Substituted n-arylbenzamides and related compounds for treating amyloid diseases and synucleinopathy

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of diaryl compounds with formulae given below ,

.

, in which M is S(O)2, Rx represents alkyl, R1, R2, R3 and R4 are each independently selected from OH and -NR7S(O)2R8, R5 and R7 each independently represents hydrogen or alkyl, R8 is alkyl; and their pharmaceutically acceptable derivatives, as well as to pharmaceutical compositions containing said compounds and their use in making a medicinal agent with inhibitory activity on Aβ, IAPP amyloid fibrils or synuclein fibrils.

EFFECT: substituted n-arylbenzamide and related compounds for treating amyloid diseases and synucleinopathy are disclosed.

11 cl, 19 ex, 6 tbl

 

RELATED APPLICATIONS

In this application claimed priority in accordance with p U.S.C. § 119(e) based on provisional application U.S. 60/570669, entitled "Substituted N-Aryl Benzamides and Related Compounds for Treatment of Amyloid Diseases and Synucleinopathies" Snow et al., filed may 12, 2004, and 60/629525, entitled "Substituted N-Aryl Benzamides and Related Compounds for Treatment of Amyloid Diseases and Synucleinopathies" Snow et al., filed November 18, 2004, the Contents of these prior applications is included here for reference.

The SCOPE of the INVENTION

The present invention relates to substituted N-alvensleben and related compounds, pharmaceutical compositions and methods for treatment of amyloid diseases, including beta-amyloid protein (Aβ), which is observed in Alzheimer's disease and down syndrome, islet amyloid polypeptide (IAPP), which is observed in diabetes type 2, and alpha synuclein such that observed in Parkinson's disease.

Prior art

Alzheimer's disease is characterized by accumulation of a peptide of 39-43 amino acids, ending with β-amyloid protein or Aβ, in fibrillar form, existing in the form of extracellular amyloid plaques, and as amyloid in the walls of cerebral blood vessels. Believe that the deposition of fibrillar Aβ amyloid in Alzheimer's disease is harmful for the patient and ultimately bring the toxicity and death of neuronal cells what is distinctive signs of Alzheimer's disease. Accumulating evidence suggests that amyloid and, more specifically, the formation, deposition, accumulation and/or persistence of Aβ fibrils are the main causal factor in the pathogenesis of Alzheimer's disease. In addition to Alzheimer's, a number of other amyloid diseases involves the formation, deposition, accumulation and persistence of Aβ fibrils, including down syndrome, disturbances, including congorilla the angiopathy, such as but not limited to, hereditary cerebral hemorrhage of the Dutch type, myositis with inclusions of Taurus, Boxing dementia, cerebral β-amyloid angiopathy, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration and moderate loss of cognitive abilities.

Parkinson's disease is another violation of a person characterized by the formation, deposition, accumulation and/or persistence of abnormal deposits of fibrillar protein that demonstrate many of the characteristics of amyloid. Consider that in Parkinson's disease accumulation cytoplasmically Taurus Levi, consisting of threads α-synuclein/NAC (non-Aβ component, plays an important role in the pathogenesis and as tera is efticiency targets. New agents or compounds capable of inhibiting the formation, deposition, accumulation and/or persistence of α-synuclein and/or NAC or destroy the previously formed α-synuclein/NAC fibrils (or parts thereof) are considered as potential drugs for the treatment of binucleate Parkinson's disease and related synucleinopathies. NAC is a fragment of 35 amino acids of α-synuclein, which are capable of forming amyloidogenic fibrils or in vitro, or as was observed in the brain in patients with Parkinson's disease. NAC fragment of α-synuclein is a relatively important therapeutic goal, as they believe that this part of the α-synuclein critical for formation Taurus Levi, as observed in all patients with Parkinson's disease, synucleinopathies and related disorders.

Many other diseases also demonstrate amyloid deposits and usually include systemic organs (i.e. organs or tissues outside the Central nervous system), and accumulation of amyloid leads to organ dysfunction or death. Such amyloid diseases (discussed below), leading to a marked accumulation of amyloid in various organs and tissues, known as system amyloidosis. In other amyloid diseases can be affected individual organs, such as pagelogo the Naya iron 90% of patients with type 2 diabetes. Believe that this type of amyloid disease beta cells in the islets Langerhans in the pancreas are destroyed by the accumulation of fibrillar amyloid deposits consisting mainly of protein, known as islet amyloid polypeptide (IAPP). Inhibition or reduction of formation, deposition, accumulation and persistence of such IAPP amyloid fibrils, as it provides new and effective ways to treat type 2 diabetes. In Alzheimer's disease, Parkinson's disease and systemic amyloid diseases at the present time there is no cure or effective treatment, and usually the patient dies within 3 to 10 years after diagnosis.

Amyloid diseases (amyloidosis) are classified according to the type of amyloid protein present, as well as the underlying disease. Amyloid diseases share a number of characteristics, including every amyloid consisting of a unique type of amyloid protein. Amyloid diseases include, but are not limited to, the amyloid associated with Alzheimer's disease, down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, dementia pugilistica, myositis with inclusions Taurus (Askanas et al., Ann. Neurol. 43:521-560, 1993) and a moderate loss of cognitive abilities (where specific amiloidosis beta-amyloid protein or Aβ), the amyloid associated with chronic inflammation, various forms of malignant fever and familial Mediterranean fever (where the specific amyloid is called AA amyloid or associated with inflammation amyloidosis), the amyloid associated with multiple myeloma and other B-cell dyscrasias (where the specific amyloid referred to as AL amyloid), the amyloid associated with type 2 diabetes (where the specific amyloid protein called amilina or islet amyloid a polypeptide or IAPP), the amyloid associated with pionowymi diseases, including disease Creutzfeldt-Jakob syndrome Gerstmann-Straussler, Kuru, and scrapie in animals (where the specific amyloid is the name of PrP amyloid), the amyloid associated with long-term hemodialysis and carpal tunnel syndrome (where the specific amyloid is called α2-macroglobulinemia amyloid), the amyloid associated with senile cardioembolism and family amyloidotic polineiropatiei (where the specific amyloid is called transthyretin or prealbumin), and the amyloid associated with endocrine malignancies, such as medullary carcinoma of the thyroid gland (where the specific amyloid is called variants of procalcitonin). In addition, α-synucleins protein, which forms amyloidogenic fibrils, and Ki is positive in relation to the Congo red and Thioflavin S (specific dyes, which is used for detecting amyloid fibrillar deposits), discovered as part of Taurus Levi in the brain of patients with Parkinson's disease Taurus levy (Lewy in Handbuch der makes sense or not, M. Lewandowski, ed., Springer, Berlin, pp.920-933, 1912; Pollanen et al., J. Neuropath. Exp.Neurol. 52:183 to 191, 1993; Spillantini et al., Proc. Natl. Acad. Sci. USA 95:6469-6473, 1998; Arai et al., Neurosci. Lett. 259:83-86, 1999), multiple system atrophy (Wakabayashi et al., Acta Neuropath. 96:445-452, 1998), dementia with calves Levi and option Taurus levy in Alzheimer's disease. In the context of the description of Parkinson's disease due to the fact that fibrils are developed in the brain of patients with this disease (which is positive in relation to the Congo red and Thioflavin S and which contain the dominant beta-folded lamellar secondary structure, considered now as a disease, which also demonstrates characteristics amyloidogenic disease.

System amyloidosis, which include the amyloid associated with chronic inflammation, various forms of malignant fever or familial Mediterranean fever (i.e. AA amyloid or associated with inflammation, the amyloidosis) (Benson and Cohen, Arth. Rheum. 22:36-42, 1979; Kamei et al. Acta Path. Jpn. 32:123-133, 1982; McAdam et al., Lancet 2:572-573, 1975; Metaxas, Kidney Int. 20:676-685, 1981), and the amyloid associated with multiple myeloma and other B-cell dyscrasias (i.e. AL amyloid) (Harada et al., J. Histochem. Cytochem.19:1-15, 1971); for example, as is known, include amyloid deposits in various organs and tissues, which are usually located outside the Central nervous system. Amyloid deposits these diseases can be, for example, in the liver, heart, spleen, gastrointestinal tract, kidney, skin and/or lungs (Johnson et al., N. Engl. J. Med. 321:513-518, 1989). For most of these amyloidosis there is not a valid or effective treatment, and, therefore, amyloid deposits can be harmful for the patient. For example, amyloid deposits in the kidneys can lead to kidney failure, whereas amyloid deposits in the heart can lead to heart failure. For such patients, amyloid accumulation in systemic organs lead to eventual death, usually within 3-5 years. Other amyloidosis can damage individual organ or tissue, for example, as observed when Aβ amyloid deposits found in the brains of patients with Alzheimer's disease and syndromeam down; when PrP amyloid deposits found in the brains of patients with the disease of Creutzfeldt-Jakob syndrome, Gerstmann-Straussler and Kuru; islet amyloid (IAPP) sediments found in the islets of Langerhans in the pancreas 90% of patients with type 2 diabetes (Johnson et al., N. Engl. J. Med. 321:513-518, 1989; Lab. Invest. 66:522 535, 1992); �ri α 2-macroglobulinemia amyloid deposits in the medial nerve causing carpal tunnel syndromes observed in patients exposed to long-term hemodialysis (Geyjo et al., Biochem. Biophys. Res. Comm. 129:701-706, 1985; Kidney Int. 30:385-390, 1986); when prealbumin/transthyretin the amyloid observed in the hearts of patients with senile cardinalism, and when prealbumin/transthyretin the amyloidosis observed in the peripheral nerves of patients with family amyloidotic polineiropatiei (Skinner and Cohen, Biochem. Biophys. Res. Comm. 99:1326-1332, 1981; Saraiva et al., J. Lab. Clin. Med. 102:590-603, 1983; J. Clin. Invest. 74:104-119, 1984; Tawara et al., J. Lab. Clin. Med. 98:811-822, 1989).

Alzheimer's disease, in addition, imposes a heavy economic burden on society. Recent studies estimate the cost of treating patients with Alzheimer's disease with severe impairment of cognitive functions at home or in a nursing home more than $47000 per year (A Guide to Understanding Alzheimer's Disease and Related Disorders). For the disease, which can range from 2 to 20 years, the full cost of treatment of Alzheimer's disease for the family and society is staggering. The annual economic cost of treating Alzheimer's disease in the United States from the point of view of patient care is expensive and monetary loss for both patients and those who care of them, are evaluated as $80-$100 billion (2003 Progress Report on Alzheimer's Disease).

Amyloid is AK therapeutic target in Alzheimer's disease

Alzheimer's disease is characterized by the deposition and accumulation of a peptide of 39-43 amino acids, ending with beta-amyloid protein, Aβ or β/A4 (Glenner and Wong, Biochem. Biophys. Res. Comm. 120:885-890, 1984; Masters et al., Proc. Natl. Acad. Sci. USA 82:4245-4249, 1985; Husby et al., Bull. WHO 71:105-108, 1993). Aβ is formed as a result proteasome off from a larger protein precursor, ending with β-amyloid protein-precursors (APPs), which can explain several alternative splicing. The most numerous forms APPs include proteins, consisting of 695, 751 and 770 amino acids (Tanzi et al., Nature 31:528-530, 1988).

