Method for counteracting formation of neurotoxic proteins addl (versions), method for modulating neuronal dysfunction or neurotoxicity by means of non-peptide compound and based composition (versions)

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medical chemistry and concerns using non-peptide compounds for inhibiting the oligomerisarion of monomer peptides Aβ1-42. There are offered methods for counteracting formation of neurotoxic proteins ADDL from monomer peptides Aβ1-42, as well as methods for suppressing, regulating and/or modulating neuronal dysfunction or neurotoxicity caused by the proteins ADDL in nerve cells or nerve tissue due to suppressing formation of the proteins ADDL, involving the contact of monomer Aβ1-42 and a compound specified in a group consisting of: (Z)-N-(2-Methoxy-phenyl)-2-oxo-2-{N'-[3-oxo-3-thiophen-2-yl-1-trifluoromethyl-propylidene]-hydrazino}-acetamide, ethyl ether of (E)-2-{[1-(2-hydroxy-3-methoxy-phenyl)-methylidene-hydrazinooxalyl]-amino}-6-metyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid, ethyl ether of (E)-2-{[1-(2-hydroxynaphthalen-1-yl)-methylidene-hydrazinooxalyl]-amino}-6-metyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid, ethyl ether of (E)-2-{[1-(2-hydroxyphenyl)-methylidene-hydrazinooxalyl]-amino}-6-metyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid, 2-(5-Hydroxy-3-isobutyl-5-(triflouromethyl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxyphenyl)-2-oxoacetamide and (E)-2-Hydroxy-N'-((1-hydroxynaphthalen-2-yl)mehtylene)banzohydrazide. There are also presented compositions containing an effective amount of the compounds stated above.

EFFECT: group of invention provides the candidate compounds for developing drug preparations for neurodegenerative disorders associated with the proteins ADDL, particularly Alzheimer's disease.

25 cl, 2 dwg, 1 tbl, 3 ex

 

The technical field to which the invention relates.

This invention relates to methods of suppression, regulation and/or modulation of the formation of soluble, globular, defibrillating, neurotoxic oligomers β1-42(proteins ADDL) of Monomeric peptides β1-42using ones compounds with molecular weight less than 1000. This invention also relates to methods of treating patients suffering from diseases associated with the formation of soluble, globular, defibrillating, neurotoxic oligomers β1-42by introducing them ones connections.

The level of technology

Alzheimer's disease (AD) is a slowly developing dementia fatal, incurable today. Although the molecular mechanism of the disease is not installed, a large number of existing data indicate that participation in the mechanism of neurotoxins derived from beta-amyloid (β) peptides and, in particular, of beta-amyloid peptide, consisting of 42 amino acid residues. β is amphipatic peptide, the relative content of which increases due to mutation of genes and risk factors associated with AD. Fibrils formed from β constitute the cores of amyloid senile plaques, which are a sign of brain with BA. Similar fibrils, the image of the mark in vitro, are lethal to cultured brain neurons. These data have been the main reasons for nominating primary hypothesis the amyloid cascade theory, in which it was assumed that the memory loss is due to death of neurons caused by fibrillar Aβ (Hardy and Higgins (1992), Science 256:184-185).

Despite good experimental confirmation and intuitive reasoning has been proven that the original hypothesis the amyloid cascade incompatible with key observations, including weak correlation of dementia with a mass of amyloid senile plaques (Katzman (1988) Ann. Neural. 23(2):138-144). Through the use of model BA-based transgenic mice, which were treated with monoclonal antibodies raised two amazing observations about β: (1) in vaccinated mice was observed process, reverse the deterioration of memory, with a clear recovery provisions are in place for 24 hours; and (2) experienced improvement in cognitive abilities after vaccination, although the level of senile plaques remained unchanged (Dodart et al. (2002) Nat. Neurosci 5:452-457; Kotilinek et al. (2002) J. Neurosci. 22:6331-6335). Similar observations do not align with the mechanism in which memory loss is due to death of neurons, called amyloid fibrils.

Obvious shortcomings of the initial hypothesis the amyloid cascade have removed the advanced hypothesis the amyloid cascade, in which a key role was assigned additional neuroactive molecules formed by self-Assembly β. These molecules are proteins derived from β-amyloid (hereinafter - ADDL), which is collected from Monomeric beta-amyloid peptides, consisting of 42 amino acid residues (hereinafter referred to Aβ1-42) at low concentrations (Lambert et al. (1998) Proc. Natl. Acad. Sci. USA 95:6448-6453). Being essentially a missing link in the original theory amyloid cascade, ADDL quickly suppress long-term potentiation (Lambert et al. (1998) Proc. Natl. Acad. Sci. USA 95:6448-6453; Walsh et al. (2002) Nature 416:535-539; Wang et al. (2002) Brain Res. 924:133-140), the classical experimental paradigm in relation to memory and synaptic plasticity. In the improved hypothesis β cascade, memory loss due to the occurrence of disorder of the synapse to the death of neurons, this disorder is called ADDL, but not fibrils (Hardy and Selkoe (2002) Science 297:353-356). Proteins ADDL occur in the brain tissue and striking way accumulate in the brain tissue of the patient BA compared with controls of the same age group (Kayed et al. (2002) Science 300:486-489; Gong et al. (2003) Proc. Natl. Acad. Sci. USA 100:10417-10422), and accumulate in models of transgenic mice with BA (Kotilinek et al. (2002) J.Neurosci. 22:6331-6335; Chang et al. (2003) J. Mol. Neurosci. 20:305-313).

A simplified mechanistic explanation of this theory can is about as follows:

where education ADDL represents a single direction that is different from the formation of amyloid senile plaques, each of these areas is in equilibrium with Monomeric β1-42.

In further experiments it was shown important neurologic ADDL. It was shown that ADDL have selective toxicity against hippocampal CA1 neurons in comparison with the SAZ neurons, and they have no toxic to neurons of the cerebellum (Kim et al. (2003) FASEB J. 17:118-120). On the basis of abdominal injection of oligomers β1-42wild rats were obtained quick model of abnormal behavior, from which full recovery within 24 hours (Cleary et al. (2005) Nat. Neurosci. 8:79-84), and such lesions attributed to oligomers of higher order, in particular oligomers of 12 links (Lesne et al. (2006) Nature 440:352-357). The ADDL binding to neurons occurs with high specificity and is localized to postsynaptic receptors of subgroups of hippocampal neurons (Lacor et al. (2004) J.Neurosci. 24:10191-10200). This binding initiates rapid and sustained incentive regulation line predannih gene products, the broadcasting of which depends on the activity of polyribosome localized on a subset of dendritic spines (Steward et al. (1998) Neuron 21:741-751; Guzowski et al. (2000 J.Neurosci. 20:3993-4001). Recently ADDL were considered as activators of phosphorylation of Tau proteins, and it has been shown that they affect the behavior of animals on femtomolar level (Matsubara et al. (2004) Neurobiol. Aging 25:833-841).

The reversibility of the process of memory loss in mice in combination with neurological properties ADDL and their contents in the brain of a patient with bronchial asthma are a good argument against the hypothesis, according to which ad is a disease associated with disorder of the synapse induced by ADDL (Lambert et al. (1998) Proc. Natl. Acad. Sci. USA 95:6448-6453; Klein et al. (2001) Trends Neuroscis. 24:219-220; Selkoe (2002) Science 298:789-791).

The use of antibodies specific to ADDL, is a powerful way to modify the equilibrium between Monomeric β1-42and ADDL that can cure painful disorders mediated ADDL. However, the delivery of antibodies is usually limited to injectable solutions, which create the problems associated with that patient mode and regimens, and also with the necessity of presence of the attending physician. Particularly useful in this case would be small molecules that alter this balance and can be delivered non-injecting means, in particular by oral administration, transdermal delivery, through the lungs, nasal area etc.

A number of small molecules, originally developed as inhib the tori amyloid fibrils, as expected, have the property of inhibiting the self-Assembly β oligomers (ADDL). Some of these compounds are Alzhemed™ (Gervais (2004) Neuirobiol. Aging 25:S11-12), kliohinol (Ritchie et al. (2003) Arch. Neural. 60:1685-1691), substituted β-cyclodextrins (Yu et al. (2002) J. Mol. Neurosci. 19:51-55), trehalose (Lui (2005) Neurobiol. Disease 20:74-81), simple amino, carbonyl - and nitrosamine phenols (De Felice et al. (2001) FASEB J.March 20; De Felice et al. (2004) FASEB J. 18:1366-1372), curcumin (Yang et al. (2005) J. Biol. Chem. 280(7):5892-5901), the analogues of cyclohexanehexol (McLaurin et al. (2006) Nature Med. 12:801-808), spirotaenia alcohols (Lecanu et al. (2004) Steroids 69:1-16) and tricyclic dowels (Maeqawa et al. (2006) J. Neurochem. 98:57-67). Of the above two compounds, Alzhemed™ and kliohinol, passed clinical trials.

Alzhemed™ (3-amino-1-propanesulfonic acid), the so-called "mimetic similar GAG (glycosoaminoglycans), as expected, reduces the level of soluble and insoluble amyloid by linking with β1-42although there is no obvious experimental details, confirming the proposed mechanism of action. Alzhemed™ recently hosted the second stage 20-month open extended tests, and reported a slow deterioration of cognitive abilities in some patients with mild BA, however, during the latent stage of the study drug showed efficacy (Gervais (2004) Neuirobiol. Aging 25:S11-12).

