial number PCT/US93/06916, filed July 23, 1993, published as WO 94/02475 3 February 1994, relating to the matter, methods are included in this description as a reference.

The above compounds can be incorporated into many forms (for example, capsules, tablets, capsules, delayed-action, syrups, suppositories, injection mold, percutaneous patches and the like), preferably in combination with a pharmaceutically acceptable carrier, diluent, or additive, for introduction into the subject. Similarly, there may be used various ways of administration (e.g. oral, transbukkalno, rectal, parenteral, intraperitoneal, skin etc). The levels used dosage can vary within wide limits and can easily be determined by experts. Usually use quantity in milligrams to decigram. Obviously, it is preferable about the social introduction (one to four times per day). Due to the unexpectedly favorable bioavailability and stability of the compounds of the present invention can be entered orally from a few to two or even once daily. Subjects for treatment with the compounds of the present invention include humans, domestic animals, laboratory animals, and the like.

Compounds of the present invention can be used, for example, as a means of research in the study of biophysical and biochemical properties of AMPA receptor and results selectively accelerated external transmission on the neural circuit. Due to the fact that the compounds of the present invention reach the Central synapses, they will allow you to test the behavioral effects during amplification of currents AMPA receptor.

Metabolically stable compounds that are positive modulators of AMPA currents, have many possible applications in humans. For example, the increased intensity exiting synapses could compensate for the loss of synapses or receptors associated with aging and brain disorders (such as Alzheimer's disease). The enhancement of AMPA receptors could cause more rapid processing multisynaptic chains found in the higher areas of the brain, and thus, could cause increased perceptual-number is InEU and cognitive activity. As another example, due to the fact that the amplification mediated AMPA receptor responses accelerates synaptic changes of the types that are believed to be responsible for the encoding of memory, then it is expected that metabolically stable AMPA modulators will act as memory enhancers.

Additional areas of use of the compounds of the present invention include improving the performance of subjects related to sensorimotor problems, depending on the brain mesh structures using AMPA receptors; improving the operations of entities associated with cognitive tasks dependent on the mesh of brain structures using AMPA receptors; improvement of activity of subjects with memory disorders; and the like, as discussed above.

Others consider the use of the compounds of the present invention include the adjustment of low communication system between and among areas of the brain responsible for the behavior associated with mental disorders such as schizophrenia.

Accordingly, the compounds of the present invention, being acceptable to use the compositions can be used to reduce the amount of time required for training of cognitive, motor or perceptual task. And nao is Orot, compounds of the present invention, being in the form acceptable for use of the compositions can be used to increase the time during which it is held cognitive, motor or perceptual task. As another variant, the compounds of the present invention, being in the form of suitable compositions can be used to reduce the number and/or severity of errors made during playback of cognitive, motor or perceptual task. This treatment may be particularly beneficial to persons suffering from damage to the nervous system, or for those who have persistent nerve damage, especially damage or disease that affect the number of AMPA receptors in the nervous system. The claimed compounds are introduced into the organism affected by a disease of a subject, and then present him with cognitive, motor or perceptual task. In each case, the compounds of the present invention can be administered to a patient or subject in need for treatment effective amount.

Having described in General the invention, below you will find links to the following examples, which are intended to illustrate certain preferred embodiments of the invention and comparison. Includes examples do not limit the scope of the claims nastojasih the invention, which is more widely presented above and in the attached claims.

EXAMPLE 1

5A,6,7,8-Tetrahydro-1,3-dioxolo[4,5-g]pyrrolo[2,1-b][1,3] benzoxazin-8(10H)-he

Monohydrate p-toluensulfonate acid (3,61 g, 19.0 mmol) was dried by azeotropic distillation in a solution of chloroform (100 ml). The remaining solution (50 ml) was cooled, added with 9.14 g (66,2 mmol)sesamol, of 10.01 g (57 mmol) of N-(oxymethyl)phthalimide and 100 ml of chloroform, and the resulting green solution was heated under reflux overnight. The reaction mixture was black was cooled to ambient temperature, diluted to 500 ml of chloroform and washed three times with saturated sodium bicarbonate solution. The combined aqueous extracts was again extracted with ethyl acetate, which was combined with a solution of chloroform and dried with sodium sulfate. The residue formed after evaporation of the solvents on a rotary evaporator, gathered in dichloromethane and filtered through a short column with silica gel. Dichloromethane after washing the silica gel was added to the eluent and boiled away, the result was obtained 9.3 g of N-(2-hydroxy-4,5-methylenedioxybenzyl)phthalimide in a solid yellow color (55%), which gave a single spot on TLC (Rfor =0.6; dichloromethane). IR: 1768 and 1699 cm-1.1H NMR (200 MHz): (7,81-of 7.90 (2H, multiplet); 7,70-7,79 (2H, multiplet); 7,76 (1H, singlet); 6,86 (1H, single is t); of 6.52 (1H, singlet); 5,88 (2H, singlet); and 4.73 million shares (2H, singlet).