Small Aβ peptide is the major component, which is amyloid deposits "plaques" in the brain of patients with Alzheimer's disease. In addition, Alzheimer's disease is characterized by the presence of numerous neurofibrillary "tangles", consisting of paired helical filaments, which are abnormally accumulate in the neuronal cytoplasm (Grundke-Iqbal et al., Proc. Natl. Acad. Sci. USA 83:4913-4917, 1986; Kosik et al., Proc. Natl. Acad Sci. USA 83:4044-4048, 1986; Lee et al., Science 251:675-678, 1991). Therefore, the pathological label of Alzheimer's disease is the presence of "plaques" and "tangles, and amyloid deposits are located in the Central part of these plaques. The other major type of lesions found in the brain in Alzheimer's disease is the accumulation of amyloid is the walls of blood vessels within the parenchyma of the brain, and in the walls of meningeal vessels, which are located outside of the brain. Amyloid deposits are localized in the walls of blood vessels, called cerebrovascular amyloid or congophilic angiopathy (Mandybur, J. Neuropath. Exp.Neurol. 45:79-90, 1986; Pardridge et al., J. Neurochem. 49:1394-1401, 1987).

For many years happen ongoing debate on the importance of "amyloid" in Alzheimer's disease and whether the presence of "plaques" and "tangles"that characterize this disease, a cause, or they are merely a consequence of the disease. Conducted in the last few years, studies show that amyloid is indeed a causal factor in Alzheimer's disease, and it should not be viewed as simply a benign side agent. It was shown that Aβ protein of Alzheimer's disease in cell culture is the cause of the degeneration of nerve cells in a short period of time (Pike et al., Br. Res. 563:311-314, 1991; J. Neurochem. 64:253-265, 1995). Studies suggest that it is a fibrillar structure (consisting of the dominant β-folded plates of the secondary structure), which is characteristic of all amyloid, which is responsible for neurotoxic effects. It was also found that Aβ is neurotoxic in culture hippocampal slices (Harrigan et al., Neurobiol. Aging 16:779-789, 1995) and induces g is the Belle of nerve cells in transgenic mice (Games et al., Nature 373:523-527, 1995; Hsiao et al., Science 274:99-102, 1996). Injection of Alzheimer's Aβ in the brain of rats also causes memory impairment and neuronal dysfunction (Flood et al., Proc. Natl. Acad. Sci. USA 88:3363-3366, 1991; Br.Res. 663:271-276, 1994).

Perhaps the most convincing evidence that Aβ amyloid directly included in the pathogenesis of Alzheimer's disease, results from genetic studies. It was found that the production of Aβ can result from mutations in the gene encoding its precursor, β-amyloid protein precursor (Van Broeckhoven et al., Science 248:1120-1122, 1990; Murrell et al., Science 254:97-99, 1991; Haass et al., Nature Med. 1:1291-1296, 1995). Identification of mutations in the beta-amyloid precursor protein gene that cause early onset familial Alzheimer's disease, is the strongest argument in favor of amyloid plays a Central role in the pathogenic process underlying this disease. Were found four cause disease mutations, demonstrating the importance of Aβ in the occurrence of familial Alzheimer's disease (review in Hardy, Nature Genet. 1:233-234, 1992).

In all of these studies suggest that the introduction of medications to reduce, eliminate or prevent the formation of fibrillar Aβ deposits, accumulation and/or persistence in the brain of the patient man will prove to be effective therapeutic method.

Parkinson's disease and synucleinopathies

Parkinson's disease is a neurodegenerative disorder that is pathologically characterized by the presence of the Taurus provides help Levi (Lewy in Handbuch der makes sense or not, M. Lewandowski, ed., Springer, Berlin, pp.920-933, 1912; Pollanen et al., J. Neuropath. Exp.Neurol. 52:183 to 191, 1993), the main components of which are yarn consisting of α-synuclein (Spillantini et al., Proc. Natl. Acad. Sci. USA 95:6469-6473, 1998; Arai et al., Neurosci. Lett. 259:83-86, 1999), protein, composed of 140 amino acids (Ueda et al., Proc. Natl Acad. Sci. USA 90:11282-11286, 1993). Two dominant mutations in α-synuclein causing early onset familial Parkinson's disease, have been described with the assumption that the cells Levi mechanistically contribute to the degeneration of neurons in Parkinson's disease and related disorders (Polymeropoulos et al., Science

276:2045-2047, 1997; Kruger et al., Nature Genet. 18:106-108, 1998). Recently, in vitro studies have demonstrated that recombinant α-synuclein really can form fibrils, similar to the Taurus levy (Conway et al.,

Nature Med. 4:1318-1320, 1998; Hashimoto et al., Brain Res. 799:301-306, 1998; Nahri et al., J. Biol. Chem. 274:9843-9846, 1999). The most important thing associated with Parkinson's disease mutations of α-synuclein accelerate this process of aggregation, demonstrating that such in vitro studies may be important for the pathogenesis of Parkinson's disease. Aggregation of alpha-synuclein and the formation of fibrils constitute the criterion for Vashego from nucleation polymerization process (Wood et al., J. Biol. Chem. 274:19509-19512, 1999). In this regard, the formation of α-synuclein fibril formation resembles the formation of fibrils of β-amyloid protein of Alzheimer's disease (Aβ). Alpha sinocleansky recombinant protein and non-Aβ component (known as NAC), which is a peptide fragment of 35 amino acids of α-synuclein, both have the ability to form fibrils when incubated them at 37°C, and are positive in relation to amyloid dyes, such as Congo red (demonstrating a red/green birefringence under polarized light) and tioflavin S (demonstrating positive fluorescence) (Hashimoto et al., Brain Res. 799:301-306, 1998; Ueda et al., Proc. Natl. Acad. Sci. USA 90:11282-11286, 1993).

Synuclein are a family of small presynaptic neuronal proteins consisting of α-, β-, and γ-synuclein, and of these, only α-synuclein units associated with several neurological diseases (Ian et al., Clinical Neurosc. Res. 1:445-455, 2001; Trojanowski and Lee., Neurotoxicology 23:457-460, 2002). The role of synucleins (and, in particular, alpha-synuclein) in the etiology of neurodegenerative and/or amyloid diseases has been clarified as a result of several observations. Pathologically synuclein was identified as the main component Taurus Levi, sign inclusions of Parkinson's disease, and its fragment isolated from the amyloid plaques in different neurologic the ski diseases, of Alzheimer's disease. Biochemically, it was shown that recombinant α-synuclein forms amyloidogenic fibrils, which repeat the ultrastructural characteristics of the alpha synuclein isolated from patients with dementia with calves Levi, with Parkinson's disease and multiple system atrophy. In addition, the identification of mutations within a gene of synuclein, although in rare cases and is a cause of familial Parkinson's disease, demonstrates a clear link between sinocleansky pathology and neurodegenerative diseases. Regular inclusion of α-synuclein in a range of diseases, such as Parkinson's disease, dementia with calves Levi, multiple system atrophy and variant Alzheimer's disease with calves Levi, led to the classification of these disorders under the General title "synucleinopathies".

α-synuclein fibrils Parkinson's disease, like the Aβ fibrils of Alzheimer's disease, also consist of a dominant β-folded plate structures. Therefore, compounds which are detected as inhibit the formation of Aβ amyloid fibrils of Alzheimer's disease, will also presumably effective for inhibiting the formation of α-synuclein/NAC fibrils, as shown in the examples presented here. Therefore, these compounds can also serve as a drug for the treatment of bolezn the Parkinson's and other synucleinopathies, in addition, can be effective as medication in the treatment of Alzheimer's disease, type 2 diabetes and other amyloid disorders.

There is an urgent need for the discovery and identification of new compounds or agents as potential drugs to stop amyloid formations, deposition, accumulation and/or persistence observed in Alzheimer's disease, Parkinson's disease, type 2 diabetes and other amyloidotic.

The ESSENCE of ISOBUTENE

The present invention is a compound and pharmaceutical compositions containing the compounds of the formulas:

and

or their pharmaceutically acceptable derivatives, where R is selected from 1) CONR' 2) C1-C10alkalinous group in which: (a) if the number of carbon atoms is at least 2, there are optionally 1 or 2 double bonds; (b) 1-3 non-adjacent methylene groups are optionally replaced by NR', O or S; (c) 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and (d) 1 or 2 methylene groups are optionally replaced cycloalkyl or heterocyclyl group, which is optionally substituted by one or more substituents selected from lower alkyl, NR', O or S;

R1is H, ALK is l or acyl;

R1, R2, R3and R4independently chosen as follows:

i) R1, R2, R3and R4independently selected from HE, -NR5C(=O)R6and-NR7S(O2R8where R5and R7each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted geterotsiklicheskikh; and R6and R8each independently represents a substituted or unsubstituted alkoxy, substituted or unsubstituted, Alcoxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or-NR9R10where R9and R10each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclic provided that at least one of R1, R2, R3and R4is not OH;

ii) R1and R2and/or R3and R4together represent-NH-C(=O)-NH-, -NH-S(O2)-NH-, -CH2-C(=O)-NH - or-CH2-S(O2)-NH and together with the carbon atoms to which they are attached, form a 5-membered heterocycle is ical ring, and the other of R1, R2, R3and R4independently is chosen as in (i); or

iii) at least one of R1, R2, R3and R4is

-NH-CRa=CRb- or-NH-S(O2)CRcRdand together with two adjacent carbon atoms of the phenyl ring forms a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaromatic ring, and the other of R1, R2, R3and R4independently chosen as in i) or ii); and

where rings A and B is substituted by one or more substituents,

selected from electron-withdrawing groups, including, but not limited to, halogen, pseudohalogen, nitro,+NH3, SO3H, carboxy and halogenoalkane.

In one embodiment, R1-R10, Ra, Rb, Rcand Rdaccordingly chosen so as to optimize the physico-chemical and/or biological characteristics, such as bioavailability, pharmacokinetics, blood-brain barrier permeability, optimized metabolism and increased efficiency in the treatment of amyloid diseases and synucleinopathies.

Also offered any pharmaceutically acceptable derivatives, including salts, esters, enol ethers or esters, acetals, ketals, complex orthoepy, hemiacetal, gemic the hoist, a solvate, hydrate or proletarienne form compounds. Pharmaceutically acceptable salts include, but are not limited to, salts of amines, such as, but not limited to, N,N'-dibenziletilendiaminom, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyethylamine, Ethylenediamine, N-methylglucamine, procaine, N-benzylpenicillin, 1-pair-of chlorbenzyl-2-pyrrolidin-1'-iletilmesinden, diethylamine and other bonds alkylamines, piperazine, Tris(hydroxymethyl)aminomethan, alkali metal salts, such as, but not limited to, salts of lithium, potassium and sodium, and salt alkaline earth metals, such as, but not limited to, salts of barium, calcium and magnesium, salts of transition metals, such as, but not limited to, salts of zinc and other metals, such as, but not limited to, sodium phosphate and disodium phosphate, and also including, but not limited to, salts of mineral acids, such as, but not limited to, hydrochloride and sulfates, organic acid salts, such as, but not limited to, acetates, lactates, malaty, tartratami, citrates, ascorbates, succinate butyrate, valerate and fumarate.

The proposed pharmaceutical preparations for the introduction of the appropriate method and means containing effective is e the concentration of one or more of these compounds or pharmaceutically acceptable derivatives, such as salts, esters, enol ethers or esters, acetals, ketals, complex orthoepy, hemiacetal, hemiketal, solvate, hydrate or proletarienne form compounds which provide amount, effective for the treatment of amyloid diseases.