It was shown that a second connection, Kliohinol, at stage II clinical trials stabilizes cognitive ability of patients compared with patients who do not undergo treatment, and lowers the level of Aβ1-42in blood plasma (Ritchie et al. (2003) Arch. Neurol. 60:1685-1691). However, toxic impurity (diadiajenia form kliohinola)appearing in the manufacture of the drug that caused the termination of the study and replacement climinal analogue called RWT (Blennow et al. (2006) Lancet 368:387-403).

And finally, it was reported that unidentified compound or compounds from the leaf extract of Ginkgo biloba reduces the level of trimmers and tetramers Aβ1-42and increases the level of high molecular weight polymers, depending on the dose (Yao et al. (2001) Brain Res. 889:181-190). It was also reported dose-dependent protection of PC-12 cells from toxicity caused by ADDL.

Apparently, only a few of those compounds that reportedly inhibit self-Assembly and ADDL binding β1-42the monomer, have a high therapeutic potential. Considering a very simple structure and hydrophilic properties Alzhemed™, it is very unlikely that he had a high and selective affinity to β1-42the monomer. Any impact Alzhemed™ on the aggregation or disaggregation of beta-amyloid (hereafter AG), probably due to houseinsulation with ionic residues near the N-terminal Aβ 1-42. Cyclodextrins have no properties of the prototype, nor the properties of the drugs so that they can be recommended for development (Oprea et al. (2001) J. Chem. Inf. Comput. Sci. 41:1308-1315; Vieth et al. (2004) J. Med. Chem. 47:224-232), and phenols De Felice contain aldehyde and microfunctional groups, which are often reactive and excluded from screening libraries (Walters and Namchuk (2003) Nat. Rev. 2:259-266). About the number of molecules containing phenolic functional groups, was reported as "common drugs in screening libraries (Roche et al. (2002) J. Med. Chem. 45:137-142). Thus, further evaluation of the activity and selectivity of phenols De Felice in order to confirm the possibility of their effective use. It was reported that some compounds with steroid skeleton can be dissimilar inhibitors in the presence of unexpected process autoaggregate (McGovern et al. (2002) J. Med. Chem. 45:1712-1722), what can explain the mixed results when using spirotaenia alcohols. Finally, still unknown, which is the active ingredient in the extract of Ginkgo biloba. Thus, most of the alleged inhibitors Assembly β not be considered as compounds suitable for development as a drug.

Despite the above imaginary results the ATA, the analysis of binding indicates that these compounds are at best moderate antagonists education ADDL.

Accordingly, the development of small molecules that would provide improved inhibition, regulation and/or modulation of education ADDL is useful.

Disclosure of inventions

This invention is related with the discovery of the fact that you can oppose the formation of soluble, globular, defibrillator, neurotoxic oligomer β1-42(ADDL) through the use of almost pure ones compounds with molecular weight less than 1500, preferably less than 1000, which counteract the formation of ADDL at a higher level compared to what could be achieved previously. In addition, this invention is directed to the discovery of the fact, which is installed in the study of a large number of structural frames, showing an increased antagonism, that antagonism does not depend on the structural frame.

Accordingly, in one aspect of this method, this invention is directed to a method of counteracting the formation of ADDL Monomeric β1-42through the interaction of Monomeric β1-42with almost pure ones connection while the connection specified is characterized by the fact that:

(a) has a molecular mass of m is it 1000;

(b) is an antagonist of education neurotoxic ADDL from β1-42; and

(c) its value IC50is at most about 5 μm, which is installed in the analysis of Example 1, which is determined by the formation of neurotoxic ADDL.

In yet another embodiment, the invention relates to a method of suppression, regulation and/or modulation disorders of the nervous activity or neurotoxicity caused ADDL, in nerve cells by suppressing the formation of ADDL. The method includes the interaction β1-42that may exist in the presence of nerve cells with an effective amount of almost pure ones connection while the connection specified is characterized by the fact that:

(a) has a molecular weight of less than 1000;

(b) is an antagonist of education neurotoxic ADDL from β1-42monomers; and

(C) its value IC50is about 5 microns or less than that established in the analysis of Example 1, which is determined by the formation of neurotoxic ADDL.

In another embodiment, the invention relates to a method of suppressing oligomerization or further oligomerization of Monomeric β1-42in neurotoxic ADDL, this method involves the interaction of Monomeric β1-42with an effective amount of almost pure ones connection, this indicated the data connection is characterized by that:

(a) has a molecular weight of less than 1000;

(b) is an antagonist of education neurotoxic ADDL from β1-42monomers; and

(C) its value IC50is about 5 microns or less than that established in the analysis of Example 1, which is determined by the formation of neurotoxic ADDL.

In another embodiment, the invention concerns a method of suppressing, regulation and/or modulation of education ADDL or activity of this ligand in the body of a patient suffering from a disease or having a risk of developing diseases associated with the formation of β1-42oligomers (ADDL). The method includes the administration to a patient a therapeutically effective amount of almost pure ones connection while the connection specified is characterized by the fact that:

(a) has a molecular weight of less than 1000;

(b) is an antagonist of education neurotoxic ADDL from β1-42monomers; and

(C) its value IC50is at most about 5 μm, which is installed in the analysis of Example 1, which is determined by the formation of neurotoxic ADDL.

In yet another embodiment, the invention is directed to a method of treating a patient suffering from the disease or having the disease risk associated with ADDL, which is selected from the group consisting of disease Allgamer, down syndrome, and the Soult, mild cognitive impairment, focal ischemia associated dementia, and neuronal degeneration. The method includes the introduction of the indicated patient a therapeutically effective amount of almost pure ones connection while the connection specified is characterized by the fact that:

(a) has a molecular weight of less than 1000;

(b) is an antagonist of education neurotoxic ADDL from β1-42monomers; and

(C) its value IC50is at most about 5 μm, which is installed in the analysis of Example 1, which is determined by the formation of neurotoxic ADDL.

In some embodiments of the invention the molecular weight compounds is less than 1500. In other embodiments, the communication characterized by the fact that suppress the formation of neurotoxine ADDL that are defined in the analysis of Example 1 by the value of the IC50that is at most about 2 microns, and more preferably at most 1 μm.

In another embodiment, the present invention relates to compositions used in the treatment of a patient suffering from a disease or having a risk of developing the disease, which is selected from the group consisting of disease Allgamer, down syndrome, stroke, mild cognitive impairment, focal ischemia associated dementia, not realnoi dystrophy, if this composition contains a therapeutically effective amount of almost pure ones connection, which is characterized by the fact that:

(a) has a molecular weight of less than 1000;

(b) is an antagonist of education neurotoxic ADDL from β1-42monomers; and

(C) its value IC50is at most about 5 μm, which is installed in the analysis of Example 1, which is determined by the formation of neurotoxic ADDL.

In addition, the present invention relates to a method of manufacture of a medicinal product containing the compound mentioned in the variants of implementation of this section.

Brief description of drawings

Figure 1 displays the estimated dose-dependent suppression of the Assembly through the connections described in this document, which is determined by the analysis CHEF (resonance energy transfer fluorescence). Shows the results of the analysis of the tested compounds And taken in a concentration of from 0.05 to 3 μm, and the results for the tested compounds, taken at a concentration of 30 μm. Also shown positive and negative controls.

On the X-axis indicates the time in minutes and the Y-axis denotes the relative fluorescence units (OEF)×103defined method of analysis CHEF in Example 1.

Figure 2 displays the estimated dose-dependent suppression of the Assembly being Agamim inhibitor of amyloid fibrils Alzhemed™ (Neurochem), tested by the method of analysis CHEF described in this document. Also shown positive and negative controls. On the X-axis indicates the time in minutes and the Y-axis denotes the relative fluorescence units (OEF)×103defined method of analysis CHEF.

The implementation of the invention

A. the Methods of the invention

Before describing how we need to keep in mind that the invention is not limited to certain of the described methodology, protocols, cell lines, analysis methods and reagents, as they may change. It should also be understood that as used in this document terminology is intended to describe certain embodiments of the present invention and in no way limits the scope of the present invention set forth in the attached formula.

It should be noted that as used in this description and the claims, the singular objects are also objects of the plural if the context is not explicitly specified otherwise.

Unless specified otherwise, all technical and scientific terms used herein have the meanings generally understood by a person skilled in the art to which this invention relates. Although the implementation or testing of the present invention can use any SP the events and materials similar or equivalent to those described in this document, hereinafter will be described the preferred methods, devices, and materials. All cited here publications are incorporated herein by reference in their General form. The absence of anything in this document does not give you the right to oppose the disclosure of the present invention with the earlier invention.

Used in this document definition limited to the use of small molecules to the extent that they relate to aggregation or oligomerization ADDL and related diseases.

This invention is directed to the discovery of the fact that you can oppose the formation of soluble, oligomeric, globular, defibrillating, neurotoxic β1-42peptides (ADDL) through the use of almost pure ones compounds with molecular weight less than 1500, preferably less than 1000. Connection counteract education ADDL at a higher level compared to what could be achieved previously.

Not limited to any theory, I believe that the introduction of a therapeutically effective amount of one or more of the compounds described in this document will impact on the key Assembly of the elements in β1-42the monomers or to the important elements in β1-42the oligomers (ADDL). This impact, in turn,will prevent the formation of neurotoxic ADDL or inhibit the activity of such proteins. The destruction of ADDL or suppressing the activity of such proteins provides long-lasting potentiation of nerve cells, eliminating and/or reducing the neurotoxicity associated with ADDL. In addition, this impact will not prevent the formation of senile plaques β.