N-(2-hydroxy-4,5-methylenedioxybenzyl)phthalimide (2.0 g; 6.7 mmol) was dissolved in 20 ml of tetrahydrofuran (THF) under argon. With stirring to this solution parts added sodium hydride (0.27 g; of 6.78 mmol) as a 60% dispersion in mineral oil, and after 30 min was added to 0.65 ml (7,01 mmol) simple chloromethylation ether. The mixture was defended during the night, and then added additional equivalents of sodium hydride and simple chloromethylation ether, and the reaction was carried out within four hours. The solution volume was reduced on a rotary evaporator and the residue distributed between water and dichloromethane. The aqueous phase is once again was extracted with dichloromethane (three times) and the combined organic layers were combined and washed with 10% sodium hydroxide (three times) and saturated salt solution before dry sodium sulfate. After evaporation of the solvent and dissolving the remaining brown liquid in ethyl ether obtained crystals, which were filtered and washed with a mixture of ethyl ether/petroleum ether (1:1). The top layer and the washing liquid were combined and allocated an additional amount of the product by chromatography on silica gel (10%-20% ethyl acetate/hexane), resulting in a total yield of N-(2-ethoxyethoxy-4,5-methylenedioxybenzyl)phthalimide amounted to 1.70 g (71%). And the (thin film): 1770 and 1709 cm -1.1H NMR (200 MHz): (7,80-of 7.90 (2H, multiplet); to 7.67-to 7.77 (2H, multiplet); 6,77 (2H, singlet); 5,88 (2H, singlet); 5,19(2H, singlet); a 4.86 (2H, singlet); to 3.73 (2H, RMS., J=? 7.04 baby mortality Hz); and to 1.21 million shares (3H, triplet, J=7,15 Hz).

N-(2-ethoxyethoxy-4,5-methylenedioxybenzyl)phthalimide (1.70 g, 4.77 mmol) was treated with 0.5 ml (16 mmol) of hydrazine in 90 ml of boiling ethanol for three hours. The reaction mixture is cooled, phthalhydrazide was filtered and washed three times with ethyl ether. The organic solutions were combined and boiled away the dryness on a rotary evaporator, obtaining a residue that was dissolved in dichloromethane. The organic solution is washed three times 10%sodium hydroxide solution, and the combined aqueous solutions were extracted twice with dichloromethane. The combined organic solutions were washed with brine and dried with sodium sulfate/potassium carbonate. After evaporation of solvent received 2 ethoxyethoxy-4,5-methylendioxy-benzylamine in the form of a slightly yellow liquid (0,98 g, yield 92%), which upon standing solidified. IR: 3298 cm-1.1H NMR (200 MHz): (6,77 (1H, singlet); 6.75 in (1H, singlet); 5,91 (2H, singlet); by 5.18 (2H, singlet);, 3,74 (2H, quadruplet, J=7,1 Hz); of 3.73 (2H, singlet); to 1.45 (2H, user. singlet); 1.24 million shares (3H, triplet, J=7,1 Hz).

4,4-Diethoxy butyric acid (716 mg, 4,06 mmol) was activated by adding to a solution of 613 mg (of 3.78 mmol) carbonyldiimidazole in 10 ml of dichloromethane. Rest the R was stirred for two hours, then added a solution of 978 mg (4.35 mmol) of 2-ethoxyethoxy-4,5-methylenedioxyphenethylamine in 15 ml dichloromethane and left to stand for three days. The solution was washed in phosphate buffer (0.1m, pH 6.8) three times and once with brine before draining it sodium sulfate. After evaporation of solvent received 1.42 g (98% yield) of a yellow liquid. IR: 1644 cm-1.1H NMR (200 MHz): (is 6.78 (1H, singlet); 6.75 in (1H, singlet); 5,95-between 6.08 (1H, user. triplet); 5,91 (2H, singlet); to 5.17 (2H, singlet); 4,49 (1H, triplet, J=5.5 Hz); 4,34 (2H, doublet, J=5.8 Hz); 3,78-3,89 (6N, multiplet); and 2.26 (2H, triplet, J=5.8 Hz); of 1.94 (2H, doublet, J=7.5 and 5.4 Hz); and 1,13-of 1.30 million shares (N, triplet, J=7,0 Hz).