Drugs must be compositions suitable for administration in any necessary way, and they include solutions, suspensions, emulsions, tablets, dispersible tablets, pills, capsules, powders, dry powders for inhalation, the compositions with delayed allocation, aerosols for insertion into the nose and Airways, TRANS-dermal patches, and any other suitable form. Compositions should be suitable for oral administration, parenteral administration by injection, including subcutaneous, intramuscular or intravenously, in the form of aqueous or oily solutions or emulsions, transdermal administration and other selected methods.

Methods of using such compounds and compositions for destruction, disaggregation and contributing to the removal, reduction or elimination of amyloid or synuclein fibrils, thereby providing new ways of treating amyloid diseases and synucleinopathies.

Proposed methods of treatment, prevention or improvement of one or more of symptoma the amyloid diseases or amyloidosis, including, but not limited to, diseases associated with the formation, sediments, accumulation, or persistence of amyloid fibrils, such as fibrils of amyloid protein selected from the Aβ amyloid, AA amyloid, AL amyloid, IAPP amyloid, PrP amyloid, α2-macroglobulinemia amyloid, transthyretin, prealbumin and procalcitonin.

Treatment of amyloid diseases include, but are not limited to, Alzheimer's disease, down's syndrome, Boxing dementia, multiple system atrophy, myopathy with inclusions of Taurus, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, disease Neumann-Pick type C, cerebral β-amyloid angiopathy, dementia associated with cortical basal degeneration, the amyloidosis of type 2 diabetes, the amyloidosis of chronic inflammation, the amyloidosis malignancy and familial Mediterranean fever, the amyloidosis of multiple myeloma and B-cell dyscrasia, amyloidosis Pranovich diseases, disease Creutzfeldt-Jakob syndrome of Gerstman-Straussler, Kuru, scrapie, the amyloidosis associated with carpal tunnel syndrome, senile cardiomyocytes, family amyloidotic polineiropatia and the amyloidosis associated with endocrine diseases.

Proposed methods of treatment, prevention or improvement of the situation of the of one or more of the symptoms synucleinopathies disease or synucleinopathies. In one embodiment, these methods inhibit or prevent the formation of α-synuclein/NAC fibril formation, inhibit or prevent the growth of α-synuclein/NAC fibrils and/or cause disassembly, disruption, and/or disaggregatio previously formed α-synuclein/NAC fibrils and related α-synuclein/NAC fat protein. Sinucleanse diseases include, but are not limited to, Parkinson's disease, familial Parkinson's disease, diseases of calves Levi, variant Alzheimer's disease with calves Levi, dementia with calves Levi, multiple system atrophy and complex Parkinsonism-dementia of GUAM island.

DETAILED DESCRIPTION

Definitions A.

Unless otherwise noted, all used here is the technical and scientific terms have the same values, which typically involve specialists are relevant to the invention. All patents, applications, published applications and other publications are included here for your reference in its entirety. In that case, if there is a multiplicity of definitions for terms used here, those listed in this section have the advantage over the other.

In the sense used here, the term "amyloid disease" or "amyloidosis" is the disease associated with the formation, deposition, accumulation or persistence AMI is odnyh fibrils, including, but not limited to, the fibrils of amyloid protein selected from the Aβ amyloid, AA amyloid, AL amyloid, IAPP amyloid, PrP amyloid, α2-macroglobulinemia amyloid, transthyretin, prealbumin and procalcitonin. These diseases include, but are not limited to, Alzheimer's disease, down's syndrome, Boxing dementia, multiple system atrophy, myopathy with inclusions of Taurus, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, disease Neumann-Pick type C, cerebral β-amyloid angiopathy, dementia associated with cortical basal degeneration, the amyloidosis of type 2 diabetes, the amyloidosis of chronic inflammation, the amyloidosis malignancy and familial Mediterranean fever, the amyloidosis of multiple myeloma and B-cell dyscrasia, amyloidosis Pranovich diseases, disease Creutzfeldt-Jakob syndrome of Gerstman-Straussler, Kuru, scrapie, the amyloidosis associated with carpal tunnel syndrome, senile cardiomyocytes, family amyloidotic polyneuropathy and the amyloidosis associated with endocrine diseases.

In the sense used here, the term "sinucleanse disease" or "synucleinopathies" refers to diseases associated with the formation, deposition, accumulation or persistence synuclein Phi is ill, including, but not limited to, α-synuclein fibrils. These diseases include, but are not limited to, Parkinson's disease, familial Parkinson's disease with calves Levi, variant Alzheimer's disease with calves Levi, dementia with calves Levi, multiple system atrophy and complex Parkisonism-dementia of GUAM island.

The term "fibrillogenesis" refers to the formation, deposition, accumulation and/or persistence of amyloid fibrils, filaments, inclusions, deposits, as well as synuclein (usually consisting of α-synuclein) and/or NAC fibrils, filaments, inclusions, deposits or other

The term "inhibition of fibrillogenesis" refers to inhibiting the formation, deposition, accumulation and/or persistence of these amyloid fibrils or sinucleanse fibrillatory deposits.

"The destruction of fibrils or fibrillogenesis" refers to the destruction of previously formed amyloid or synuclein fibrils, which are usually predominantly in the β-folded lamellar secondary structure. Specified destruction here represented by compounds may include a noticeable reduction or removal of amyloid or synuclein fibrils, which assess a variety of ways, such as fluorometry with thioflavin T, the binding of Congo red, SDS-PAGE/Western blot testing, as demonstrated by the examples presented in this application.

The term "mammal" includes both humans and other mammals, such as Pets (cats, dogs etc), laboratory animals (such as mice, rats, Guinea pigs etc) and household animals (cattle, horses, sheep, goats, pigs and the like).

The term "pharmaceutically acceptable excipient" means excipient, which is usually used in obtaining pharmaceutical compositions, which are usually safe, non-toxic and desirable, and includes excipients that are acceptable for veterinary use, or for pharmaceutical use in humans. These excipients can be solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous.

The term "therapeutically effective amount" means an amount, which when administered to a subject or an animal for treatment of the disease is sufficient to achieve the desired degree of treatment, prevention or symptoms improvement in the disease. "Therapeutically effective amount" or "therapeutically effective dose" in some embodiments, inhibit, reduce, destroy, dismantle the formation, deposition, accumulation and/or persistence of amyloid or synuclein fibrils or treats, done by the screens prevent or facilitate one or more of the symptoms of the disease, associated with the specified conditions, such as amyloid disease or synucleinopathies, in the measured quantity in one embodiment, at least 20%, in another embodiment, at least 40%, in another embodiment at least 60%, and in yet another variant, at least 80% compared to not exposed to processing entity. Effective amounts presented here compounds or their compositions for the treatment of mammals range from about 0.1 to about 1000 mg/kg body weight of the subject per day, for example from about 1 to about 100 mg/kg/day, in another embodiment from about 10 to about 100 mg/kg/day. Consider that a wide range of doses disclosed compositions is both safe and effective.

The term "component with delayed allocation" is defined here as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or combinations thereof, to facilitate slow release of active ingredient.

If the complex is soluble in water, it can be prepared in a suitable buffer, such as phosphate buffered saline or other physiologically compatible solutions. In another embodiment, if the resulting complex is poorly soluble in aqueous solvents, then it can be prepared with neio the major surface-active agent, such as Tween or polyethylene glycol. Thus, the compounds and their physiological solvents can be prepared, for example, for administration by inhalation or insufflation (or through the mouth or through the nose) or oral, buccal, parenteral or rectal administration.

In the sense, as used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, complex orthoepy, hemiacetal, hemiketal, solvate, hydrate or proletarienne form. Such derivatives can easily get specialists using known methods for obtaining such derivatives. The compounds obtained can be entered to animals or humans without substantial toxic effects, regardless of whether they are pharmaceutically active or are proletarienne forms. Pharmaceutically acceptable salts include, but are not limited to, salts of amines, such as, but not limited to, N,N'-dibenziletilendiaminom, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyethylamine, Ethylenediamine, N-methylglucamine, procaine, N-benzylpenicillin, 1-pair-of chlorbenzyl-2-pyrrolidin-1'-iletilmesinden, diethylamine and other bonds alkylamines, piperazine and Tris(hydroxymethyl)aminomethane; alkali metal salts, t is such as, but not limited to, lithium, sodium and potassium; salts of alkaline earth metals such as, but not limited to, barium, calcium and magnesium; salts of transition metals, such as, but not limited to, zinc; and salts of other metals, such as, but not limited to, sodium phosphate and centripetal; and also including, but not limited to, salts of mineral acids, such as, but not limited to, hydrochloride and sulfates; and salts of organic acids, such as, but not limited to, acetates, lactates, malaty, tartratami, citrates, ascorbates, succinate, butyrate, valerate and fumarate. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkeline, alkyline, aryl, heteroaryl, kalkilya, heteroalkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acid, phosphoric acid, phosphinic acid, sulfonic acid, sulfinate acid and boranova acid. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula

C=C(OR)where R is hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl or g is eroticly. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R), where R is hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable solvate and hydrates are complexes of the compounds with one or more molecules of solvent or water, or from 1 to about 100, or from 1 to about 10, or from one to about 2, 3 or 4 molecules of solvent or water.

In the sense used here, the term "treatment" means any method by which one or more symptoms of diseases or disorders weakened or changed in a favorable direction. The treatment also includes the prevention of a disease in respect of the subject which may be predisposed to a specific disease, but have yet to experience or do not show symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or stopping its development), providing relief of symptoms or side effects of the disease (including palliative treatment), and the weakening of the disease (causing regression of the disease), for example, by the destruction of previously formed amyloid or synuclein fibrils. One way to prevent such diseases may be the use of the proposed connections to moderate weakening of cognitive abilities (MCI).

In the sense used here, the expression "the weakening of the symptoms of a specific disease by introducing a specific compound or pharmaceutical composition" refers to any weakening regardless of whether it is permanent or temporary, lasting or transient that can be attributed to or associated with the introduction of the specified composition.

In the sense used here, the term "NAC" (non-Aβ component) represents a peptide fragment of α-synuclein composed of 35 amino acids, which is similar to α-synuclein has the ability to form amyloidogenic fibrils, if it is incubated at 37°C, and it is positive in relation to amyloid dyes, such as Congo red (demonstrating in polarized light birefringence type red/green) and tioflavin S (demonstrating positive fluorescence) (Hashimoto et al., Brain Res. 799:301-306, 1998; Ueda et al., Proc. Natl. Acad. Sci U.S.A. 90:11282-11286, 1993). Consider that the inhibition of the formation, deposition, accumulation, aggregation and/or persistence NAC fibrils can be an effective method for the treatment of several disorders associated with α-synuclein, such as Parkinson's disease Taurus Levi and multiple system atrophy.