The term "ones compound" refers to compounds, examples of which are described in this document and do not include the peptides and/or proteins. It is believed that the presence of 1-10, 1-5, or 1-2 amino acid residues associated with the structural frame of the compounds disclosed in this document, does not make such frames peptide, provided that the molecular weight of the compound is less than 1500, preferably less than 1000, and amino acid residues do not have any function of binding antigens, and provided that the frame itself in the absence of amino acid residues capable of inhibiting the formation of ADDL, as described in Example 1 of this document. In a preferred embodiment, ones of the connections described in this document does not contain amino acid residues derived from natural amino acids 1-20.

The terms "peptides" and "proteins" refers to high molecular weight compounds containing multiple amino acid residues, corresponding amide linkages-C(O)-NR-. Amino acid residues, typically, there is C 1-20 natural amino acids.

The term "soluble" refers to the ability of certain substances to dissolve in any solvent (an example of such a substance in the present invention is β1-42oligomer). In the context of the present invention are soluble β1-42the oligomers are amenable to fractionation by centrifugation.

The term "oligomer" refers to a protein complex of a certain number of monomer units. In the context of this invention, the oligomers are called trimers, oligomers with a small number (n) of links, dodecameric (containing 12 parts) and multimer with a large number (n) of links consisting of β1-42. The term "oligomeric" does not include senile amyloid plaques.

The term "globular" means a major soluble protein complex, which can be separated from fibrils and amyloid plaques. Preferably, the globular structure size is from 4 to 12 nanometers (nm), preferably from 4.7 to 11 nm, as determined by analysis using atomic force microscope (AFM) supernatant fractions soluble drugs β1-42oligomer (ADDL), described in U.S. patent No. 6218506.

The term "defibrillate" means β1-42peptides and oligomeric complexes that are not lined up with the formation of morphologically distinct structures, the so called the most amyloid protofibril or amyloid fibrils.

The term "ADDL" usually denoted diffusible ligands derived from beta-amyloid, which have the following characteristics: they are soluble, oligomeric, globular, brillare, neurotoxic β1-42the peptides.

The term "almost pure" means that the substance contains almost no impurities, for example, contains impurities at less than 20%.

In one embodiment, the connection is considered to be almost pure if it contains impurities at less than 10%, and in another embodiment less than 1%.

Compounds described herein are used in the method of suppressing, regulation and/or modulation of ADDL Assembly in vitro or in vivo. The terms "disease", "violation" and "disorder" are used as including each other and refer to any condition that is at least partly mediated ADDL. In the context of this invention, the disease may be associated with insoluble amyloid fibrils, senile plaques, neurofibrillary clews and/or overexpression of amyloid β1-42the protein. Examples of such diseases include Alzheimer's disease, down's syndrome, mild cognitive impairment, stroke, focal ischemia associated dementia, and neuronally dystrophy. Patients susceptible to treatment include individuals is big, the s with the risk of developing the disease, but do not show symptoms, and patients with symptoms at the moment. Thus, the compounds described in this document, you can enter all segments of the population with the purpose of prevention without the need for any assessment group of patients.

The term "patient" refers to animals, including mammals, people, etc. In some cases, the implementation of the patient is an animal, particularly an animal selected from such mammals as the rat, rabbit, bull, sheep, pig, dog, cat, mouse, horse, Primate, particularly human.

The referenced methods are particularly useful for individuals that have a genetic risk of developing Alzheimer's disease. Such individuals include individuals, relatives are diagnosed with a disease or has been determined the risk of its development by analysis of genetic or biochemical markers. Genetic markers of risk of developing Alzheimer's disease are mutations of the gene of the protein precursor of amyloid a (BPA), particularly mutations at position 717 and 670 and 671 positions, called mutations hardy and Swedish mutations, respectively. Other markers of risk are mutations of genes presenilins PS1 and PS2, and Area, a family history of Alzheimer's disease, hypercholesterolemia or atherosclerosis. Individuals suffering from in n is present from Alzheimer's disease, can be recognized by their characteristic dementia, and the presence of risk factors listed above. In addition, there are a number of diagnostic tests to identify individuals with Alzheimer's disease. These tests include measurement of the Tau protein and β1-42in the cerebrospinal fluid. Individuals suffering from Alzheimer's disease can also be diagnosed by the criteria of the disease Allgamer and related disorders (ADRDA) or by way opened in this document.

Patients who do not have symptoms of disease can be treated at any age (for example, 10-, 20-, 30-years old). However, as a rule, treatment should be initiated as long as the patient reaches 40-, 50-, 60 - or 70 years of age. Usually treatment includes repeated dosing over a certain period of time. Over the course of treatment can be observed by analyzing the content of ADDL over time.

The term "treatment" of a disease includes: (1) preventing the disease, i.e. stopping the development of clinical symptoms in a patient who is at risk of developing the disease or predisposed to the disease but has not yet experiencing or manifesting symptoms of the disease; (2) suppression of the disease, i.e. the relief or reduction of risk times the development of the disease or its clinical symptoms; or (3) the relief of the disease, i.e. stimulation of recurrence of the disease or its clinical symptoms.

The phrase "suffering" in the context of the term "treatment" refers to the patient or to the individual who is diagnosed or who are predisposed to the disease. Can also say that the patient has a risk of developing the disease." The patient has not manifested the characteristic pathology of the disease, however, it is known that he was predisposed to the disease due to family history, i.e. it is genetically predisposed to the disease or diagnose disease or disorder that predisposes to development of the disease that should be cured.

In addition to Alzheimer's disease, there are several other diseases associated with the formation of β1-42which include down syndrome, stroke and mild cognitive impairment (the list is not limited). It can be assumed that, as in the case of disease Allgamer, treating patients suffering from or having the risk of developing these diseases can be performed by parallel mechanisms of the disease.

The term "senile plaque" or "the formation of senile plaques" refers to extracellular deposits of amyloid in the gray matter of the brain. Deposits associated with degenerate nervous structures. Units is Malaysia, that senile plaques differ from ADDL or, in other words, between them and ADDL you can distinguish.

Similarly, overexpression of β1-42associated with focal ischemia associated dementia, or is associated with neuronal degeneration. Overexpression of β1-42is believed to be a consequence of the accumulation ADDL that cause neurotoxicity. Treatment of a patient suffering from or having the risk of developing one of these diseases, by introducing him one or more of the described compounds will contribute to the elimination of neurotoxicity sverhagressivnomu β1-42.

The term "neurotoxicity" refers to toxic effects ADDL on nerve cells in vitro and/or in vivo. ADDL bind specific nerve receptors, initiating the anomalous transmission of nerve signals, which violates long-term potentiation and causes memory impairment. Thus, ADDL change the function of nerve cells in such a way that, despite its viability, the neurons stop functioning properly. Such modified functionality is called in this document "neuronal dysfunction, which is a subspecies of neurotoxicity. Prolonged exposure ADDL transmission of signals leads to incorrect transcription and the progressive disappearance of the synapse is in, and at very long exposure and the accumulation of structural pathologies is the final death of nerve cells and severe degeneration of the brain.

In the medical purposes of the patient with suspected presence of a disease (or who already suffer from the disease), associated with the accumulation ADDL administered pharmaceutical composition comprising one or more of the described compounds, the compound is administered in an amount sufficient to cure or at least partial suppression of the symptoms of the disease (biochemical, histologic and/or behavioral), including in case of complications or intermediate pathological phenotypes in development of the disease.

In preventive pharmaceutical composition comprising one or more of the described compounds is administered to a patient susceptible to disease or having a risk of developing diseases associated with the accumulation ADDL, these compounds is administered in an amount sufficient to eliminate or reduce the risk of disease, reduce the severity, or delay the onset of the disease. This includes biochemical, histologic and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes manifested in the development of the disease.

In some ways PR is the introduction of the connection is reduced or eliminated mild cognitive impairment in patients have not yet developed the characteristic pathology of Alzheimer's disease. In some cases, the implementation under therapeutically effective amount is meant an amount of one or more of the described compounds, administered or delivered to the patient in which the patient most likely to manifest the desired response to treatment. Detailed description of embodiments relating to the improvement of cognitive functions can be found in the patent application # PCT/US2007/_____, entitled "Methods of improving cognitive function using ones connections", subject 12 July 2007, the register of attorney No. 089265-1450, which is included in this document by reference in its General form.

"Effective amount" is a quantity of one or more of the compounds described in this document through which treat diseases mediated ADDL. Preferably the compounds of this invention reduce education ADDL either in vitro or in vivo, at least 10%, 25%, 40%, 60%, 80%, 90% or 95% compared to control.

"Therapeutically effective amount" will vary depending on the connection type and severity of the disease, and the age, weight and other characteristics of the patient being treated, with each of these parameters is within the competence of easigo doctor. It is assumed that a therapeutically effective amount of one or more of the compounds described in this document will affect education ADDL (including to help suppress or change the direction of education ADDL) in a patient in comparison with ADDL binding process without treatment. In fact, while inhibiting deterioration of long-term potentiation and subsequent memory loss. Therapeutically effective amount different from the amount of exerting a biological effect ("biologically effective amount"). The compound of the present invention has one or more biological effects in vitro or even in vivo, for example, to some extent, reduces the formation of ADDL. However, the biological effects may not lead to the manifestation of the above-described therapeutic effect on a clinically significant level, which is determined by methods that are within the competence of the doctor.