Amide/acetal (1.20 g, of 3.12 mmol), obtained at the previous stage, was combined with 4 ml of 2-propanol and 200 ml of concentrated Hcl in 20 ml of THF and left to stand at room temperature overnight. The residue formed after evaporation of the solvents, was distributed between water and dichloromethane. The aqueous layer was extracted three times with dichloromethane and the combined organic fractions washed twice with 10% Hcl, three times 10%sodium hydroxide solution and once with brine, before draining it sodium sulfate. After removal of solvent received solid white, which was purified on silica gel (20% eteltetet/hexane) and recrystallized from dichloromethane/ethyl ether, resulting in h is th received 301 mg (41%) of elvenskin with so pl.=163-164°C. IR: 1697 cm-1.1H NMR (200 MHz): δ 6,51 (1H, singlet); 6,40 (1H, singlet); 5,91 (2H, singlet); 5,31 (1H, DV. doublet, J=5.3 and 1.6 Hz); 4,85 (1H, doublet, J=16.5 Hz); 4,20 (1H, doublet, J=16.4 Hz); and 2.14-2,69 million shares (4H, multiplet).

EXAMPLE 2

6A,7,8,9-Tetrahydro-1,4-dioxin[2,3-g]pyrrolo[2,1-b] [1,3]benzoxazin-9(11N)-he

N-(oxymethyl)phthalimide (97,46 g, 42.1 mmol), 3,4-atlanticcity (96.4 g, 42.1 mmol) and monohydrate p-toluensulfonate acid (0.87 g, 4.6 mmol) was dissolved in 80 ml of chloroform and the mixture is boiled with a refrigerator for three days with trap Dean-stark with periodic water drainage. The brown solution was filtered through a plug of silica, a tube of silicon dioxide was washed with chloroform and the combined organic solutions evaporated, getting a solid yellow color, which was purified by thin-layer chromatography with dichloromethane as eluent. The intermediate compound was obtained as a solid yellow (5.8 g), which consisted of a mixture of isomers which was used further without additional purification.

The solid obtained at the previous stage, (1.4 g, 4.5 mmol) was dissolved in 15 ml of THF and was treated with 0.7 g (7.4 mmol) simple chloromethylation ether and 0.3 g (7.5 mmol) of sodium hydride (60% dispersion in mineral oil) under argon for one hour. EXT the wheelie water and the separated aqueous phase was extracted three times with dichloromethane. The combined organic phases are washed three times 10%sodium hydroxide solution and once with brine before draining their sodium sulfate. After evaporation of the solvent was obtained an oil which was dissolved in ethyl acetate and was led, resulting in a received 0,63 g (38%) of white crystals. So pl.=97-98,5°C. IR: 1771 and 1709 cm-1.1H NMR (200 MHz): δ of 7.6 to 7.9 (4H, multiplet); 6,70 (1H, singlet); 6,69 (1H, singlet); to 5.17 (2H, singlet); 4,82 (2H, singlet); 4,18 (4H, multiplet); 3,71 (2H, quadruplet, J=7.2 Hz); and 1.2 million shares (3H, triplet, J=7,1 Hz).

N-(2-ethoxyethoxy-4,5-atlantooccipital)phthalimide (625 mg, 1,69 mmol) was mixed with 0.2 ml (6.4 mmol) of hydrazine in 30 ml of ethanol and boiled at reflux for three hours. The reaction mixture is cooled, to the mixture was added 30 ml of ethyl ether, and the precipitated white precipitate was filtered. The filtered substance is washed three times with diethyl ether, and the combined organic solutions were boiled away, resulting in a residue, which was distributed between ethyl ether and 10%sodium hydroxide solution. The organic phase is washed three times 10%sodium hydroxide solution and the aqueous phase was combined and was again extracted twice with dichloromethane. The organic solutions were combined and washed with brine and dried with sodium sulfate/potassium carbonate. After subsequent evaporation of the solvent p is obtained 2-ethoxyethoxy-4,5-atlantikdesigner in the form of a light yellow oil (346 g, 86% of crude product, which solidifies upon standing. IR: 3375 cm-1.

4,4-Diethoxymethane acid (270 mg, 1.53 mmol) was activated by adding to a solution of 213 mg (1,31 mmol) carbonyldiimidazole in 5 ml of dichloromethane. The solution was stirred for 30 minutes, then added a solution of 347 mg (1,45 mmol) 2-ethoxyethoxy-4,5-ethylenedioxythiophene in 1 ml dichloromethane and left to stand over night. The solution was washed in phosphate buffer (0.1m, pH 6.8) three times and once with brine before dry sodium sulfate. The solution was filtered through a small funnel with silica gel and boiled away, resulting in a received 436 mg (84% crude product oil. IR: 3293 and 1644 cm-1.