In the sense used here, the term "proletarienne form" refers to a connection that after the introduction of in vivo Prem is pevet metabolism on one or more of the stages of the process or in some other way is converted to the biologically, pharmaceutically or therapeutically active form of connection. To obtain proletarienne form pharmaceutically active compound modified so that the active connection could recover as a result of metabolic processes. Proletarienne forms can be designed to alter the metabolic ability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the taste of the medicine or alter other characteristics or properties of drugs. If it is known pharmaceutically active compound, on the basis of knowledge of pharmacodynamic processes and drug metabolism in vivo experts in this field can create proletarienne forms of the compounds (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

It should be understood that the present compounds may contain chiral centers. These chiral centers may have either (R) or (S) configuration, or may have a mixture. Thus, the present compounds may be enantiomerically pure, or to submit a stereoisomeric or diastereoisomer mixture. In the case of amino acid residues, these residues can be either L - or D-form. The configuration of the natural amino acid OS is Atkov usually corresponds to an L-shape. If no specific instructions, I mean L-shape. In the sense used here, the term "amino acid" refers to α-amino acids that may be racemic or may have, or D - or L-configuration. The symbol "d" in front of an amino acid (e.g., dAla, dSer, to dval etc) belongs to the D-isomer amino acids. The designation "dl" amino acids (e.g., dlPip) refers to a mixture of L - and D-isomers of amino acids. It should be understood that the chiral centers of the compounds represented here can undergo the epimerization in vivo. In essence, the person skilled in the art it should be clear that the introduction of the compound in its (R) form is equivalent to (for compounds that undergo epimerization in vivo) introducing the compound in its (S) form.

In the sense used here, the term "almost pure means sufficiently homogeneous, apparently do not contain easily identifiable impurities in the study of standard analytical methods such as thin layer chromatography (TLC), electrophoresis in the gel, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by experts to assess such purity, or sufficiently pure, so that further purification is not significantly change the physical and chemical properties, such as enzymatic and biological activity of substances. the ways cleaning compounds to obtain practically chemically pure compounds known in the art. Almost chemically pure compound may, however, be a mixture of stereoisomers. In such cases, further treatment may increase the specific activity of the connection.

In the sense, as used herein, the terms "alkyl", "Alchemilla" and "Alchemilla carbon chains, if no specific instructions are chains that contain from 1 to 20 carbon atoms or from 1 or 2 to 16 carbon atoms and can be unbranched or branched. Alkeneamine carbon chain comprising from 2 to 20 carbon atoms, in some embodiments, contain 1 to 8 double bonds, and alkeneamine carbon chains of 2 to 16 carbon atoms, in some embodiments, contain 1-5 double bonds. Alkyline carbon chain comprising from 2 to 20 carbon atoms, in some embodiments, contain 1-8 triple relations, and alkyline carbon chains of 2 to 16 carbon atoms, in some embodiments, contain 1-5 triple bonds. Examples of alkyl, alkenyl and etkinlik groups here include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, allyl (propenyl) and propargyl (PROPYNYL). In the sense, as used herein, the terms "lower alkyl", "lower alkenyl" and "lower quinil" autosets is to carbon chains, containing from about 1 or from about 2 carbon atoms up to about 6 carbon atoms. In the sense used here, the term "ALK(EN)(Il)Il" refers to an alkyl group containing at least one double bond and at least one triple bond.

In the sense used here, the term "cycloalkyl" refers to a saturated mono - or polycyclic ring system containing in some embodiments, from 3 to 10 carbon atoms, in other embodiments from 3 to 6 carbon atoms; cycloalkenyl and cycloalkenyl refers to mono - or polycyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenyl and cycloalkenyl groups may, in some embodiments, contain from 3 to 10 carbon atoms, and cycloalkenyl group, in other embodiments, contain from 4 to 7 carbon atoms, and cycloalkenyl group, in other embodiments, contain from 8 to 10 carbon atoms. Ring system cycloalkyl, cycloalkenyl and cycloalkyl groups can consist of one ring or two or more rings, which can be joined together as a condensed, bridged or spinosissima. The term “cyclol(EN)(INF)Il” refers to cycloalkyl group containing at least one double bond and at least one triple bond.

In the sense used here, the term "aryl" refers to aromatic monocyclic or polycyclic group containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl.

In the sense used here, the term "heteroaryl" refers to monocyclic or polycyclic aromatic ring system containing, in some embodiments, from about 5 to about 15 members where one or more, in one embodiment 1 to 3 of the atoms in the ring system is a heteroatom, that is, the element that is different from carbon, including, but not limited to, nitrogen, oxygen or sulfur. Heteroaryl group may be optionally condensed with a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, triazolyl, chinoline and ethenolysis.

In the sense used here, the term "heterocyclyl" refers to monocyclic or polycyclic aromatic ring system, in one embodiment, consisting of 3-10 members, in another embodiment of 4-7 members and another one is a variant of 5-6 members, where one or more, in some embodiments 1-3 of the ring atoms is a heteroatom, that is, the element that is different from carbon, including, but not limited to, nitrogen, oxygen or sulfur. In those embodiments, where the heteroatom (heteroatoms) represents nitrogen, the aforementioned nitrogen is optionally substituted by alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkylation, heterocyclisation, acyl, guanidino, or the nitrogen may be quaternity with the formation of the ammonium group, where the substituents are chosen as above.

In the sense used here, the term "aralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl substituted aryl group.

In the sense used here, the term "heteroalkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl substituted heteroaryl group.

In the sense, as used herein, the terms "halo", "halogen" or "halide" refers to F, Cl, Br or I.

In the sense used here, the term "pseudohalogen or pseudohalogen group" represents a group that behave pretty much the same as the halides. Such compounds can be used in the same way and processed in the same way as the halides. Pseudo LoginID include, but not limited to, cyanide, cyanate, thiocyanate, selenocyanate, triptoreline and azide.

In the sense used here, the term "halogenated" refers to an alkyl group in which one or more hydrogen atoms replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, and 1-chloro-2-feratel.

In the sense used here, the term "halogenoalkane" refers to a group of RO-in which R represents halogenoalkane group.

In the sense, as used herein, the terms "sulfinil" or "tional" refers to-S(O)-. In the sense, as used herein, the terms "sulfonyl" or "tional" refers to-S(O)2-. In the sense used here, the term "sulfo" refers to-S(O)2O-.

In the sense used here, the term "carboxy" refers to the divalent radical, -C(O)O-.

In the sense used here, the term "aminocarbonyl" applies to

-C(O)NH2.

In the sense used here, the term "alkylaminocarbonyl" refers to the group-C(O)other, in which R is alkyl, including lower alkyl. In the sense used here, the term "dialkylaminoalkyl” refers to the group-C(O)NR'r R, in which R' and R each independently is alkyl, including lower alkyl; carboxamide" refers to a group of formula-NR'r COR, in which the Oh R' and R each independently represents alkyl, including lower alkyl.

In the sense used here, the term "arylalkylamines" refers to the group-C(O)NRR', in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R' is alkyl, including lower alkyl.

In the sense used here, the term "allumination” refers to the group-C(O)other, in which R is aryl, including lower aryl, such as phenyl.

In the sense used here, the term "hydroxycarbonyl" refers to-COOH.

In the sense used here, the term "alkoxycarbonyl" refers to the group-C(O)OR where R is alkyl, including lower alkyl.

In the sense used here, the term "aryloxyalkyl" refers to the group-C(O)OR where R is aryl, including lower aryl, such as phenyl.

In the sense, as used herein, the terms "alkoxy" and "alkylthio" refers to the group RO - and RS-, in which R is alkyl, including lower alkyl.

In the sense, as used herein, the terms "aryloxy and aaltio" refers to the group RO - and RS-, in which R is aryl, including lower aryl, such as phenyl.

In the sense used here, the term "alkylene" refers to an unbranched, branched or cyclic, in some embodiments, an unbranched or branched, divalent Alif the political hydrocarbon group, in one embodiment, consisting of from 1 to about 20 carbon atoms, in another embodiment, consisting of 1-12 carbon atoms. In yet another embodiment, alkylen includes a lower alkylene. In alkylenes group can be optionally inserted one or more atoms of oxygen, sulfur, including S(=O) and S(=O)2group, or substituted or unsubstituted nitrogen atoms, including-NR -, and-N+RR - group, where a Deputy (deputies) of nitrogen are alkyl, aryl, aralkyl, heteroaryl, heteroalkyl or COR'where R' is alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, -OY or-NYY, where Y represents hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-(CH2)3-), methylenedioxy (-O-CH2-O -), Ethylenedioxy (-O-(CH2)2-O-). The term "lower alkylene" refers to alkalinous group containing 1-6 carbon atoms. In some embodiments alkalinous group is lower alkylene, including alkylen consisting of 1-3 carbon atoms.

In the sense used here, the term "Isaakyan" refers to the group -(CRR)n-NR-(CRR)m-, where n and m each independently represents an integer from 0 to 4. In the sense used here, the term "oxyalkylene" refers to the group -(CRR)n-O-(CRR)m

In the sense used here, the term "talkiin" refers to the groups -(CRR)n-S-(CRR)m-, -(CRR)n-S(=O)-(CRR)m- and -(CRR)n-S(=O)2-(CRR)m-, where n and m each independently represents an integer from 0 to 4.

In the sense used here, the term "albaniles" refers to an unbranched, branched or cyclic, in one embodiment, an unbranched or branched, divalent aliphatic hydrocarbon group, in some embodiments contain from 2 to about 20 carbon atoms and at least one double bond, in other embodiments 1-12 carbon atoms. In other embodiments, alkenylamine groups include lower albaniles. In alkenylamine group can be optionally inserted one or more atoms of oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the Deputy nitrogen is alkyl. Alkenylamine groups include, but are not limited to, -CH=CH-CH=CH - and-CH=CH-CH2-. The term "lower albaniles" refers to alkenylamine groups containing 2-6 carbon atoms. In some embodiments alkenylamine groups are lower alkenylamine groups, including albaniles containing 3 to 4 carbon atoms.

In the sense used here, the term "akinyan" refers to closely evennou, branched or cyclic, in some embodiments, an unbranched or branched, divalent aliphatic hydrocarbon group, in one of the variants containing from 2 to about 20 carbon atoms and at least one triple bond, in another embodiment from 1 to 12 carbon atoms. In another embodiment, akinyan includes a lower akinyan. In alkynylamino group can be optionally inserted one or more atoms of oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the Deputy nitrogen is alkyl. Alkenylamine groups include, but are not limited to,

-C≡C-C≡C-, -C≡C - and-C≡C-CH2-. The term "lower akinyan" refers to alkynylaryl groups containing 2-6 carbon atoms. In some embodiments alkenylamine groups are lower alkenylamine groups, including akinyan containing 3 to 4 carbon atoms.

In the sense used here, the term "ALK(EN)(Jn)ilen" refers to an unbranched, branched or cyclic, in some embodiments, an unbranched or branched, divalent aliphatic hydrocarbon group, in one of the variants containing from 2 to about 20 carbon atoms, and at least one triple bond, and at least one double bond, in another embodiment from 1 to 12 carbon atoms. In another embodiment, ALK(EN)(Jn)ilen includes n is SSI ALK(EN)(Jn)ilen. In alkynylamino group can be optionally inserted one or more atoms of oxygen, sulfur or substituted or unsubstituted nitrogen atoms, where the Deputy nitrogen is alkyl. ALK(EN)(Jn)renovia groups include, but are not limited to, -C=C-(CH2)n-C≡C-, where n is 1 or 2. The term "lower ALK(EN)(Jn)ilen" refers to ALK(EN)(Jn)imanovym groups containing up to 6 carbon atoms. In some embodiments, ALK(EN)(Jn)renovia groups contain about 4 carbon atoms.