"Nerve cell or neuron is a cell that transmits and processes signals in the brain the brain or other organs of the nervous system. In addition, used in the present invention nerve cells can be separated from animal tissue or brain tissue or grown in tissue culture. Detached cells can consist of resistant lines nervous the notches, selected, for example, from MS; HCN-2; SH-SY5Y; SK-N-AS SK-N-FI SK-N-DZ; H19-7/IGF-IR; QNR/D; QNR/K2; C8-D30; C8-S, C8-D1A; OLGA-PH-J/92; Daoy; RSC96; SW10; RT4-D6P2T; RN33B; PC-12; DBRTG-05MG; C8-B4; SK-N-SH; B35; R3[33-10ras3]; Neuro-2A and HCN-IA or any of their genetically, chemically and/or biochemically modified variations (and this list is not limited). Detached cells may also be composed of embryonic and/or astroglial cells of the nervous tissue, selected, for example, in the hippocampus, cerebellum, cerebral cortex, hypothalamus, mid-brain, spinal cord, striatum, frontal, temporal, parietal, occipital lobe of the brain and any genetically, chemically and/or biochemically modified variations. Allocated, cultured animal cells can consist of neural stem cells or any modified, genetically, chemically and/or biochemically modified variations of these cells.

Used in this document the term "nervous tissue" refers to any part of the Central nervous system, including, in particular, the brain or spinal cord. Nervous tissue may consist at least partly of nerve cells.

The term "amyloid fibrils" refers to protein mass with special structural characteristics. In histopathological methods are usually set patterns due to double refraction of light-green light when painting their KRA what ielem Congo red with subsequent browsing under polarised light.

The term "balls" means neurofibrillary tangles formed inside the degenerated neurons when linking paired helical fragments, which are collected from hyperphosphorylated forms of proteins associated with microtubules, called "Tau."

C. Connections

Compounds used in the described methods, are almost pure ones compounds with molecular weight less than 1000. In one embodiment, the compounds used in the methods of the invention preferably have one or more of the following characteristics: (1) low or submicromolar content in medicinal drug when tested in the analysis CHEF described in this document; (2) the absence of aggregation; (3) little or no neurotoxicity when administered to a patient; (4) easy solubility in water; (5) amenable to chemical treatment; (6) have a dose-dependent characteristics; (7) reversible binding β protein; (7) the ability to bind β-amyloid monomer; (8) the ability to bind soluble β-amyloid oligomers.

In one embodiment of the invention the compounds used for the treatment of patients suitable for ingestion. In this embodiment, the compounds correspond to the rule Lipinski 5, which provides a criterion Lek is stannah properties. In this rule, in General, it is stated that the drug active when administered orally, has: no more than 5 donors of hydrogen bonds (groups HE and NH); not more than 10 acceptors of hydrogen bonds (in particular, atoms N and O); molecular weight less than 500 g/mol and the distribution coefficient log P less than 5.

1. The choice of connections

The preferred method for selecting compounds for use in the methods of the invention includes the analysis of compounds on resonance energy transfer fluorescence (CHEF). Method RPAF used for measurement, detection, identification, evaluation, analysis and characterization of various interactions and processes in biological systems (see, for example, Mitra et al. (1996) Gene 173:13-17; De Angelis (1999) Physiol. Genomics. 21:93-99; Latif and Graves (2000) Thyroid 10(5):407-412; Rye (2001) Methods 24(3):278-288; Kenworthy (2001) Methods 24 (3):289-296; Periasamy (2001) J. Biomed. Opt. 6(3):287-291; Truong and Ikura (2001) Curr. Opin. Struct. Biol. 11(5):573-578; Zhang et al. (2002) Nat. Rev. Mol. Cell. Biol. 3(12):906-918; Sitte and Freissmuth (2003) Eur. J. Pharmacol. 479:229-236; Milligan (2004) Eur. J. Pharm. Sci. 21(4):397-405; Herman et al. (2004) Methods Mol. Biol. 261:351-370; Roda et al. (2004) Trends Biotechnol. 22(6):295-303; Wallrabe and Periasamy (2005) Curr. Opin. Biotechnol. 16(1):19-27; Milligan and Bouvier (2005) FEBS J. 272(12):2914-2915; and references in any of these documents and so on).

Methods, protocols, techniques, assessments and other similar procedures used in the analysis CHEF described in General and in particular in the number of patents and patent applications in the om, including: U.S. patent No. 6908769; U.S. patent No. 6824990; U.S. patent No. 6762280; U.S. patent No. 6689574; U.S. patent No. 6661909; U.S. patent No. 6642001; U.S. patent No. 6639078; U.S. patent No. 6472156; U.S. patent No. 6456734; U.S. patent No. 6376257; U.S. patent No. 6348322; U.S. patent No. 6323039; U.S. patent No. 6291201; U.S. patent No. 6280981; U.S. patent No. 5914245; U.S. patent No. 5661035; and references to any of the listed documents, etc.

Similarly, for measurement, detection, identification, evaluation, analysis and characterization of various interactions and processes in biological systems used method fluorescence polarization (FP) (see, for example, Lundblad et al. (1996) Mol. Endocrinol. 10(6):607-612; Nasir and Jolley (1999) Comb. Chem. High Throughput Screen. 2(4):177-190; Park and Raines (2004) Methods Mol. Biol. 261:161-166; and references in any of the above documents and the like).

Methods, protocols, techniques, assessments and other similar procedures used in the method of FP, described in General and in particular in the number of patents and patent applications, including: U.S. patent No. 6794158; U.S. patent No. 6632613; U.S. patent No. 6630295; 6596546; U.S. patent No. 6569628; 6555326; U.S. patent No. 6511815; U.S. patent No. 6448018; U.S. patent No. 6432632; U.S. patent No. 6331392; U.S. patent No. 6326142; U.S. patent No. 6284544; U.S. patent No. 6207397; U.S. patent No. 6171807; U.S. patent No. 6066505; U.S. patent No. 5976820; U.S. patent No. 5804395; U.S. patent No. 5756292; U.S. patent No. 5445935; U.S. patent No. 5427960; U.S. patent No. 5407834; U.S. patent No. 5391740; U.S. patent No. 5315015; the patent is U.S. No. 5206179; U.S. patent No. 5070025; U.S. patent No. 5066426; U.S. patent No. 4952691; U.S. patent No. 4863876; U.S. patent No. 4751190; U.S. patent No. 4681859; U.S. patent No. 4668640; U.S. patent No. 4614823; U.S. patent No. 4585862; U.S. patent No. 4510251; U.S. patent No. 4476229; U.S. patent No. 4429230; U.S. patent No. 4420568; U.S. patent No. 4203670; and references to any of the listed documents, etc.

Methods CAF and FP use in the study of amyloid (see, for example, U.S. patent No. 6927401; U.S. patent No. 6906104; U.S. patent No. 6905827; U.S. patent No. 6881546; U.S. patent No. 6864290; U.S. patent No. 6864103; U.S. patent No. 6858383; U.S. patent No. 6846813; U.S. patent No. 6828106; U.S. patent No. 6803188; U.S. patent No. 6770448; U.S. patent No. 6713276; U.S. patent No. 6600017; U.S. patent No. 6515113; U.S. patent No. 6495664; U.S. patent No. 6323039; U.S. patent No. 6294330; patent U.S. No. 6280981; U.S. patent No. 6197928; U.S. patent No. 5981200; Kim and Lee (2004) Biochem. Biophys. Res. Commun. 316(2):393-397; Bacskai et al. (2003) J. Biomed. Opt. 8(3):368-375; Gorman, P.M. et al. (2003) J. Mol. Biol. 325(4):743-757; Garzon-Rodrequez et al. (1997) J. Biol. Chem. 272(34):21037-21044; Lindgren et al. (2005) Biophys. J. 88 (6): 4200-4212; Lewis et al. (2004) Neurobiol. Aging 25(9):1175-1185; Leissring et al. (2003) J. Biol. Chem. 278(39):37314-37320; Taylor et al. (2003) J. Protein Chem. 22(1):31-40; on Allsop et al. (2001) Biochem. Soc. Symp. 67:1-14; on Allsop et al. (2001) Biochem. Biophys. Res. Commun. 285(1):58-63; Huang et al. (2000) J. Biol. Chem. 275(46):36436-36440; and references in these documents and so on).

2. Application method RPAF to search for an appropriate connection

Method of analysis CHEF in Example 1 was investigated according to CNAE compounds from commercially available libraries on the subject-specific inhibition of the formation of soluble oligomers β 1-42. Identified compounds-prototypes and the obtained compound libraries. In addition, the dependence of the activity of the compounds of the prototype structure, which allows to increase their activity.

3. Exemplary compounds used in the methods of the invention

Specific examples of the compounds used in the invention are presented hereinafter in Table 1. It is understood that the illustration of these compounds is in no way limits the invention the compounds listed in tables, and it is therefore assumed that other compounds suitable for use in this invention.

The table also presents the values of the IC50compounds tested by the method of analysis described in Example 1. In each case, these connections are equally available for purchase from companies listed in the table. It should be noted that these compounds have a spatial isomers (i.e. E and Z isomers), and the invention involves the use of any of the possible isomers or mixtures thereof.

Table 1
Exemplary compounds
No.The structure of connections Connection nameIC50(µm)Source
1(Z)-N-(2-Methoxy-phenyl)-2-oxo-2-{N'-[3-oxo-3-thiophene-2-yl-1-trifluoromethyl-propylidene]-hydrazino}-ndimethylacetamidea 3.9deCODE
2Ethyl ester of (E)-2-{[1-(2-hydroxy-3-methoxy-phenyl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid3,5Aldrich
3Ethyl ester of (E)-2-{[1-(2-hydroxynaphthalene-1-yl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid4,4Aldrich
No.The structure of connectionsConnection nameIC50(µm)Source
4 Ethyl ester of (E)-2-{[1-(2-hydroxyphenyl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid1,1Aldrich
52-(5-Hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-yl)-N-(2-methoxyphenyl)-2-oxoacetate3,2Chem Div
6(E)-2-Hydroxy-N'-((1-hydroxynaphthalene-2-yl)methylene)benzhydrazidethe 3.8deCODE

C. Testing and introduction

Effective doses of the compositions of the present invention used for the treatment of the above diseases may vary depending on various factors, including route of administration, physiological state of the patient, other injected drugs, whether the patient is human or an animal, and the purpose of treatment: prophylactic or therapeutic. Usually the patient is a man, but in some cases, the implementation of the patient is an animal, particularly an animal selected from the Miu is apicauda, including rat, rabbit, ox, sheep, pig, dog, cat, mouse, horse, and primacy.