Amide/acetal (436 mg, 1.1 mmol)obtained in the preceding stage, combined with 2 ml of 2-propanol and 100 μl of concentrated Hcl in 10 ml of THF and left to stand at room temperature overnight. The residue obtained after evaporation of the solvent, was treated with dichloromethane and washed three times 10%Hcl, three times with 10% sodium hydroxide solution and once with brine before dry sodium sulfate. After removal of solvent received a white solid, which was recrystallize from dichloromethane/ethyl ether and washed twice with ethyl ether/petroleum ether, resulting in the received 123 mg (45%) of elvenskin with so PL-152° C. IR: 1708 and 1689 cm-1.1H NMR (200 MHz): δ to 6.58 (1H, singlet); 6,41 (1H, singlet); 5,32 (1H, DV. doublet); a 4.86 (1H, doublet, J=16,7 Hz); 4,22 (4H, multiplet); 4,20 (1H, doublet, J=16,3 Hz); and 2,12-2,70 million shares (4H, multiplet).

EXAMPLE 3

6A,7,8,9-Tetrahydro-1,4-dioxane[2,3-g]pyrido[2,1-b][1,3] benzoxazin-10(NN)-dione

Trimethylaluminum in the form of a 2M solution in toluene (2.3 ml, 4.6 mmol) were placed in a two-neck flask under argon atmosphere and cooled to -5--10°C. 2-ethoxyethoxy-4,5-atlantikdesigner (1.0 g, 4,18 mmol; mixture of isomers) in 5 ml dry chloroform was added into the reaction flask and the resulting solution was kept at the same temperature for 20 minutes. After the solution was warmed to room temperature, added 0,81 g (4.6 mmol) of methyl-5,5-dimethoxyacetate and the resulting solution was boiled under reflux overnight. The reaction was interrupted with methanol and phosphate buffer (0.1 M, pH 6.8) and was extracted three times with dichloromethane. The combined organic phases are washed three times with phosphate buffer and once with brine and dried with sodium sulfate. Amide was purified to obtain the oil light yellow color on silica gel, using as eluent dichloromethane/ethyl ether (4:1) and proved (NMR)that it is a mixture of free and protected phenolic compounds, and used without additional purification. IR: 3279 and 1632 cm -1.

The oil obtained in the preceding stage, dissolved in 10 ml of THF, 2 ml of 2-propanol and 100 μl of concentrated Hcl and left to stand for 24 hours. The solvent was removed under vacuum and the residue was treated with dichloromethane, washed three times, 10%Hcl, three times -10%sodium hydroxide solution and once with brine before dry sodium sulfate. After evaporation of the solvent obtained white solid, which was recrystallize from dichloromethane/ethyl ether and received 141 mg ε-lactam. Obtained in the form of crystals, the product was heated, the transformation occurs at 147°and a new form, which melts at 163°C. IR: 1647 and 1639 cm-1(unresolved doublet).1H NMR (200 MHz): δ to 6.58 (1H, singlet); to 6.39 (1H, singlet); 5,31 (1H, doublet, J=16.4 Hz); 5,16 (1H, triplet, J=3,4 Hz); 4,22 (4H, multiplet); 4,12 (1H, doublet, J=16,7 Hz); 2,30-2,60 (2H, multiplet); 1,00-of 2.20 (3H, multiplet); 1,70-1,90 million shares (1H, multiplet).

EXAMPLE 4

5A,6,7,8-Tetrahydro-1,3-dioxolo[4,5-g]pyrrolo[2,1-b][1,3] benzoxazin-8,10(10H)-dione

4,5-Methylenedioxyaniline (496 mg; is 2.74 mmol) was dissolved in 10 ml triperoxonane acid, to which was added 491 mg (2,79 mmol) 4,4-diethoxymethane acid. After 24 hours, the volume of the reaction solution was reduced to 5 ml on a rotary evaporator, and adding additional 526 mg of 4,4-diethoxymethane acid is isalo the formation of a white precipitate. Triperoxonane acid was removed by evaporation and the solid residue was collected, in turn, ethyl acetate and ethanol and has again provided a solid by evaporation of the solvent. Finally the solid residue was dried under high vacuum. IR: 1720, 1657, 1617, 1470, 1260 and 1177 cm-1.1H NMR (200 MHz); d6DMSO/CDCl3): δ 8,32 (1H, user. singlet); 7,17 (1H, singlet); 6,47 (1H, singlet); of 6.02 (2H, singlet); the 5.25 (1H, triplet, J=4.5 Hz); 2,48-2,6 (2H, multiplet); 2.06 to 2.2 million shares (2H, multiplet).