In the sense used here, the term "cycloalkyl" refers to divalent saturated mono - or polycyclic ring system, in some embodiments, consisting of 3-10 carbon atoms, in other embodiments 3-6 carbon atoms; cycloalkenyl and cycloalkenyl refer to bivalent mono - or polycyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenyl and cycloalkenyl groups may, in some embodiments, contain from 3 to 10 carbon atoms, and cycloalkenyl group in some embodiments contain from 4 to 7 carbon atoms, and cycloalkanones group in some embodiments contain from 8 to 10 carbon atoms. Ring system cycloalkanones, cycloalkanones, cycloalkene the ene groups can consist of one ring or two or more rings, which can be joined together as a condensed, bridged or spirotrichous. The term "cyclol(EN)(Jn)ilen" refers to cycloalkanones group containing at least one double bond and at least one triple bond.

In the sense used here, the term "Allen" refers to monocyclic or polycyclic, in some embodiments, monocyclic, divalent aromatic group, one of the variants containing from 5 to about 20 carbon atoms and at least one aromatic ring, in another embodiment, containing from 5 to 12 carbon atoms. In other embodiments, Allen includes a lower arisen. Allenbyi groups include, but are not limited to, 1,2-, 1,3 - and 1,4-phenylene. The term "lower Allen" refers to Allenby groups containing 6 carbon atoms.

In the sense used here, the term "heteroaryl" refers to a divalent monocyclic or polycyclic aromatic ring system, in one embodiment contains from about 5 to about 15 atoms in the ring (rings), where one or more, in some embodiments from 1 to 3, of the atoms in the ring system is a heteroatom, that is, elements that are different from carbon, including, but not limited to, nitrogen, oxygen or sulfur. The term "lower heteroaryl" refers to GE eroyalnavy groups, containing 5 or 6 atoms in the ring.

In the sense used here, the term "heterocyclyl" refers to a divalent monocyclic or polycyclic non-aromatic ring system, in some embodiments, consisting of 3-10 members, in one embodiment of 4-7 members, in another embodiment of 5-6 members, where one or more, including 1 to 3 of the atoms in the ring system is a heteroatom, that is, elements that are different from carbon, including, but not limited to, nitrogen, oxygen or sulfur.

In the sense, as used herein, the terms "substituted alkyl","substituted alkenyl", "substituted quinil", "substituted cycloalkyl", "substituted cycloalkenyl", "substituted cycloalkenyl", "substituted aryl", "substituted heteroaryl", "substituted heterocyclyl", "substituted alkylene", "substituted albaniles", "substituted akinyan", "substituted cycloalkyl", "substituted cycloalkenyl", "substituted cycloalkenyl", "substituted Allen", "substituted heteroaryl" and "substituted heterocyclyl" refer to alkyl, alkenylphenol, alkenylphenol, cycloalkyl, cycloalkenyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, alkilinity, alkenylamine, alkynylamino, cycloalkanones, cycloalkanones, cycloalkanones, Allenova, heteroarenes and geterotsiklicheskikh groups is m, respectively, which is substituted by one or more substituents, in some embodiments, one, two, three or four substituents, where the substituents have the values defined here, in one embodiment, the substituents selected from Q'.

In the sense used here, the term "alkylidene" refers to a divalent group, such as=CR'R", which are attached to one another atom group forming a double bond. Alkylidene groups include, but are not limited to, Meriden (=CH2and ethylidene (=CHCH3). In the sense used here, the term "arylalkylamine" refers to alkylidene group, or R', or R" represents an aryl group. "Cycloalkylcarbonyl" groups are those groups in which R' and R" are associated with the formation of a carbocyclic ring. "Heterocyclisation" groups are such groups, where at least one of R' and R" contains a heteroatom in the chain, and R' and R" are associated with the formation of heterocyclic rings.

In the sense used here, the term "amido" refers to the divalent group-C(O)NH-. "Thioamide" refers to the divalent group-C(S)NH-. "Acetamide" refers to the divalent group-OC(O)NH-. "Thioamide" refers to the divalent group-SC(O)NH-. "Dicyanamide" refers to the divalent group-SC(S)NH-. "Ureido" refers to the divalent group-HNC(O)NH-. "Tio is reido" refers to the divalent group-HNC(S)NH-.

In the sense used here, the term "formation" refers to-NHC(O)NHNH-. "Carboset" refers to the divalent group-OC(O)NHNH-. "Isothiocyanate" refers to the divalent group-SC(O)NHNH-. "Thiocarbonate" refers to the divalent group-OC(S)NHNH-. "Sulfonylhydrazide" refers to the divalent group-SO2NHNH-. "Hydrazide" refers to the divalent group-C(O)NHNH-. "Azo" refers to the divalent group-N=N-. "Hydrazine" refers to the divalent group-NH-NH-.

If not specified the number of any substituents (for example, halogenated), can be present one or more substituents. For example, "halogenoalkane" can include one or more of the same or different Halogens. As another example, example "C1-3alkoxyphenyl may include one or more of the same or different alkoxygroup containing one, two or three carbon atom.

In the sense, as used herein, the abbreviations for any protective groups, amino acids and other compounds correspond, unless otherwise indicated, conventional use of known abbreviations or information on IUPAC-IUB Commission on Biochemical Nomenclature (see(1972) Biochem. 77:942-944).

C. Connections

In the present invention proposed compounds and pharmaceutical compositions containing the compounds of the formulas:

or

or pharmaceutically acceptable derivative, where R is chosen as follows: 1) R is CONR' or 2) R represents a C1-C10alkylenes group, in which: (a) if the number of carbon atoms is at least 2, optionally contains 1 or 2 double bonds; (b) 1-3 non-adjacent methylene groups are optionally replaced by NR', O or S; (c) 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and (d) 1 or 2 methylene groups are optionally replaced cycloalkyl or heterocyclyl group, which is optionally substituted by one or more substituents selected from lower alkyl, NR', O or S;

R' represents H, alkyl or acyl;

A1and B1each independently selected from halogen, pseudohalogen, nitro,+NH3, SO3H, carboxy and halogenoalkane;

t and v each independently represents 0-3;

R1, R2, R3and R4each independently chosen as follows:

i) R1, R2, R3and R4each independently selected from OH, -NR5C(=O)R6and-NR7S(O2R8where R5and R7each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or illegal is ewenny heteroalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted geterotsiklicheskikh; and R6and R8each independently represents a substituted or unsubstituted alkoxy, substituted or unsubstituted, Alcoxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or-NR9R10where R9and R10each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclic provided that at least one of R1, R2, R3and R4is not OH;

ii) R1and R2and/or R3and R4together represent-NH-C(=O)-NH-, -NH-S(O2)-NH-, -CH2-C(=O)-NH - or-CH2-S(O2)-NH and together with the carbon atoms to which they are attached, form a 5-membered heterocyclic ring, and the other of R1, R2, R3and R4each independently is chosen as in (i); or

iii) at least one of R1, R2, R3and R4is

-NH-CRa=CRb- or-NH-S(O2)CRcRdand together with two adjacent carbon atoms of the phenyl ring forms a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaromatic ring, and the other of R1, R2, R and R4each independently is chosen as in i) or ii); where Ra, Rb, Rcand Rdeach independently represents hydrogen or substituted or unsubstituted alkyl,

where the substituents, when present, is selected from one or more substituents, in one embodiment one to three or four substituents, each of which is independently selected

of Q1where Qlrepresents halogen, pseudohalogen, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonyl, alkyl, halogenated, POLYHALOGENATED, aminoalkyl, diaminoalkyl, alkenyl containing 1-2 double bonds, quinil containing 1-2 triple bond, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, heteroaryl, aralkyl, aralkyl, aralkyl, heteroaromatic, trialkylsilyl, dialkylanilines, alkyldimethyl, triallelic, alkylidene, arylalkylamine, alkylsulphonyl, arylcarbamoyl, heteroarylboronic, alkoxycarbonyl, alkoxycarbonylmethyl, aryloxyalkyl, aryloxyalkyl, arelaxation, alcoxycarboxylates, arylcarboxylic, aminocarbonyl alkylaminocarbonyl, dialkylaminoalkyl, allumination, dietilaminoetanola, arylalkylamines, alkoxy, aryloxy, heteroaromatic, heteroaromatic, heterocyclic, cycloalkane, performace, the alkene is lexi, alkyloxy, Alcoxy, alkylcarboxylic, arylcarboxylic, aralkylamines, alkoxycarbonyl, aryloxypropanolamine, aramcobrats, aminocarboxylate, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dietilaminoetanola, guanidino, isothiourea, ureido, N-allylurea, N-amiloride, N'-allylurea, N',N'-dialkylamino, N'-alkyl-N'-amiloride, N',N'-diarylamino, N'-amiloride, N,N'-dialkylamino, N-alkyl-N'-amiloride, N-aryl-N'-allylurea N,N'-diarylamino, N,N',N'-trialkylamine, N,N'-dialkyl-N'-amiloride, N-alkyl-N',N'-diarylamino, N-aryl-N',N'-dialkylamino, N,N'-diaryl-N'-allylurea, N,N',N'-trailored, amidino, alkylamino, arylamino, imino, hydroxyimino, alkoxyimino, arylacetamide, arelaxing, alkylate, arylazo, aralkylated, aminothiazolyl, alkylaminocarbonyl, allumination, amino, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, alluminati, diarylamino, alkylarylsulfonates, alkylamino, dialkylamino, halogenoalkanes, arylamino, diarylamino, alkylamino, alkylcarboxylic, alkoxycarbonyl, alcoxycarbenium, arylcarboxamide, arylcarbamoyl, aryloxypropanolamine, aryloxypropanolamine, aryloxypropanolamine, alkylsulfonyl, arylsulfonyl, heteroarylboronic, GE is eroticlingerie, heteroaromatic, azido,

-N+R51R52R53P(R50)2OP(=O)(R50)2, P(=O)(R50)2, -NR60C(=O)R63, dialkylphenol, alkylarylsulfones, diarylphosphino, hydroxyphosphonic, alkylthio, aaltio, perforatio, hydroxycarbonylmethyl, Tiziano, isothiocyante, alkylsulfonate, alkylsulfonate, arylsulfonate, arylsulfonate, hydroxysulfonic, alkoxycarbonyl, aminosulfonyl, alkylarylsulfonate, dialkylaminoalkyl, allmenareliars, dietilaminsalicilata, alkylarylsulfonate, alkylsulfanyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, hydroxysulfonic, alkoxycarbonyl, aminosulfonyl, alkylaminocarbonyl, dialkylaminoalkyl, arylamination, diarylpyrazole or alkylaminocarbonyl; or two Q1groups, which substitute atoms in a 1,2 - or 1,3-positions together form alkylenedioxy (i.e.- O-(CH2)y-O-), tolkienite (i.e.- S-(CH2)y-O-) or alkylenedioxy (i.e.- S-(CH2)y-S-)where y is 1 or 2; or two Q1the group, which are substituents on the same atom, together form alkylene; where

R50represents hydroxy, alkoxy, Alcoxy, alkyl, heteroaryl, heterocyclyl, aryl, or-NR70R71where R70 and R 71each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclyl, or R70and R71together form alkylene, Isaakyan, oxyalkylene or ticarcillin;

R51, R52and R53each independently represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl or geterotsiklicheskikh;

R60represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl or geterotsiklicheskikh; and

R63represents alkoxy, Alcoxy, alkyl, heteroaryl, heterocyclyl, aryl or

-NR70R71.