Connection, you can enter multiple times, and the intervals between single dosages can be days, weeks, months, or years. The intervals can be different, which is determined by measuring the content of β1-42protein ADDL, or complexes ADDL in the patient's blood. Alternatively, one or more compounds of the invention can be introduced in the form of a composition with delayed release, in this case, the introduction of the drug with less frequency. Dosage and frequency of injection can vary depending on the half-life of the compounds of the invention. For medicinal purposes is sometimes necessary to introduce a relatively high dosage at relatively short intervals until until no decrease or stop the progression of the disease, and preferably as long as the patient will not experience a partial or complete elimination of symptoms. After this, the patient can be translated into prevention mode.

Introduction pharmaceutical compositions containing the compounds described herein, can be implemented in various ways, in particular through the mouth, lungs, local, rectal, subcutaneous, intradermal, intranasal, intracerebral, intramuscular, intraocular pic is the means intra-articular injections and other similar methods. The most preferred method of administration is the administration of the drug inside, although equally effective may be other ways. One or more compounds described herein can optionally be entered in combination with other biological or chemical agents that are at least partly effective in treatment of diseases associated with β1-42. Examples of such agents are antibodies against β1-42described in international application number WO 2003/253673, WO 2006/014478, U.S. patent No. 2489195, the publication of U.S. patent No. 2007-0048312 and the application for U.S. patent No. 11/571532, which are included in this document by reference.

Described here are the links you can enter the patient in a quantity sufficient to inhibit, regulate and/or modulate the formation of neurotoxic ADDL or activity of these ligands in the body referred the patient. A qualified physician can easily set the appropriate number of compounds described herein, which would effectively suppressed, regulated and/or modulated education neurotoxic ADDL or activity of these ligands in the body referred the patient. The estimated number of compounds described herein are, for example, from 0.05 to 2000 mg/(m2/day) for one or more connection the changes.

As noted above, the compounds described herein can be entered, for example, orally, topically, through the lungs, rectum, subcutaneously, intradermally through the nose, intracranial, intramuscular, intraocular, intraarterial, and other similar methods. The carrier or excipient, or a mixture of excipients in the drug can be a solvent or dispersion medium containing, for example, various polar or nonpolar solvents, suitable mixture or oil. Used in this document, the term "carrier" or "excipient" refers to pharmaceutically acceptable carrier or excipient and includes any and all solvents, dispersion means or medium, coating, antimicrobial agents, ISO/Hypo/hypertonic substances, substances that alter the absorption, etc. the Use of such substances and means for pharmaceutically active compounds is well known in the art. Moreover, in the final composition may include any other or auxiliary active ingredients.

To diseases, treat ways described here, include Alzheimer's disease, down syndrome, stroke, mild cognitive disorders, focal ischemia associated dementia, and neuronally dystrophy.

D. Pharmaceutical compositions and routes of administration

When and what to use as medicines, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered in a number of ways, including orally, topically, through the lungs, rectum, subcutaneous, subcutaneous, intradermal, intranasal, intracerebral, intramuscular, intraocular or intra-articular injection. These compounds are effective in the compositions, administered by injection and by mouth. Such compositions are prepared according to methods well known in the pharmaceutical industry, and contain at least one active connection. This invention also includes pharmaceutical compositions which contain as active ingredient one or more compounds described herein together with a pharmaceutically acceptable carrier. In the preparation of compositions of the invention the active ingredient is usually mixed with an excipient, diluted with filler or placed inside carrier, which may be in the form of a capsule, packet, sachet, paper or other container. Used filler, generally suitable for administration to a patient. In that case, if the filler acts as a diluent, it may be solid, semi-solid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, pellets, paketo the sachet, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid substance or inside a liquid medium), ointments containing, for example, the active compound in an amount up to 10% by weight, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In the preparation of the composition may need to grind the active compound to obtain a suitable particle size with the purpose of mixing it with other ingredients. If the active compound is substantially insoluble, it is usually crushed to obtain particles with a size less than 200 mesh. If the active compound is substantially water soluble, the particle size is usually adjusted by crushing of the compound to obtain almost uniform distribution, for example, receiving a particle size of about 40 mesh.

K some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum Arabic, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, antiparasite, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil, humectants, emulsifying and suspendresume AG is, for example, protecting means, such as methyl - and propylhydroxybenzoate, sweeteners and flavorings. Compositions of the invention can be designed that provide fast, steady and slow release of the active ingredient after administration to their patient by methods known in the art.

Intravenous administration of therapeutic agents is well known in the pharmaceutical industry. Compositions for intravenous administration should have certain properties, not to mention the fact that therapeutic agent should be dissolved in them. For example, the composition should contribute to the overall stability of the active(s) ingredient(s)and the production of the composition should be cost-effective. All these factors ultimately determine the overall success of the application and usefulness of intravenous composition.

In the pharmaceutical compositions of the compounds of the present invention can include other adjuvants, such as solvents: ethanol, glycerol, propylene glycol; stabilizers:

ethylenediaminetetraacetic acid (EDTA), citric acid; antimicrobial preservatives: benzyl alcohol, methylparaben, propylparaben, buffer substances: citric acid/sodium citrate, potassium bitartrate, bitartrate, sodium, acetic acid/sodium acetate, maleic acid/maleate soda is I, hydroptila sodium, phosphoric acid/potassium dihydrophosphate, phosphoric acid/disodium hydrogen phosphate; modifiers toychest: sodium chloride, mannitol, dextrose.

The buffer may be needed to maintain the pH of the water solution in the range from 4 to 8 and, more preferably, in the range from 4 to 6. The buffer system is typically a mixture of a weak acid and its soluble salts, for example a mixture of sodium citrate and citric acid; or advocational or ducational salt of the dibasic acid, such as potassium bitartrate, bitartrate sodium, a mixture of phosphoric acid and potassium dihydrophosphate and a mixture of phosphoric acid and disodium hydrogen phosphate.

The used amount of the buffer system depends on (1) from the desired pH and (2) the amount of the drug. Usually used in an amount of buffer in a molar ratio to the drug is from 0.5:1 to 50:1 (the number of the buffer is taken in the calculation of the total number of moles of buffer ingredients, such as sodium citrate and citric acid), to maintain a pH in the range from 4 to 8 molar ratio of buffer (total) to the medication should be from 1:1 to 10:1.

One of the buffers that are suitable for the invention is a mixture of sodium citrate and citric acid in the amount of 5-50 mg/ml of sodium citrate at 1-15 mg/ml of citric acid sufficient to maintain the pH of the aqueous composition on the level 4-6.

A buffering agent can also be added to prevent precipitation of the drug in the formation of soluble metal complex under the action of dissolved metal ions, for example ions of CA, Mg, Fe, Al, Ba, which can leach from the glass vessels or rubber tubes, or may be contained in ordinary tap water. The additive can be also used as complexing agents, competing with medication, and to give a soluble metal complex, resulting in the formation of undesirable particles.

In addition, this may require the presence of any additives, such as sodium chloride in an amount of 1-8 mg/ml for control toychest level toychest human blood, to prevent swelling or compression of red blood cells when administered intravenously composition, which leads to undesirable side effects such as nausea and diarrhea, and even related blood disorders. In General, toychest composition corresponds to toychest human blood, which ranges from 282 to 288 mOsm/kg and, as a rule, 285 mOsm/kg, which is equivalent to the osmotic pressure created 0.9% sodium chloride solution.

Intravenous composition can be entered direct intravenous injection, through an intravenous bolus or by infusion of an appropriate infusion solution such as 0.9% sodium chloride solution or the other compatible infusion solution.

The compositions can be formulated in dosage forms for oral administration. The term "dosage form" refers to physically discrete units to be used as the standard dose for the patient, with each dose contains, together with a suitable pharmaceutical excipient predetermined quantity of active material calculated to obtain the desired therapeutic effect.

The active compound is effective in a wide range of dosages and is normally administered in pharmaceutically effective amounts. It is understood that actually enter the number of connections will be predates physician taking into account the relevant circumstances, including the conditions of treatment, the chosen route of administration, type of connection, the input at the moment, the age, weight and response of the individual patient, the severity of symptoms of the patient, etc.

In the preparation of solid compositions in the form of tablets, the main active ingredient is mixed with a pharmaceutical excipient, getting a preliminary composition containing a homogeneous mixture of the compounds of the present invention. At the mention of a homogeneous pre compositions is meant that the active ingredient is uniformly dispersed throughout the composition so that it can easily be divided into dozirovania.srednie forms with the same efficiency, such as tablets, pills and capsules. Then the solid preliminary composition is divided into the above-described dosage forms containing, for example, from 0.05 to 2000 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or to be otherwise, receiving pharmaceutical form prolonged action. For example, the tablet or pill may contain internal or external dosage component, the latter is a membrane covering the internal component. These two components can be separated intersolubility layer, which prevents the grinding process in the stomach and permits the inner component to enter the duodenum in solid form or be delayed in release. For such intersolubility layers or coatings can be used a variety of materials, including a number of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol and cellulose acetate.