The intermediate acid was added to a solution of 1.09 g (6,17 mmol) carbonyldiimidazole in 20 ml of methylenechloride. After 24 hours was observed the formation of a milky-white suspension. Analysis by TLC suggested that remained of the original material, and therefore, to the suspension was added 474 mg CBI. No response was observed, and the white precipitate was filtered and washed with dichloromethane. UV and IR spectra showed that this intermediate product (310 mg) is allmydata, and so it is suspended in 10 ml of dichloromethane and treated with 105 mg of triethylamine in 4 days, during which the reaction solution was homogeneous. The solution was washed in 10%Hcl solution (3 times) and once with brine and finally dried his Na2SO4. After evaporation of solvent received 205,6 mg of a white solid. This substance was dissolved in triperoxonane Ki the lot, but no changes have occurred (TLC) during the day. The product is re-allocated and recrystallize from CHCl3/Et2O and got the material so pl.=224-225°C. IR: 1750 (s), 1673 (m) and 1625 (m) cm-1.1H NMR (500 MHz) δ to 7.4 (1H, singlet); 6,47 (1H, singlet); 6,05 (2H, singlet); 5,77 (1H, DV. doublet, J=5.0 and a 7.1 Hz); 2,69-2,78 (1H, multiplet); 2,53-of 2.64 (2H, multiplet); and to 2.29-2.39 million shares (1H, multiplet) FAB MS: m/z=248 (P + 1)

BIOLOGICAL DATA

EXAMPLE 5

Physiological testing

Physiological effects of compounds of the present invention can be assessed in vitro using slices of the hippocampus of rats according to the following procedure. Externae responses (field Espow) measured in hippocampal slices, which are in registration chamber is continuously supplied with artificial cerebrospinal fluid (ISMI). In 15-30 minute intervals include one perfusion medium containing various concentrations of test compounds. The responses collected immediately before and at the end of the perfusion of the drug, impose on each other to be calculated as the percentage increase in the amplitude of EPSP, and the percentage increase of the width of the response at half the peak height (width).

To conduct these tests took hippocampus shot from 2-month-old rats Spraque-Dawley and in vitro slices (thickness 400 μm) were prepared and placed in contact the th camera at 35° With using known methods, see, for example, Dunwiddie and Lynch, J. Physiol. 276:353-367 (1978). The camera was continuously perfesional ISMG at a rate of 0.5 ml/min, which contained (in mm): NaCl 124, KCl 3, KN2RHO41,25, MgSO42,5; CaCl23,4; NaHCO326; glucose 10 and L-ascorbate 2. Bipolar nichrome stimulating electrode was placed in the dendritic layer (stratum radiatum) of subfields CA1 of the hippocampus near the border of subfields SO.

The current pulses (0.1 MS) through the stimulating electrode to activate a set commissural nerve fibers Shaffer (HQ)arising from neurons in the subgroup S and ending in the synapses on the dendrites of CA1 neurons. Activation of these synapses causes the release of transmitter glutamate. Glutamate binds to postsynaptic AMPA receptors, which are then temporarily open channel associated ions and allow the sodium current to enter the postsynaptic cell. This current causes the potential in the extracellular space (field externado postsynaptic potential or field EPSP"), which is recorded in a recording electrode with high resistance, located in the middle of stratum radiatum CA1.

For the experiments whose results are presented in table 1, the intensity of stimulation was adjusted to achieve half of the maximum Espow (usually PR is approximately 1.5 to 2.0 mV). Paired stimulating pulses were given every 40 seconds with an interval between pulses of 200 MS (see below). Appspy the second answer was filmed in numbers and analyzed to determine the amplitude, half-width and the square of the response. If the responses were stable for at least 15-30 minutes (baseline), test compounds were added in line perfusion for about 15 minutes. Then the perfusion was continued normal ISMG.

Used the paired stimulation pulse, because the stimulation of fibers SHK, at least partially, activates intermediate neurons that produce inhibitory postsynaptic potential (IPSP) in pyramidal cells of CA1. This relationship with IPSP usually installed after EPSP reaches its peak. It speeds up re-polarization and shortens the decay phase of EPSP and, thus, can partially mask the effects of these compounds. One of the characteristics of IPSP is that it cannot be re-activated within a few hundred milliseconds after pulse stimulation. This phenomenon can be used successfully to eliminate IPSP by creating paired pulses separated by 200 milliseconds, and use the second ("primary") response length of the data analysis.