In some embodiments, the present compounds have the formula:

or

or their pharmaceutically acceptable derivatives, where R is selected from C1-C10alkalinous group, in which, (a) if the number of carbon atoms is at least 2, optionally contains 1 or 2 double bonds; (b) 1-3 non-adjacent methylene groups are optionally replaced by NR' (where R' represents H, alkyl or acyl), O, or S; (c) 1 or 2 methylene groups are optionally replaced by a carbonyl or hydroxymethylene group; and (d) 1 or 2 methylene groups are optionally replaced cycloalkyl or heterocyclyl group, which is optionally substituted by one or bol is e substituents, selected from lower alkyl, NR' (where R1represents H, alkyl or acyl), O, or S,

R1, R2, R3and R4independently chosen as follows:

i) R1, R2, R3and R4independently selected from OH, -NR5C(=O)R6and-NR7S(O2R8where R5and R7each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted geterotsiklicheskikh; and R6and R8each independently represents a substituted or unsubstituted alkoxy, substituted or unsubstituted, Alcoxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or-NR9R10where R9and R10each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclic provided that at least one of R1, R2, R3and R4not represent OH;

ii) R1and R2and/or R3and R4together represent-NH-C(=O)-NH-, -NH-S(O2)-NH-, -CH2-C(=O)-NH - or-CH2-S(O2)-NH and pax is with carbon atoms, to which they are attached, form a 5-membered heterocyclic ring, and the other of R1, R2, R3and R4independently is chosen as in (i); or

iii) at least one of R1, R2, R3and R4represents-NH-CRa=CRbor

-NH-S(O2)CRcRdand together with two adjacent carbon atoms of the phenyl ring forms a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaromatic ring, and the other of R1, R2, R3and R4independently chosen as in i) or ii); where Ra, Rb, Rcand Rdeach independently represents hydrogen or substituted or unsubstituted alkyl,

where the substituents, when present, is selected from one or more substituents, in one embodiment one to three or four substituents, each of which is independently selected from Q1where Q1represents halogen, pseudohalogen, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonyl, alkyl, halogenated, POLYHALOGENATED, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, quinil containing 1 to 2 triple relations, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, heteroaryl, aralkyl, aralkyl, aralkyl, heteroaromatic, three is lilcely, dialkylanilines, alkyldimethyl, triallelic, alkylidene, arylalkylamine, alkylsulphonyl, arylcarbamoyl, heteroarylboronic, alkoxycarbonyl, alkoxycarbonylmethyl, aryloxyalkyl, aryloxyalkyl, arelaxation, alcoxycarboxylates, arylcarboxylic, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, allumination, dietilaminoetanola, arylalkylamines, alkoxy, aryloxy, heteroaromatic, heteroaromatic, heterocyclic, cycloalkane, performace, alkenylacyl, alkyloxy, Alcoxy, alkylcarboxylic, arylcarboxylic, aralkylamines, alkoxycarbonyl, aryloxypropanolamine, aramcobrats, aminocarboxylate, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dietilaminoetanola, guanidino, isothiourea, ureido, N-allylurea, N-amiloride, N'-allylurea, N',N'-dialkylamino, N'-alkyl-N'-amiloride, N',N'-diarylamino, N'-amiloride, N,N'-dialkylamino, N-alkyl-N'-amiloride, N-aryl-N'-allylurea, N,N'-diarylamino, N,N',N'-trialkylamine, N,N'-dialkyl-N'-amiloride, N-alkyl-N',N'-diarylamino, N-aryl-N',N'-dialkylamino, N,N'-diaryl-N'-allylurea, N,N',N'-trailored, amidino, alkylamino, arylamino, imino, hydroxyimino, alkoxyimino, arylacetamide, arelaxing, alkylate, arylazo, aralkylated, aminothiazolyl, alkylaminocarbonyl, allumination, amino, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, alluminati, diarylamino, alkylarylsulfonates, alkylamino, dialkylamino, halogenoalkanes, arylamino, diarylamino, alkylamino, alkylcarboxylic, alkoxycarbonyl, alcoxycarbenium, arylcarboxamide, arylcarbamoyl, aryloxypropanolamine, aryloxypropanolamine, aryloxypropanolamine, alkylsulfonyl, arylsulfonyl, heteroarylboronic, heterocyclization, heteroaromatic, azido,

-N+R51R52R53P(R50)2, P(=O)(R50)2OP(=O)(R50)2, -NR60C(=O)R63, dialkylphenol, alkylarylsulfones, diarylphosphino, hydroxyphosphonic, alkylthio, aaltio, perforatio, hydroxycarbonylmethyl, Tiziano, isothiocyante, alkylsulfonate, alkylsulfonate, arylsulfonate, arylsulfonate, hydroxysulfonic, alkoxycarbonyl, aminosulfonyl, alkylarylsulfonate, dialkylaminoalkyl, allmenareliars, dietilaminsalicilata, alkylarylsulfonate, alkylsulfanyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, hydroxysulfonic, alkoxycarbonyl, aminosulfonyl, alkylaminocarbonyl, dialkylaminoalkyl, arylamination, diarylamino is of IMT or alkylaminocarbonyl; or two Q1groups, which substitute atoms in a 1,2 - or 1,3-positions together form alkylenedioxy (i.e.- O-(CH2)y-O-), tolkienite (i.e.- S-(CH2)y-O-) or alkylenedioxy (i.e.- S-(CH2)y-S-)where y is 1 or 2; or two Q1the group, which are substituents on the same atom, together form alkylene; where

R50represents hydroxy, alkoxy, Alcoxy, alkyl, heteroaryl, heterocyclyl, aryl, or-NR70R71where R70and R71each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclyl, or R70and R71together form alkylene, Isaakyan, oxyalkylene or ticarcillin;

R51, R52and R53each independently represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl or geterotsiklicheskikh;

R60represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl or geterotsiklicheskikh; and

R63represents alkoxy, Alcoxy, alkyl, heteroaryl, heterocyclyl, aryl or

-NR70R71.

In some embodiments, Q1is oxo, alkyl, halogenated, POLYHALOGENATED, aminoalkyl, diaminoalkyl, alkenyl containing 1-2 double bonds, quinil containing 1-2 triple bond, cycloalkyl, cycloalkenyl is, heterocyclyl, geterotsiklicheskikh, aryl, heteroaryl, aralkyl, aralkyl, aralkyl or heteroaromatic.

In some embodiments, Q1represents oxo or alkyl. In some embodiments, Q1is oxo. In some embodiments, Q1represents alkyl. In some embodiments, Q1is lower alkyl. In some embodiments, Q1represents methyl.

In some embodiments, R' is H or alkyl. In other embodiments, R' is H.

In some embodiments, t is 0, 1 or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 1. In some embodiments, v is 0, 1 or 2. In some embodiments, v is 0 or 1. In some embodiments, v is 1.

In one embodiment, R is -(CH2)mC(O)(CH2)sNH(CH2)r-, -(CH2)P-

or -(CH2)sY(CH2)r-where Y represents cycloalkyl or heterocyclyl group, which is optionally substituted by one or more substituents selected from alkyl, NR', O or S; p is 1-10; and m, s and r each independently represents

0-6.

In one embodiment, R is-C(O)NH, CH2CH2- or -(CH2)Y(CH2)-. In one embodiment, R is-C(O)NH-. In one embodiment, R is-CH2CH2-. In one of the options is anty R is -(CH 2)Y(CH2)-.

In one embodiment, Y represents heterocyclyl, optionally substituted by one or more substituents selected from alkyl and oxo. In one embodiment, Y represents a bridge heterocyclyl, optionally substituted by one or more substituents selected from alkyl and oxo. In one embodiment, Y represents bicycloheptadiene, replaced by stands and oxo. In one embodiment, Y represents bicycloheptadiene, where the heteroatom is N. In another embodiment, Y is

where Q2represents alkyl.

In some embodiments, Y is

In some embodiments, R is substituted alkyl, alkenyl, quinil, cycloalkyl, cycloalkylation, heterocyclyl, heterocyclisation, aryl, heteroaryl, aralkyl or heteroalkyl.

In some embodiments, R is substituted alkyl. In other embodiments, R is substituted by lower alkyl. In some embodiments, R is substituted by the stands.

In another embodiment, compounds for use in the proposed compositions and methods represented by the formula:

In another embodiment, compounds for use in the proposed compositions and methods represented by the formula:

In some embodiments, R1, 2, R3and R4independently selected from

i) OH, formylamino, alkylamide, alkylolamides, aralkylated, arylamino, N-alkyl-N-alkylsulfonamides, alkylsulfonamides, alkylarylsulfonates, arylsulfonamides or aralkylated provided that at least one of R1, R2, R3and R4is not OH;

ii) R1and R2and/or R3and R4together represent-NH-C(=O)-NH-, -NH-S(O2)-NH-, -CH2-C(=O)-NH - or-CH2-S(O2)-NH and together with the carbon atoms to which they are attached, form a 5-membered heterocyclic ring, and the other of R1, R2, R3and R4independently is chosen as in (i); or

iii) at least one of R1, R2, R3and R4represents-NH-CRa=CRbor

-NH-S(O2)CRcRdand together with two adjacent carbon atoms of the phenyl ring forms a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaromatic ring, and the other of R1, R2, R3and R4independently chosen as in i) or ii); where Ra, Rb, Rcand Rdeach independently represents hydrogen or alkyl.

In one embodiment, R1, R2, R3and R4each independently represents OH, formulated, alkylamide, alkylsilane, aralkylated, arylamide, alkylsulfonate, N-alkyl-N-alkylsulfonamides, alkylarylsulfonate, arylsulfonate or aralkylated provided that at least one of R1, R2, R3and R4is not OH.

In another embodiment, R1, R2, R3and R4each independently represents OH, formulated or alkylsulfonate provided that at least one of R1, R2, R3and R4is not OH.

In another embodiment, R1, R2, R3and R4each independently represents OH, formulated or methylsulfonate provided that at least one of R1, R2, R3and R4is not OH.

In another embodiment, R1and R2and/or R3and R4together represent-NH-C(=O)-NH - and the other of R1, R2, R3and R4each independently represents OH, formulated, alkylsulfonate. In another embodiment, R1and R2together represent

-NH-C(=O)-NH-, and R3and R4each independently represents OH, formulated or methylsulfonate.

In another embodiment, R3and R4together represent-NH-C(=O)-NH - and R1and R2each independently represents OH, formulated or methylsulfonate.

In another embodiment, at least one of R1, R2, R3or R4is

-NH-CRa=CRb- or-NH-S(O2)CRc Rdand together with two adjacent carbon atoms of the phenyl ring forms a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaromatic ring, and the other of R1, R2, R3and R4independently chosen as in i) or ii); where Ra, Rb, Rcand Rdeach independently represents hydrogen or alkyl, and the other of R1, R2, R3and R4each independently selected from OH, formylamino, alkylamide, alkylolamides, aralkylated, arylamide, alkylsulfonamides, alkylarylsulfonates, arylsulfonamides and aralkylated.

In another embodiment, at least one of R1, R2, R3or R4is

-NH-CH=CH - and together with two adjacent carbon atoms of the phenyl ring forms an indole ring, and the other of R1, R2, R3and R4independently selected from OH, formylamino, alkylamide, alkylolamides, aralkylated, arylamide, alkylsulfonamides, alkylarylsulfonates, arylsulfonamides and aralkylated.

In another embodiment, at least one of R1, R2, R3or R4is

-NH-CH=CH - and together with two adjacent carbon atoms of the phenyl ring forms an indole ring, and the other of R1, R2, R3and R4each independently selected from OH, fo is Melamid and methylsulfonate.