For liquid dosage forms, which include new compositions of the present invention and which can be administered by mouth or by injection include aqueous solutions, scented appropriately syrups, aqueous or oil suspensions, and flavored emulsions with pixely and oils, such as cotton, sesame, coconut, peanut or vegetable oil, as well as elixirs and similar pharmaceutical basics.

The compositions, administered by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or their mixtures, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients described above. Preferably the composition is administered through the mouth or respiratory tract to provide local or systemic effect. The composition in the preferred pharmaceutically acceptable solvents can be sprayed using inert gases. Sprayable solutions can be produced directly from the spray device, or you can attach the spray device to a support and protective masks or breathing apparatus with intermittent positive pressure. Dissolved, suspension, or powder compositions can preferably be introduced through the mouth or nose of the devices that are appropriate delivery structure.

The following examples illustrate compositions alleged pharmaceutical compositions of the present invention.

Example composition 1

Prepare hard gelatin capsules containing the following ingredients:

IngredientQuantity (mg/capsule)
The active ingredient30.0
Starch305.0
Magnesium stearate5.0

Mix above ingredients and fill with a mixture of hard gelatin capsules in the amount of 340 mg.

Example composition 2

The composition of the tablets prepared using the following ingredients:

IngredientQuantity (mg/tablet)
The active ingredient25.0
Cellulose, microcrystalline200.0
Colloidal silicon dioxide10.0
Stearic acid5.0

Mix the components, and the resulting mixture is compressed, receiving tablets weighing 240 mg each.

An example of a structure of 3

Inhalation of the dry powder is prepared using the following components:

Ingredientweight%
The active ingredient5
Lactose95

The active ingredient is mixed with the lactose and the mixture is added in the device for inhalation of a dry powder.

Example of part 4

Tablets, each containing 30 mg of active ingredient, are prepared as follows:

IngredientQuantity (mg/tablet)
The active ingredient30.0 mg
Starch45.0 mg
Microcrystalline cellulose35,0 mg
Polyvinylpyrrolidone (as 10% solution in sterile water)4.0 mg
Sodium carboxymethyl cellulose4.5 mg
Magnesium stearate0.5 mg
Talc1.0 mg

The active ingredient, starch, cellulo who have passed through a sieve with a pore size of 20 mesh (U.S. standard) and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the obtained powder, and the resulting mixture is passed through a sieve with a pore size of 16 mesh. Thus obtained granules are dried at 50-60°C and passed through a sieve with a pore size of 16 mesh. Sodium carboxymethylcellulose, magnesium stearate and talc pass through a sieve with a pore size of 30 mesh, and then added to the granules which, after mixing grip on tablet press machine, getting a tablet weight of 120 mg

Example of part 5

Capsules, each containing 40 mg of active ingredient, was prepared as follows:

IngredientQuantity (mg/capsule)
The active ingredient40,0 mg
Starch109,0 mg
Magnesium stearate1.0 mg
The total number of150,0 mg

Mix the active ingredient, starch and magnesium stearate, pass the mixture through a sieve with a pore size of 20 mesh and fill her hard gelatin capsules in the amount of 150 mg.

Example of compound 6

Suppositories, each containing 25 mg of active ingredient,was prepared as follows:

IngredientNumber
The active ingredient25 mg
Glycerides of saturated fattyup to 2000 mg
acids

The active ingredient is passed through a sieve with a pore size of 60 mesh and suspended in the glycerides of saturated fatty acids, pre-melted with minimal heating. The mixture is then poured into a suppository form with a nominal capacity of 2.0 g and leave to cool.

Example of compound 7

Suspensions, each containing 50 mg of drug substance 5.0 ml dose, receive the following way:

IngredientNumber
The active ingredient50.0 mg
Xanthan gum4.0 mg
Sodium carboxymethyl cellulose
(11%)
Microcrystalline C is llulose 50.0 mg
(89%)
Sucrose1,75 g
IngredientNumber
Sodium benzoate10.0 mg
Flavoring and coloringsufficient
number
Purified waterto 5.0 ml

Mix the active ingredient, sucrose and xanthan gum, the mixture is passed curse a sieve with a pore size of 10 mesh and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. Sodium benzoate, flavoring and coloring diluted with a little water and add to first mixture with stirring. Then bring the volume of the solution to the desired value by addition of water.

Example of compound 8

IngredientQuantity (mg/capsule)
The active ingredient15,0 mg
Starch407,0 mg
Magnesium stearate3.0 mg
The total number of425,0 mg

Mix the active ingredient, starch and magnesium stearate, pass the mixture through a sieve with a pore size of 20 mesh and filled it hard gelatin capsules in an amount of 425,0 mg.

Example of compound 9

Subcutaneous composition can be prepared as follows:

IngredientNumber
The active ingredient5.0 mg
Corn oil1.0 ml

An example of a composition of 10

Intravenous composition can be prepared as follows:

IngredientNumber
The active ingredient250 mg
Isotonic1000 ml

For another composition used in the methods of the present invention, used devices for transdermal delivery ("the layer is ri"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in a predetermined quantity. The structure and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. patent No. 5023252, issued June 11, 1991 and incorporated in this document by reference. Such patches can be designed for continuous, pulsating delivery of pharmaceutical products or to deliver them occur when necessary.

Often you want or need to enter the pharmaceutical composition to the brain by a direct or indirect way. Direct methods usually involve placing a catheter for drug delivery in the ventricular system of the body of the patient when the shunting of the blood-brain barrier. One such implantable delivery systems used for the transfer of biological factors in specific anatomical areas of the body, is described in U.S. patent No. 5011472 that is included in this document by reference.

Indirect methods typically include the preparation of compositions for making the medication is hidden by transformation of hydrophilic drugs in lipitorhistory form. Latency is usually achieved by blocking the hydroxyl, carbonyl, sulfate and primary amino groups, available in medicine, with the aim of keeping medicines in a more lipitorstallion and available when transporting it cross the blood-brain barrier. Alternatively, delivery of hydrophilic drugs can be improved by intra-arterial infusion of hypertonic solutions, which can be briefly open gemeentelijke barrier.

Other compositions suitable for use in the present invention, can be found in Remington''s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

As noted above, the compounds described herein are suitable for use in various systems of drug delivery described above. In addition, with the aim of increasing in vivo half-life of injected drugs from serum connection can be enclosed in a capsule, to enter into the cavity of liposomes, prepared in the form of a colloid or you can use other ways to increase the half-life of compounds from the blood serum. Available a variety of ways to obtain liposomes described, e.g., Szoka et al. in U.S. patent No. 4235871, 4501728 and 4837028, each of which is incorporated herein by reference.

In the preventive purposes of the composition is administered to a patient at risk of developing AD (as determined, for example, the study of the genome of the patient or hereditary characteristics), dostat cnom to suppress the initial symptoms of the disease. Number satisfying this condition is called "prophylactically effective dose." Amounts effective for this purpose depend on the prescription of the attending physician, who determines, taking into account such factors as age, weight and General condition of the patient, etc.

As noted above, the compounds introduced to the patient, are in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be subjected to sterilizing filtration. The resulting aqueous solutions can be packaged and used in the form in which they are, or they can be dried in vacuum, while before the introduction of the dried product is mixed with sterile water media. the pH of the preparations of compounds is usually in the range from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. Assume that when using the above specific fillers, carriers, or stabilizers will take the form of pharmaceutical salts.

The following examples are given to illustrate the invention and in no way limit the scope of the present invention. Unless specified otherwise, all temperature values are in degrees Celsius.

EXAMPLES

This invention bumblee understood with reference to the following examples, which are intended only to illustrate the invention. Scope of the present invention is not limited to the above implementation options that are only illustrations of individual aspects of the invention. Any functionally equivalent methods are within the scope of the invention. Various modifications of the invention, in addition to the described herein will be obvious to experts in the art from the foregoing description and the accompanying drawings. Such modifications fall within the scope of the attached claims.

In the examples and elsewhere in this document, the abbreviations have the following meanings:

μl = microliter

DMSO = dimethyl sulfoxide

g = grams

h = hour

Hz = Hertz

M = mol / litre

mg = milligrams

min = minute

ml = milliliter

mm = millimoles per litre

mm = mm

mmol = millimoles

mol. = moles

MS = mass spectroscopy

N = normality

nm = nanometer

μm = micromoles per liter

Example 1. Analysis CHEF

Color resonant energy transfer fluorescence (CHEF) Forster is dependent on the internuclear distances, nonradiative transfer of energy, in which disburden one fluorophore (the donor) is correlated with the excitation of another fluorophore (the acceptor). CHEF occurs if (1) the quantum of energy emitted to the a priori fluorophore, corresponds to the excitation energy of the acceptor fluorophore, (2) the directions of the dipole moments of the transitions for the donor and acceptor are almost parallel, and (3) the spectrum of the fluorescence emission of the donor overlaps with the absorption spectrum of the acceptor.

In this analysis for the formation of assemblies β1-42the oligomer is supervised by CHEF using N-terminal conjugated fluorescein-β1-42as a donor and acceptor fluorophore (fluorescein conjugate-fluorescein RO~ 45 Å). Assembly β1-42monomers in the oligomer particles leads to a decrease in fluorescence as β1-42labeled with fluorescein, are approaching each other, and also to increase the efficiency CHEF. Inhibition of the Assembly of oligomers β1-42(ADDL) is manifested by the absence or weakening of quenching fluorescence.