EPSP fields recorded in field CA1 after stimulation oxonol-mediated Americanarama: receptors are present in synapses [Kessler et. al., Brain Res. 560:337-341 (1991)], and drugs that selectively block the receptor that selectively block EPSP fields [Muller et. al., Science, supra]. Aniracetam increases the mean open time of the channel AMPA receptor and, as expected on the basis of this, increases the amplitude of the synaptic current and prolongs its action [Tang et. al., Science, supra].

As published in the literature [see, for example, Staubli et. al., Psychobiology, supra; Xiao et. al., Hippocampus supra; Staubli et. al., Hippocampus 2:49-58 (1992)], these effects appear Apsame field. Similar results published previously disclosed benzamide derived aniracetam [International Patent Application Publication No WO 94/02475 (PCT/US93/06916) (Lynch and Rogers, Regents of the University of California)].

The claimed compounds were evaluated in the physiological system of the test described above, for the data set presented below in table 1. In addition, in the fifth row presents data for a connection that does not have the rigidity of benzoxazines of the present invention. They serve as a comparison which illustrates a significant increase in activity with the exception of two degrees of freedom rotation inherent not hard benzylpyrrolidine (compare 20% increase in response at 300 μM for compounds 1 20% 2 (μM for benzylpyrrolidine).

It is also important to note that kidna connection structure 4, which could be considered as a rigid model anira the father of Etam, inactive in the model sections at 300 μm. Given biological activity, which demonstrated benzamide in which one carbonyl residue is located next to the aromatic ring (Rogers et. al., U.S. patent 5650409), one would expect that etilbenzimidazola of the present invention will have low or no activity. However, it is now evident that, if the presence of two carbonyl groups in the rigid structure of benzoxazine (to ensure imide) is not conducive to biological activity, one carbonyl residue at any position is sufficient. Moreover, it was quite unexpected that the carbonyl in position alpha to the nitrogen atom in the gamma position relative to the aromatic ring (in contrast to the compounds disclosed in U.S. patent No. 5650409) provides significantly greater bioavailability and increased action.

In the first two columns of the data table 1 presents the values of half-life from plasma (58 min) and bioavailability (100%) in rats for compound example 1. These data can be compared with corresponding data for benzamide (example 1 of U.S. patent No. 5736543, issued April 7, 1998), which shows the half-life and bioavailability of 31 min and 35%, respectively. In the third data column presents the size of the increase in the amplitude of EPSP when when my low concentrations, where there is a significant increase. The connection property to give an increase in the response of EPSP was a reliable parameter to predict the possibility of improving memory in task 8-channel maze. The last column of table 1 describes the threshold dose for the most potent compounds to enhance memory in rats, which were tested on the paradigm of learning by using (8-channel radial maze, as described in Staubli et. al., PNAS 91:11158-1162 (1994).

Table 1
ConnectionmnRThe half-life*(min)Bioavailability#

(%)
EPSP response+(conc.)Mad maze++(mg/kg)
12345678
111CH25810025 (300μM)NT∝
221CH2NTNT20 (30μM)0,1
322 CH2NTNT10 (30μM)NT

Continuation of table 1
12345678
411C=0NTNT0 (300μM)NT
NTNT20 (2 mM)NT
* Elimination from plasma after intravenous introduction rats

# AUC for oral administration in percent of the AUC for the/in the

+The percentage increase in the area of EPSP response

++The minimum effective dose for improving the performance of rats in an eight radial maze

NT=not tested

The invention will be described in detail with reference to the specific version of its realization. However, it should be understood that it is possible to make various changes and modifications within the essence and scope of the claims of the invention defined by the following claims.

1. Derivatives elvenskin having the following structure:

where the radicals X1and X2independently selected from a hydrogen atom, -OR3, -CH2OR3; or taken together represent-OCR

4
2
O-, -OC2R
4
4
O-, -OC2R
4
2
O-;

in each case, the radical R in the residue (CR2represents a hydrogen atom, hydroxy, C1-C6alkoxy;

R3represents a hydrogen atom or a C1-C6alkyl;

in each case, the radical R1represents a hydrogen atom or a C1-C6-alkyl;

in each case, the radical R4represents a hydrogen atom or a C1-C6alkyl;

n is 1, 2, 3, or 4.

2. The compound according to claim 1, characterized in that both the radical X1and X2taken together, represent-O-CR

4
2
O-, -OC2R
4
4
O - or-OC2R
4
2
O-; n is 2 or 3.