In another embodiment, at least one of R1, R2, R3or R4is

-NH-S(O2)CH2and together with two adjacent carbon atoms of the phenyl ring forms benzisothiazole-1,1-dioxide, and the other of R1, R2, R3and R4each independently selected from OH, formylamino and methylsulfonate.

In some embodiments, the compounds have a formula selected from:

and

where (i) if M is C(O)Rxrepresents hydrogen or alkyl, and

ii) if M is S(O)2, Rxrepresents alkyl. In one embodiment, M is C(O) and Rxrepresents alkyl. In one embodiment, M is C(O) and R5represents isopropyl. In one embodiment, M represents S(O)2and Rxrepresents methyl.

In some embodiments, the compounds have a formula selected from:

and

In some embodiments, the compounds have a formula selected from:

and

In other embodiments, compounds are selected from compounds of the following formulas:

and

In some embodiments, compounds have the formula:

or,

where A2, A3B2and B3independently selected from halogen, cyanide, cyanate, thiocyanate, selenocyanate, triptoreline, azide, nitro and trifloromethyl;

R1, R2, R3and R4choose the following way:

i) R1and R2represent OH, and R3and R4each independently chosen, as here specified, or

ii) R3and R4represent IT, and R1and R2each independently chosen, as is indicated here, and the other variables have the values defined here.

In some embodiments, the compound has the formula:

where A2, A3B2and B3independently selected from halogen, pseudohalogen, nitro,+NH3, SO3H, carboxy and halogenoalkane; and the other variables have the values defined here.

In some embodiments, the compound has the formula:

or

where the variables have the values defined here.

In some embodiments, the compound has the formula:

or

where the variables have the values defined here.

In one embodiment, the compound is chosen from 2-oxo-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; N-(3,4-dihydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; and 3,4-dihydroxy-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)benzamide.

In another one embodiment, the compound is chosen from 3,4,3',4'-tetrahydroxybenzophenone; 3,4,3',4'-tetrahydroxybenzophenone; 3,4,3',4'-tetrahydroxyphenyl; 1,2-bis(3,4-dihydroxyphenyl)ethane; 1,3-bis(3,4-dihydroxyphenyl)propane; 3,4,3',4'-tetrahydroquinoline; 3,5-bis(3,4-dihydroxyphenyl)-1-methyl-2-pyrazoline; 4,6-bis(3,4-dihydroxyphenyl)-3-cyano-2-methylpyridine; 1,4-bis(3,4-dihydroxybenzyl)piperazine; N,N'-bis(3,4-dihydroxybenzyl)-N,N'-dimethylethylenediamine; 2,5-bis(3,4-dihydroxybenzyl)-2,5-diaza[2.2.1]bicycloheptane; N,N'-bis(3,4-dihydroxybenzyl)-TRANS-1,2-diaminocyclohexane; N,N'-bis(3,4-dihydroxybenzyl)-TRANS-1,4-diaminocyclohexane; N,N'-bis(3,4-dihydroxybenzyl)-CIS-1,3-bis(aminomethyl)cyclohexane; N-(3,4-dihydroxybenzyl)Proline-3,4-dihydroxybenzylamine; 3,4-dihydroxyphenethylamine 2-(3,4-dihydroxybenzyl)isoquinoline-3-carboxylic acid; 2,6-bis(3,4-dihydroxybenzyl)cyclohexanone; 3,5-bis(3,4-dihydroxybenzyl)-1-methyl-4-piperidinol; 2,4-bis(3,4-dihydroxybenzyl)-3-tropinona; Tris(3,4-dihydroxybenzyl)methane; 3,4-dihydroxybis is ylamide α-(3,4-dihydroxybenzamide)-3,4-dihydroxytrino acid; 4-(3,4-dihydroxybenzylamine)-2-(3,4-dihydroxyphenyl)oxazoline-5-it; 1,4-bis(3,4-dihydroxybenzyl)piperazine; N,N'-bis(3,4-dihydroxybenzyl)-N,N'-dimethylethylenediamine; 2,5-bis(3,4-dihydroxybenzyl)-2,5-diaza[2.2.1]bicycloheptane; N,N'-bis(3,4-dihydroxybenzyl)-TRANS-1,2-diaminocyclohexane; N,N'-bis(3,4-dihydroxybenzyl)-CIS-1,3-bis(aminomethyl)cyclohexane; 3,6-bis(3,4-dihydroxybenzyl)-2,5-diketopiperazine; 3,6-bis(3,4-dihydroxybenzamide)-1,4-dimethyl-2,5-diketopiperazine; N-(3,4-dihydroxyphenylacetic)Proline-3,4-dihydroquinoline; 2,3-bis(3,4-dihydroxyphenyl)butane; 1,3-bis(3,4-dihydroxybenzyl)benzene; 1,4-bis(3,4-dihydroxybenzyl)benzene; 2,6-bis(3,4-dihydroxybenzyl)pyridine; 2,5-bis(3,4-dihydroxybenzyl)thiophene; 2,3-bis(3,4-dihydroxybenzyl)thiophene; 1,2-bis(3,4-dihydroxyphenyl)cyclohexane; 1,4-bis(3,4-dihydroxyphenyl)cyclohexane; 3,7-bis(3,4-dihydroxyphenyl)bicyclo[3.3.0]octane; 2,3-bis(3,4-dihydroxyphenyl)-1,7,7-trimethylbicyclo[2.2.1]heptane; 1,2-bis(3,4-dihydroxybenzoic)ethane; 1,3-bis(3,4-dihydroxybenzoic)propane; TRANS-1,2-bis(3,4-dihydroxybenzoic)cyclopentane; N-(3,4-dihydroxybenzyl)-3-(3,4-dihydroxybenzoic)-2-hydroxypropylamino; 3,4-dihydroquinoline 3,4-dihydroxyphenylethanol acid; 3,4-dihydroxybenzylamine 3,4-dihydroxyphenylethanol acid; 3,4-dihydroxyphenethylamine 3,4-dihydroxyphenylethanol acid; n-(3,4-dihydroxybenzoic)anilide 3,4-d the hydroxybenzoic acid; o-(3,4-dihydroxybenzoic)anilide 3,4-dihydroxybenzoic acid; 2,6-bis(3,4-dihydroxybenzoic)pyridine; 3,4-dihydroquinoline 3,4-dihydroxybenzoic acid; 3,4-dihydroxybenzylamine 3,4-dihydroxybenzoic acid; 3,4-dihydroxyphenethylamine 3,4-dihydroxybenzoic acid; 3,4-dihydroquinoline 3,4-dihydroxyphenylacetic acid; 3,4-dihydroxybenzylamine 3,4-dihydroxyphenylacetic acid; 3,4-dihydroxyphenethylamine 3,4-dihydroxyphenylacetic acid; 3,4-dihydroquinoline 3-(3,4-dihydroxyphenyl)propionic acid; 3,4-dihydroxybenzylamine 3-(3,4-dihydroxyphenyl)propionic acid; 3,4-dihydroxyphenethylamine 3-(3,4-dihydroxyphenyl)propionic acid; 3,4-dihydroquinoline 3,4-dihydroxytrino acid; 3,4-dihydroxybenzylamine 3,4-dihydroxytrino acid; 3,4-dihydroxyphenethylamine 3,4-dihydroxytrino acid; bis(3,4-dihydroquinoline) oxalic acid; bis(3,4-dihydroxybenzylamine) oxalic acid; bis(3,4-dihydroxyphenethylamine) oxalic acid; bis(3,4-dihydroquinoline) succinic acid; bis(3,4-dihydroxybenzylamine)succinic acid; bis(3,4-dihydroxyphenethylamine) succinic acid; bis(3,4-dihydroquinoline) maleic acid; bis(3,4-dihydroxybenzylamine) maleic acid; bis(3,4-dihydroquinoline) fumaric acid; bis(3,4-dihydroxybenzylamine) fumaric acid; bis(3,4-dihydro shall dibenzyl)amine; N-(3,4-dihydroxybenzyl)-3,4-dihydroxyphenethylamine; Tris(3,4-dihydroxybenzyl)amine; 1,3-bis(3,4-dihydroxyphenyl)urea;

1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxybenzyl)urea; 1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)urea; 3-deoxy-3-(3,4-dihydroxybenzyl)aminopyridine; 3-deoxy-3-(3,4-dihydroxyphenyl)aminopyridine; 2,3,6,7-tetrahydroxy-9,10-epoxy-9,10-dihydrouridine; 10-aminoanthracene-1,2,7,8-tetraol; acridine-1,2,6,7-tetraol; phenoxazin-2,3,7,8,10-pentola; dibenzo[c,f][2,7]naphthiridine-2,3,10,11-tetraol; and 6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,10,11-triol, where at least one of the phenolic hydroxy groups of the compound is replaced by:

i) -NR5C(=O)R6, -NR7S(O2R8where R5and R7each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted geterotsiklicheskikh; and R6and R8each independently represents a substituted or unsubstituted alkoxy, substituted or unsubstituted, Alcoxy, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or illegal is ewenny aryl, or-NR 9R10where R9and R10each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclyl;

ii) R1and R2and/or R3and R4together form benzimidazolinone, benzothiadiazole-S,S-dioxide or benzoxazolinone; or

iii) at least one of R1, R2, R3and R4together with the adjacent carbon atom forms a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaromatic ring, where the substituents, when present, is selected from one or more substituents, each independently selected from Q1where Qlrepresents halogen, pseudohalogen, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonyl, alkyl, halogenated, POLYHALOGENATED, aminoalkyl, diaminoalkyl, alkenyl containing 1-2 double bonds, quinil containing 1-2 triple bond, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, heteroaryl, aralkyl, aralkyl, aralkyl, heteroaromatic, trialkylsilyl, dialkylanilines, alkyldimethyl, triallelic, alkylidene, arylalkylamine, alkylsulphonyl, arylcarbamoyl, heteroarylboronic, alkoxycarbonyl, alkoxycarbonylmethyl, aryloxyalkyl, aryloxyalkyl, arelaxation, alcoxides nilackal, arylcarboxylic, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, allumination, dietilaminoetanola, arylalkylamines, alkoxy, aryloxy, heteroaromatic, heteroaromatic, heterocyclic, cycloalkane, performace, alkenylacyl, alkyloxy, Alcoxy, alkylcarboxylic, arylcarboxylic, aralkylamines, alkoxycarbonyl, aryloxypropanolamine, aramcobrats, aminocarboxylate, alkylaminocarbonyl, dialkylaminoalkyl, alkylaminocarbonyl, dietilaminoetanola, guanidino, isothiourea, ureido, N-allylurea, N-amiloride, N'-allylurea, N',N'-dialkylamino, N'-alkyl-N'-amiloride, N',N'-diarylamino, N'-amiloride, N,N'-dialkylamino, N-alkyl-N'-amiloride, N-aryl-N'-allylurea, N,N'-diarylamino, N,N',N'-trialkylamine, N,N'-dialkyl-N'-amiloride, N-alkyl-N',N'-diarylamino, N-aryl-N',N'-dialkylamino, N,N'-diaryl-N'-allylurea, N,N',N'-trailored, amidino, alkylamino, arylamino, imino, hydroxyimino, alkoxyimino, arylacetamide, arelaxing, alkylate, arylazo, aralkylated, aminothiazolyl, alkylaminocarbonyl, allumination, amino, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, alluminati, diarylamino, alkylarylsulfonates, alkylamino, dialkylamino, halogenosilanes, arylamino, diarylamino, alkylamino, alkitab is ylamino, alkoxycarbonyl, alcoxycarbenium, arylcarboxamide, arylcarbamoyl, aryloxypropanolamine, aryloxypropanolamine, aryloxypropanolamine, alkylsulfonyl, arylsulfonyl, heteroarylboronic, heterocyclization, heteroaromatic, azido,