Analyses CHEF and FP carried out in 384-well black, opaque microtiter tablet of calcium-borophosphate glass with neisvaziuosiu surface, and a buffer for analysis consists of MOPS-Tris (3-(N-morpholine)propanesulfonic acid - N-Tris(hydroxymethyl)-aminomethane) with a concentration of 50 mm (pH 8.0) and MgCl2with concentratie 100 mm. The analyzed volume, containing FITZ-β(1-42) (fluorescein-isothiocyanate - Aβ(1-42)concentration of 0.2 μm) and Aβ(1-42) (0.8 μm), 50 ál, and the temperature is 37°C. For sborka the ADDL see on the tablet-reader Tecan GENios Pro with wavelength excitation 485 nm, measuring the emission at a wavelength of 515 nm. Conclusion on the kinetic mechanisms do on the measured fluorescence intensity and by reading polarisation every five minutes for 3-6 hours. In the negative control reactions, in which there is no appreciable build in ADDL for a specified period of time, not involved MgCl2but included all other buffer and peptide components. In the reactions of the positive control contains all buffer components, with no additional reagents based on small molecules and antibodies. To test for suppression Assembly ADDL ones connection incubated with a mixture of peptides, preparing solutions with six different concentrations, which is gradually reduced from 30 ám to 0.05 ám.

When using the above method of analysis in which the concentration of the tested compounds And ranged from 0.05 to 3 mm, it was found that for the tested compounds And is characterized by dose-dependent inhibition of the Assembly of oligomeric β1-42(ADDL), as shown in figure 1. Test compound a is a compound 4 of Table 1. At the same time, for test connection, analyzed at a concentration of 30 μm, is characterized by only partial suppression Assembly at very high concentrations (Figure 1). Others use the s compounds with molecular weight less than 1000, with the necessary activity that is installed by this method of analysis presented in Table 1.

Example 2. A comparative example of the proposed inhibitor Assembly of oligomers β1-42(ADDL)

Using the above method of analysis CHEF have multiple connections, originally developed as inhibitors of amyloid fibrils, on the subject of suppression Assembly of monomer β1-42in β oligomers. The tested compounds include Alzhemed™ (Neurochem), scyllo-Inositol, also known as AZD-103 (Ellipsis), SP-235 (Samaritan), benzofuranyl (GE), 9-acridinone (Warner-Lambert), cyclodextrins (University of Illinois, Chicago), RS-406 (Sankyo), kliohinol (Prana) and curcumin (UCLA/UCI). Standard analysis RPAF the conditions described in example 1. The inability connection Alzhemed™ to inhibit the Assembly β1-42monomer in β oligomers shown in figure 2. These results are typical for all of the compounds listed above, which was originally developed as inhibitors of amyloid fibrils.

Example 3. The model on the basis of rats performing alternate pressing the levers on the cyclic sequence

Drugs β1-42oligomers (ADDL) and potential therapeutic compounds have on the model rats with BA engaged alternately pressing the levers on the cyclical consequences of the successive (ALCR), to assess in vivo efficacy. Using this sensitive model allows detection of cognitive disorders with direct injection β oligomers cell of origin in the brain of rats. This way you can test direct injection ADDL consisting of synthetic β1-42and the intended therapeutic compounds analyzed by the method of ALCR.

It was proved that the test model ALCR is much more sensitive than previously published methods of measuring the impact of the drug on cognitive function. When performing this task, rats should be accustomed to a complex sequence of queries by pressing on the lever, in which they receive food reinforcement in the experimental chamber with two levers. Subjects must produce pressing two levers alternately, switching to the second lever should be done only after sufficient pressing the first lever, for which they receive a food reward. Replacement of food is carried out after a certain number of clicks, which initially increases from 2 to 56 responses for one nutrient tablet, and then reduced back to 2 responses for one nutrient tablet. Intermediate values calculated by the quadratic function x2agricultural One cycle represents the total members shall etelnost increase and decrease the number of queries by pressing on the lever (for example, 2, 6, 12, 20, 30, 42, 56, 56, 42, 30, 20, 12, 6 and 2 clicks for one food reward). One day session is held six full cycles of this type. Count the errors, which include those cases where the subject stubbornly continues to press the lever after the initial pressing, sufficient to obtain a food reward, i.e., it does not go to another lever (perseverative error), or when the subject moves from one arm to another until the full execution of the query by clicking on the first lever (error).

Materials and methods

Synthetic powder β1-42dissolved in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)getting the solution β1-42in HFIP with a concentration of about 1 mm, which is kept at ambient temperature for 1 h the resulting solution was cooled in an ice bath for 5-10 minutes and then take aliquot in Eppendorf tubes in an amount of 50 μl of solution per tube. The tubes are placed in a chemical fume hood and allowed to stand overnight to give the opportunity GRIP to evaporate under a weak stream of nitrogen. To remove the remaining traces GRIP tubes vacuum at room temperature and a pressure of 15-25 mm Hg for two quick cycle of 15 minutes the Resulting film Monomeric β1-42peptide keeping the over desiccant at -80°C until use.

Tube Monomeric β1-42peptide warmed to room temperature and dissolved β1-42in anhydrous DMSO, getting the mother liquor β1-42peptide in DMSO with a concentration of from 10 to 100 μm. To 998 ál of neural basal medium (without dye phenol red, Gibco 12348-017) add 2 ál of 20 mm stock solution of test compound in anhydrous DMSO, and thus, a 40 mm solution of the test compound in neural basal medium.

When treatment is only β1-42peptide mother solution of the peptide in DMSO added at a temperature of 37°C to neural basal medium, bringing the concentration β1-42peptide monomer to the desired value, provided that the maximum concentration of DMSO is 1% or less, then the contents of the tubes are mixed on a vortex for 30 to 60 seconds, after which for a short time slow rotation in microcentrifuge and maintain the solution at 37°C for 15 minutes before injection.

When treatment β1-42peptide and tested the connection to the mother solution of the peptide in DMSO added at 37°C to a solution of connections in neural basal medium, bringing the concentration β1-42peptide monomer to the desired value, provided that the maximum concentration of DMSO is 1% or less is, then the contents of the tubes are mixed on a vortex within 30-36 seconds, then for a short time slow rotation in microcentrifuge and maintain the solution at 37°C for 15 minutes before injection.

When the injection control solution connections in neural basal medium incubated at 37°C for 15 min before injection.

Rats: Rats obychaut procedure ALCR up until the frequency error will not be constant. After moving rats to end the tub ALCR conduct daily training sessions before the end of the study.

Surgery: All rats administered a single cannula 28 size, locking it on the skull and guiding in the region of the lateral ventricle. Half of the rats cannula is injected into the right ventricle, and the other half is in the region of the left ventricle. Rats given 5 days to recover from surgery, and then resume training.

Injection of the test substance and the test ALCR: the Test is carried out during each of the fifth day. Animals injected 20 μl injection control peptide or peptide solution with a solution of the compound through implatirovannogo cannula for 3-4 minutes. Animals examined after approximately 3 hours after entering the injection.

The analysis of error rate: All the error rate is correlated with databases the red line for frequency error, consisting of at least a 3-day period of no treatment, which is the time immediately after the injection. When analyzing the effects of using student test for statistical inference.

Expected results

It is expected that a significant increase in the frequency of occurrence perseverative errors will occur in the interval between the base frequency error and the frequency error, which occurs under the influence of oligomeric β1-42(ADDL). It is also assumed that the separate addition of one or more of the compounds described in this document, will not cause an increase in the error rate, while adding them together with oligomeric β1-42(ADDL) will be retiring increase perseverative errors. Thus, it is assumed that the errors arising from oligomeric β1-42(ADDL), will be eliminated by at least one or more of the compounds described in this document.

When reading the above description specialists in the art will be apparent various modifications and changes that can be made on the compositions or methods of the invention. It is implied that all such modifications falling within the scope of the attached formula, included in this invention.

1. How prot is against the formation of neurotoxic proteins ADDL of Monomeric peptides β 1-42comprising contacting a Monomeric β1-42with almost pure ones connection, which is selected from the group of compounds including:
(Z)-N-(2-methoxy-phenyl)-2-oxo-2-{N'-[3-oxo-3-thiophene-2-yl-1-trifluoromethyl-propylidene]-hydrazino}-ndimethylacetamide,
ethyl ester of (E)-2-{[1-(2-hydroxy-3-methoxy-phenyl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxynaphthalene-1-yl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxyphenyl)-methylidene-hydrazino-oxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-yl)-N-(2-methoxyphenyl)-2-oxoacetate and
(E)-2-hydroxy-N'-((1-hydroxynaphthalene-2-yl)methylene)benzhydrazide.

2. The method according to claim 1, in which the specified connection suppresses the formation of neurotoxic proteins ADDL with IC50amounting to, at most, about 2 microns.

3. The method of suppression, regulation and/or modulation of neuronal dysfunction or neurotoxicity induced proteins ADDL, in nerve cells or nerve tissue by suppressing the formation of proteins ADDL including interaction of Monomeric peptides β1-42that may exist in the presence of nerve cells, with efficiency the sector number of nearly pure ones connection, which is selected from the group of compounds including:
(Z)-N-(2-methoxy-phenyl)-2-oxo-2-{N'-[3-oxo-3-thiophene-2-yl-1-trifluoromethyl-propylidene]-hydrazino}-ndimethylacetamide,
ethyl ester of (E)-2-{[1-(2-hydroxy-3-methoxy-phenyl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxynaphthalene-1-yl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxyphenyl)-methylidene-hydrazino-oxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-yl)-N-(2-methoxyphenyl)-2-oxoacetate and
(E)-2-hydroxy-N'-((1-hydroxynaphthalene-2-yl)methylene)benzhydrazide.