3. The compound according to claim 1 or 2, characterized in that in each case the radical R in the residue (CR2) independently represents a hydrogen atom, hydroxy, C1-C6alkoxy, in each case, the radical R1independently represents a hydrogen atom; in each case, the radical R4represents independently a hydrogen atom, a C1-C6alkyl.

4. A way to improve the performance of the subject's sensory-motor problems or cognitive task-dependent brain mesh structures using AMPA receptors, which improves the intensity of the encoding memory specified subject or in which improves brain function in subjects suffering from a deficiency in the number of synapses or AMPA receptors, characterized in that the method consists in the introduction of a specified subject an effective amount of a compound according to claims 1-3.

5. The way to reduce the time necessary for the subject to assimilation of cognitive tasks, tasks to perform movements or tasks on the perception or increasing the time during which the specified entity retains cognitive tasks, tasks n the execution of movements or tasks on the perception or decrease the number or severity of errors, made by the subject during playback of cognitive tasks to perform movements or tasks on perception, characterized in that the method comprises the introduction of a specified subject an effective amount of a compound according to claims 1-3.

6. Method of strengthening synaptic response mediated by AMPA receptors in a subject, characterized in that the method consists in the introduction of a specified subject an effective amount of a compound according to claims 1-3.

7. The pharmaceutical composition used for enhancing synaptic responses mediated by AMPA receptors containing the derived elvenskin and a pharmaceutically acceptable carrier, filler or additive, characterized in that the derived elvenskin contains an effective amount of at least one compound according to any one of claims 1 to 3.

8. The composition according to claim 7, characterized in that theit is a composition for oral or parenteral administration.

9. The composition according to claim 7, characterized in that theit is suitable for oral administration.

10. The compound according to any one of claims 1 to 3, is suitable in the manufacture of medicaments intended for use in order to improve the activity by sensory-motor or cognitive tasks, dependent on the mesh structures of the brain, using AMR Retz who ptory.

11. The compound according to any one of claims 1 to 3, is suitable in the manufacture of medicaments intended for use in order to reduce the amount of time needed by the subject for teaching cognitive, motor or perceptual tasks or for increasing the time during which the specified entity holds cognitive, motor or perceptual task, or to reduce the number and severity of errors made by the subject during playback of cognitive, motor or perceptual task.

12. The compound according to any one of claims 1 to 3, is suitable in the manufacture of medicaments intended for use in a method of enhancing synaptic response mediated by AMPA receptors.

13. The compound according to any one of claims 1 to 3, suitable for use as a medicine intended for enhancing synaptic responses mediated by AMPA receptors.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

where is a five - or six-digit, optionally containing nitrogen, sulfur and/or oxygen ring;

X denotes one of the groups-CH2, -CH2CH2-, -NH-, NHCH2-, -CH2NH-, -CH(NH2)--CH2CH2NH-, -C(=NOCH3)-, -OCH2-, -SCH2-;

A represents lower alkyl, hydroxy-(lower alkyl, vinyl, cianfrini, lower alkoxy, optionally phenylselenenyl lower alkylsulfonate, the remainder is-S-Het or-S- 2-L, where L is a lower alkanoyloxy, respectively carbamoylated, low-alkoxycarbonyl, carboxy, azido, lower alkanolamine, lower alkylsulfonyl, six-membered ring attached to the nitrogen atom, or a residue - or-S-CH2-Het, where Het has the above significance,

and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: medicine, neurology.

SUBSTANCE: the present innovation describes arylalkylamines that specifically affect certain types of receptor-operated Ca2+-canals, their application and pharmaceutical compositions for treating neurological disorders or diseases.

EFFECT: higher efficiency.

55 cl, 29 ex, 11 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine.

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

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

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

13 cl, 1 tbl, 30 ex

FIELD: medicine, pediatrics.

SUBSTANCE: the present innovation deals with treating motor-autonomic disorders in children associated with affected function of central nervous system. For this purpose one should puncture perineural areas in the region of the main nervous trunks with alfetin dissolved in cerebrolysine. Additionally, one should puncture in projection area of cervical and lumbar spinal thickenings and areas that correspond to segmentary innervation of organs with affected function and, also, in scalp areas depending upon the character of patient's disorders. The method suggested provides improved autonomic-trophic impact of nervous system.

EFFECT: higher efficiency of therapy.