4. The method according to claim 3, in which the specified connection suppresses the formation of neurotoxic proteins ADDL with IC50amounting to, at most, about 2 microns.

5. A way to counteract the formation of neurotoxic proteins ADDL of Monomeric peptides β1-42comprising contacting a Monomeric β1-42with an effective amount of compounds encompassed by structural formula And

where R represents a phenyl or heteroaryl containing sulphur, each of which is substituted in position 2 by a Deputy, selected from the group consisting of hydroc and, methoxy,- C(O)O-C1-C2-alkyl,
R1represents hydrogen or trifluoromethyl,
R2is heteroaryl containing sulfur or6-C10aryl, where the specified aryl optionally substituted by 1-3 substituents selected from the group of substituents, including hydroxy and methoxy,
L is a covalent bond or-NHC(O)-, and
L' represents a covalent bond or-CH2S(O).

6. A way to counteract the formation of neurotoxic proteins ADDL of Monomeric peptides β1-42, comprising contacting the Monomeric Aβ1-42with an effective amount of compounds encompassed by structural formula And

where R represents a phenyl or 4,5,6,7-tetrahydroindazole, each of which is substituted in position 2 by a Deputy selected from the group comprising hydroxy, methoxy,- C(O)O-C1-C2-alkyl, and where specified 4,5,6,7-tetrahydroindazole replaced by stands in position 7,
R1represents hydrogen or trifluoromethyl,
R2is heteroaryl containing sulfur or6-C10aryl, where the specified aryl optionally substituted by 1-3 substituents selected from the group of substituents, including hydroxy and methoxy,
L is a covalent bond or-NHC(O)-, and
L' represents the Wallpaper covalent bond or-CH 2S(O).

7. Composition for combating the formation of neurotoxic proteins ADDL of the Monomeric peptide β1-42which contains an effective amount of nearly pure ones connection, which is selected from the group of compounds including:
(Z)-N-(2-methoxy-phenyl)-2-oxo-2-{N'-[3-oxo-3-thiophene-2-yl-1-trifluoromethyl-propylidene]-hydrazino}-ndimethylacetamide,
ethyl ester of (E)-2-{[1-(2-hydroxy-3-methoxy-phenyl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxynaphthalene-1-yl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxyphenyl)-methylidene-hydrazino-oxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-yl)-N-(2-methoxyphenyl)-2-oxoacetate and
(E)-2-hydroxy-N'-((1-hydroxynaphthalene-2-yl)methylene)benzhydrazide.

8. The composition according to claim 7, in which the specified connection suppresses the formation of neurotoxic proteins ADDL with IC50amounting to, at most, about 2 microns.

9. The composition according to claim 7, in which almost pure ones, the compound is administered in an amount of from 0.05 to 1000 mg, at least once a day.

10. The composition according to claim 7, which further comprises a pharmacist who Cesky acceptable filler.

11. The composition according to claim 7, in which proteins ADDL associated with insoluble amyloid fibrils, senile plaques or tangles.

12. The composition according to claim 7, in which proteins ADDL associated with a disease selected from the group of diseases, including Alzheimer's disease, down syndrome, stroke and mild cognitive disorder.

13. The composition according to claim 7, in which proteins ADDL associated with a disease selected from the group of diseases that includes focal ischemia associated dementia, and neuronal degeneration.

14. The composition according to claim 7, in which proteins ADDL are associated with overexpression of amyloid β1-42 protein.

15. Composition for suppression, regulation or modulation of neuronal dysfunction or neurotoxicity induced proteins ADDL, in nerve cells by suppressing the formation of proteins ADDL containing an effective amount of nearly pure ones connection, which is selected from the group of compounds including:
(Z)-N-(2-methoxy-phenyl)-2-oxo-2-{N'-[3-oxo-3-thiophene-2-yl-1-trifluoromethyl-propylidene]-hydrazino}-ndimethylacetamide,
ethyl ester of (E)-2-{[1-(2-hydroxy-3-methoxy-phenyl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
ethyl ester of (E)-2-{[1-(2-hydroxynaphthalene-1-yl)-methylidene-hydrazinolysis]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid is,
ethyl ester of (E)-2-{[1-(2-hydroxyphenyl)-methylidene-hydrazino-oxalyl]-amino}-6-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid,
2-(5-hydroxy-3-isobutyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-1-yl)-N-(2-methoxyphenyl)-2-oxoacetate and
(E)-2-hydroxy-N'-((1-hydroxynaphthalene-2-yl)methylene)benzhydrazide.

16. The composition according to item 15, in which the specified connection suppresses the formation of neurotoxic proteins ADDL, with the value of the IC50, at most, about 2 microns.

17. The composition according to item 15, in which almost pure ones, the compound is administered in an amount of from 0.05 to 1000 mg once or several times per day.

18. The composition according to p. 15, which further comprises a pharmaceutically acceptable filler.

19. The composition according to item 15, in which proteins ADDL, if any, are associated with insoluble amyloid fibrils, senile plaques or tangles.

20. The composition according to item 15, in which proteins ADDL, if any, are associated with a disease selected from the group consisting of Alzheimer's disease, down syndrome, stroke and mild cognitive impairment.

21. The composition according to item 15, in which proteins ADDL, if any, are associated with a disease selected from the group consisting of focal ischemia associated dementia, and neuronal degeneration.

22. The composition according to item 15, in which proteins ADDL, esline generally there are, associated with overexpression of amyloid β1-42 protein.

23. The composition according to item 15, in which these nerve cells isolated from the brain tissue of the animal and grown in tissue culture.

24. Composition for combating the formation of neurotoxic proteins ADDL of the Monomeric peptide Aβ1-42which contains an effective amount of nearly pure ones connections covered by the structural formula And

where R represents a phenyl or heteroaryl containing sulphur, each of which is substituted in position 2 by a Deputy selected from the group comprising hydroxy, methoxy,- C(O)O-C1-C2-alkyl,
R1represents hydrogen or trifluoromethyl,
R2is heteroaryl containing sulfur or6-C10aryl, where the specified aryl optionally substituted by 1-3 substituents selected from the group of substituents, including hydroxy and methoxy,
L is a covalent bond or-NHC(O)-, and
L' represents a covalent bond or-CH2S(O).

25. Composition for combating the formation of neurotoxic proteins ADDL of the Monomeric peptide Aβ1-42which contains an effective amount of nearly pure ones connections covered by the structural formula And

where R represents a phenyl or 4,5,6,7-tetrahydroindazole, each of which is substituted in position 2 by a Deputy selected from the group comprising hydroxy, methoxy,- C(O)O-C1-C2-alkyl, and where specified 4,5,6,7-tetrahydroindazole replaced by stands in position 7,
R1represents hydrogen or trifluoromethyl,
R2is heteroaryl containing sulfur or6-C10aryl, where the specified aryl optionally substituted by 1-3 substituents selected from the group of substituents, including hydroxy and methoxy,
L is a covalent bond or-NHC(O)-, and
L' represents a covalent bond or-CH2WITH(ABOUT).



 

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12 cl, 2 tbl

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3 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns veterinary science. A pharmaceutical composition in the form of a water suspension containing benzimidazole carbamate particles, surfactant polysorbate and a pharmaceutically acceptable carrier, where at least 90% of the benzimidazole carbamate particles have a mean particle size is less than 450 nm. A method for preparing a pharmaceutical composition comprises dispersion of the benzimidazole carbamate particles in a mixture containing the pharmaceutically acceptable carrier and the surfactant polysorbate; and mechanical size reduction of the benzimidazole carbamate particles to an effective mean particle size less than 450 nm. A method for producing therapeutic drinking water involves making said pharmaceutical composition, adding the pharmaceutically acceptable carrier to the composition and adding the end product to drinking water. Therapeutic drinking water contains 10 to 150 particles/mil. benzimidazole carbamate particles where at least 90% of the benzimidazole carbamate particles have the mean particle size less than 450 nm. Using said pharmaceutical composition for preparing a drug for control of parasites in animals.

EFFECT: invention provides stability of the suspension over 24 hours and enables to distribute therapeutic drinking water with homogenous distribution of the drug along the system tube designed for drinking water supply, and respectively maintained dose accuracy for all animals.

5 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I

,

where A represents S or Se; B represents H or ; R1 represents aryl selected from the following structures:

R2 represents H or ; R3 represents H or C1-C8 alkyl; R4 and R5 independently represent H or C1-C8 alkyl; R6 represents H, C1-C8 alkyl, C2-C7 alkenyl, alkaline metal or alkaline earth metal; R11 and R12 independently represent H, C1-C8 alkyl or halogen; R21 represent H, halogen or C1-C7 alkyl; m and n independently represent integers having values 1-4; p represents an integer having a value of 1-5; q represents an integer having a value of 1-4; r represents an integer having a value of 1-3; s represents an integer having a value of 1-5; as an activator of peroxisome proliferator-activated receptor (PPAR) and its hydrate, solvate, stereoisomer and pharmaceutically acceptable salt, and to a pharmaceutical composition.

EFFECT: preparing an agent for muscle strengthening, an agent for memory improvement, a therapeutic agent for dementia and Parkinson's disease.

15 cl, 8 tbl, 348 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolo-[1,2-a]benzimidazole derivatives of formula I , where NR2 assumes morpholino or diethylamino values, and Ar is 4-methoxyphenyl or 4-chlorophenyl, having antioxidant and antiradical properties.

EFFECT: obtaining novel sulphates possessing useful biological properties.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

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