2 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new highly efficient ligands (agonists, antagonists, modulators, etc.) nicotinic receptors - new substituted 1,2-dihydro[2,7]naphthirydines General formula 1 in the form of single stereoisomers, racemic or additive mixtures, or their pharmaceutically acceptable salts, N-oxides or hydrates

in which: R1and R2independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, or R1and R2together represent polymethene chain, including 2-5 optionally substituted methylene group; R3and R4independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, optionally substituted C1-6allyloxycarbonyl group, optionally substituted karbamoilnuyu group; R5located at the carbon atoms of the pyridine fragment represents: a hydrogen atom, an inert Deputy, optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl is the function group; or R5if it is at the nitrogen atom of the pyridine fragment, form a pyridinium salt with a pharmacologically acceptable anion and is inert Deputy

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation used in treatment of lung, moderate and severe infections of lower respiratory ways, organs of otorhinolaryngology sphere, urinary ways, kidneys, genital organs, skin and soft tissues caused by sensitive strains of microorganisms. The medicinal formulation consists of a core and envelope wherein a core comprises the following components, wt.-%: levofloxacin, 60-69; crospovidone, 2.9-4.5; magnesium stearate, 0.1-1.0; lauryl sulfate sodium, 0.5-2.0; polyvinylpyrrolidone, 2.0-3.5; microcrystalline cellulose, the balance; envelope comprises the following components, wt.-%: yellow iron oxide, 0.05-0.1; red iron oxide, 0.05-0.1; hydroxypropylcellulose, 35.0-42.0; polyethylene glycol, 10.0-20.0; titanium dioxide, 4.8-9.0, and hydroxypropylmethylcellulose, the balance. Also, invention discloses a method for making this medicinal formulation. Invention provides rapid release of active substance in digestive tract and high strength of the proposed medicinal formulation.

EFFECT: improved preparing method, enhanced and valuable medicinal and pharmaceutical properties of formulation.

5 cl, 1 tbl, 3 ex

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

SUBSTANCE: invention relates to novel substituted esters of 1,2,3,7-tetrahydropyrrolo[3,2-f][1,3]benzoxazin-5-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates possessing the antiviral effect. In compounds of the general formula (1) each R1 and R4 represents independently of one another a substitutes of amino group chosen from hydrogen atom, optionally substituted linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides; R2 represents alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl or cycloalkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, optionally substituted linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and optionally an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides; R6 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and optionally annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms or their oxides. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention. Proposed compounds can be used as active components of drugs used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza.

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

22 cl, 3 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of the formula (1a) or its pharmaceutically acceptable salt, esters or imides where A is a thiophenyl group containing, probably, substitution, the thiophenyl group A containing, probably, substitution with one or several groups as follows: alkyl, halo or arylalkyl, Y is O, S or NR2 where R2 is hydrogen or alkyl group containing 1 to 6 carbon atoms, and R1 is an non-ramified alkyl group containing 6 to 25 carbon atoms, ramified alkyl group containing 6 to 25 carbon atoms, aryl alkyl group where the alkyl group contains 2 to 25 carbon atoms or phenyl group containing substitution with one or several groups as follows: phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR16- phenyl, NR16CO-phenyl or NR16 -phenyl containing, probably, substitution where R16 is hydrogen or alkyl group containing 1 to 4 carbon atoms, the groups phenyloxy, phenylthio, SO2-phenyl, alkylphenyl, CO-phenyl, CONR-phenyl or NR-phenyl containing, probably, substitution with one or several groups as follows: halo, alkyl, alkylhalo or phenyl group containing substitution with one or several groups or alkyl groups provided the above compound is not 5-methyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on, 6-amyl-2-(4-chlorophenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on or 6-amyl-2-(4-metoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazine-4-on Invention also relates to method of obtaining compounds of the formula (Ia) or (IIa), to pharmaceutical compound and application, as well as cosmetic technique.

EFFECT: obtaining of new biologically active compounds and pharmaceutical compounds based on them.

27 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and concerns method of production of pharmaceutical composition containing N[(1-butyl-4-piperidinyl) methyl]-3,4-dihydro-2n -[1,3]oxazino[3,2]indole-10-carboxamide (SB 207266) piboserod or its pharmaceutically acceptable salt in combination with one or more pharmaceutically acceptable excipients, thus method includes formation of part or whole SB 207266 or its salts in granules by air-stream granulation. In invention there is also pharmaceutical composition offered which can be produced by air-stream granulation and/or which is produced by air-stream granulation. Declared invention enables to improve parameters of finished composition, and also to scale manufacture.

EFFECT: reception of a pharmaceutical composition with the improved parameters and possibility of its scale production process.

75 cl, 16 ex, 2 tbl, 4 dwg

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