-N+R51R52R53P(R50)2, P(=O)(R50)2OP(=O)(R50)2, -NR60C(=O)R63, dialkylphenol, alkylarylsulfones, diarylphosphino, hydroxyphosphonic, alkylthio, aaltio, perforatio, hydroxycarbonylmethyl, Tiziano, isothiocyante, alkylsulfonate, alkylsulfonate, arylsulfonate, arylsulfonate, hydroxysulfonic, alkoxycarbonyl, aminosulfonyl, alkylarylsulfonate, dialkylaminoalkyl, allmenareliars, dietilaminsalicilata, alkylarylsulfonate, alkylsulfanyl, alkylsulfonyl, arylsulfonyl, arylsulfonyl, hydroxysulfonic, alkoxycarbonyl, aminosulfonyl, alkylaminocarbonyl, dialkylaminoalkyl, arylamination, diarylpyrazole or alkylaminocarbonyl; or two Q1groups, which substitute atoms in a 1,2 - or 1,3-positions together form alkylenedioxy (i.e.- O-(CH2)y-O-), tolkienite (i.e.- S-(CH2)y-O-) or alkylenedioxy (i.e.- S-(CH2) y-S-)where y is 1 or 2; or two Q1the group, which are substituents on the same atom, together form alkylene; where

R50represents hydroxy, alkoxy, Alcoxy, alkyl, heteroaryl, heterocyclyl, aryl, or-NR70R71where R70and R71each independently represents hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroalkyl or heterocyclyl, or R70and R71together form alkylene, Isaakyan, oxyalkylene or ticarcillin;

R51, R52and R53each independently represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl or geterotsiklicheskikh;

R60represents hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, heterocyclyl or geterotsiklicheskikh; and

R63represents alkoxy, Alcoxy, alkyl, heteroaryl, heterocyclyl, aryl, or-NR70R71.

In some embodiments, the compound is chosen from

In other embodiments, the compound is chosen from

In other embodiments, the compound is chosen from

In some embodiments, the compound is chosen from

In some embodiments, the compound is chosen from

In some embodiments, the connection is

In other embodiments, the compound is chosen from

In other embodiments, the compound is chosen from

In some embodiments, the compound is chosen from

2,4-bis(3,4-dihydroxybenzyl)-8-methyl-8-azabicyclo[3.2.1]Octan-3-one

In some embodiments, provided compounds are of the formula:

where A1and B1independently selected from halogen, pseudohalogen, nitro,+NH3, SO3H, carboxy and halogenoalkane; and t1and v1each independently represents 1-3;

other variables have the values defined here.

In some embodiments, t1and v1each independently represents 1 or 2. In some embodiments, t1is 1. In some embodiments, v1is 1.

In some embodiments, the compound is chosen from

where the variables have the values defined here.

In some embodiments, the compound is chosen from

where A2, A3B2and B3independently selected from Cl, F cyanide, cyanate, thiocyanate, selenocyanate, triptoreline, azide, nitro and trifloromethyl.

C. Receiving connections

The present compounds can be obtained using well-known specialists of the standard methods of synthesis, and they are given here for General schemes. The following examples, the disclosed exemplary embodiments, and they in no way limit the scope of the claimed subject matter of the invention. It is assumed that the description together with the following examples should be considered only as an example, while the amount and nature of the declared object of the invention is defined in the claims which follows these examples. Other options corresponding to the amount of the claims, must be obvious to specialists in this area when considering the present description.

Starting materials and reagents used for obtaining these compounds can either be obtained from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO) or Lancaster Synthesis Inc. (Windham, NH), or get them known in the art methods in accordance with the procedures disclosed in such references as Fieser and Fieser''s Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, NY, 1991; Rodd''s Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-0, John Wiley and Sons, New York, NY, 1991; J. March: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, NY; and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

In most cases, the protective groups for hydroxyl groups are first introduced and in the end removed. Suitable protective groups are disclosed in Greene et al., Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991. Other source materials or early intermediate compounds can be obtained by processing the above materials, for example using methods well-known to specialists in this field. Raw materials, intermediate and presents here the connection can be extracted and cleaned using standard methods, including sedimentation, filtration, distillation, crystallization, chromatography and the like, Compounds of the present invention can be characterized using conventional methods, including physical constants and the results of spectroscopic studies.

Below is a General scheme of reactions to obtain the approximate connections.

i) Achesom et al. J.Med. Chem. (1981) 24, 1300-1304, disclose the use of thionyl chloride to obtain S,S-dioxide benzothiadiazole as follows:

ii) Obtain S,S-dioxide nitrobenzothiazole raskryvayut Burke et al. in JCS Perkin Transactions (1984) 11, 1851-4, as follows:

iii)

In addition to t the th, the present compounds can be obtained by using described in the literature of the reaction, as follows:

Cm. Roberts et al., J.O.Chem. (1997) 62, 568-577.

iv)

Cm. Hughes et al., J. Med.Chem. (1957) 18, 1077-1088.

D. Pharmaceutical compositions and methods of their introduction

The present compounds can be used as they are, you can enter in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, or used in combination with one or more pharmaceutically acceptable excipients. The expression "pharmaceutically acceptable salt" means those salts which from the point of view of medical specialists suitable for use in contact with tissues, do not have undesirable toxicity, and do not cause irritation, allergic reactions, etc. and provide a reasonable ratio of benefit/risk. Pharmaceutically acceptable salts are well known in the art. These salts can be obtained either in situ on the final isolation and purification of compounds represented here, either separately, interacting acidic or alkaline medicinal substance with a suitable base or acid, respectively. Typical salts derived from organic or inorganic acids include, but is s limited to, the hydrochloride, hydrobromide, hydroiodide, acetate, adipate, alginate, citrate, aspartate, benzoate, bisulfate, gluconate, fumarate, hydroiodide, lactate, maleate, oxalate, palmitate, pectinate, succinate, tartrate, phosphate, glutamate, and bicarbonate. Typical salts derived from organic or inorganic bases include, but are not limited to, salts of lithium, sodium, potassium, calcium, magnesium, ammonium, monoalkylammonium, such as meglumine, dialkylammonium, trialkylamine and tetraalkylammonium.

In some embodiments, the composition contains the compound which is at least almost clean. Usually the term "net" refers to the degree of purity of above 95%, and the term "almost pure" means that the compound obtained that is suitable for inclusion in a therapeutic dose, contains only those impurities that are difficult or does not make sense to remove by ordinary cleaning methods.

Route of administration the pharmaceutical compositions may be oral, rectal, intravenous, intramuscular, intracisternal, intravaginal, intraperitoneal, baculinum, subcutaneous, intrasternally, nazalnam or external. The composition can also type in the desired area by means of a catheter, intracoronary stent (a tubular device composed of a thin wire mesh), biratnager the polymer or biological media, including, but not limited to, antibodies, Biotin-evidenoe complexes and other Dosage forms for topical application of the compounds represented here include powders, sprays, ointments and agents for inhalation. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffering agents or propellants. It also provides ophthalmic compositions, eye ointments, powders and solutions.

The actual levels of doses of active ingredients and techniques presented here, the pharmaceutical compositions can be modified in such a way as to achieve an effective therapeutic response of the individual patient. The phrase "therapeutically effective amount" is presented here connecting means such number of connections, which is enough for the treatment of disorders with a reasonable ratio of benefit/risk, applicable to any medical treatment. However, it should be understood that the amount proposed to be used full daily dose of the compounds and compositions will be set by the attending physician in accordance with the volume of medical knowledge. A full daily dose of the compounds represented here may be in the range of from about 0.0001 to about 1000 mg/kg/day. The oral dose can sostav the be from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be divided for administration of several doses; therefore, the composition unit doses may contain such amounts or small parts that will make up the daily dose. The specific level of therapeutically effective dose for any patient will depend on various factors, including the subject of the treatment of the violation and the gravity of the violation; the history of the specified patient activity specifically used compounds; specifically used composition, age, weight, General health, sex and diet of the patient, time of administration, route of administration, duration of treatment, the rate of excretion of the specific compound, the drugs used in combination or in parallel with specifically used by the connection; and so on

Presents compounds may be prepared with one or more non-toxic pharmaceutically acceptable diluents, carriers, adjuvants, and antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. Appropriate fluidity can be provided, for example, using opaque materials, such as lecithin, obespechiva the required particle size in the case of dispersions, and by using surface-active agents. In some cases, extended the I action of the drugs it is necessary to reduce the speed of absorption of drugs after subcutaneous or intramuscular injection. This can be achieved by suspending crystalline or amorphous drug substance in media with low solubility in water, such as oil. Then the speed of absorption of the drug will depend on its rate of dissociation, which, in turn, may depend on the size of the crystals or crystalline form. Prolonged absorption injectively pharmaceutical forms can be achieved by using slow absorption agents, such as aluminiumfenster or gelatin.

Presented here are the links you can enter interline or parenterally in a solid or liquid form. Compositions suitable for parenterally injection may include physiologically acceptable sterile isotonic aqueous or not aqueous solutions, dispersions, suspensions or emulsions and sterile powders for the recreation of sterile solutions or dispersions for injection. Examples of suitable water and not water carriers, diluents, solvents or carriers include water, ethanol, polili (propylene glycol, polyethylene glycol, glycerin and the like), vegetable oils (such as olive oil), organic esters for injection, such as etiloleat, and suitable mixtures thereof. These compositions may also contain auxiliary substances such as preservatives, wetting, emulsifying and disperser the matter of agents. Suspension in addition to the active compounds can contain suspendresume agents, such as ethoxylated isostearyl alcohols, polyoxyethylenated and sorbitane esters, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, or mixtures of these substances.

The present compounds can also be administered by injection or infusion, or subcutaneously, or intravenously, or intramuscularly, or intrasternally, or intranasally, or by infusion in the form of a sterile aqueous or oily suspensions. These suspensions can be prepared, known in the art methods using suitable dispersing or wetting agents which have been listed above. Sterile injectable preparations can also be sterile solutions or suspensions for injection in a non-toxic parenterally acceptable diluent or solvent, for example, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, you must specify the water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically use sterile, non-volatile oils. For this purpose it is usually possible to use any mixture of non-volatile oils, including synthetic mono - or diglyceride is. In addition, to obtain drugs for injection you can use fatty acids such as oleic acid. Dosing regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose can be proportionally reduced in cases of extreme necessity in difficult therapeutic situations.

Form of depot injections get, creating microencapsulation matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used to adjust the release rate of drugs. Examples of other biodegradable polymers include poly(complex orthoevra) and poly(anhydrides). Composition depot injection also receive, including the drug in liposomes or microemulsions that are compatible with body tissues. Compositions for injection can be sterilized, for example by filtration through a retaining bacteria filter or incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersing in sterile water or other sterile environment for injection immediately before use.

Solid dosage forms of the La oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or increasing the amount of agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and resin acacia; c) humectants such as glycerol; (d) loosening agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (e) slow-dissolving agents, such as paraffin; (f) agents, accelerating absorption, such as Quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerylmonostearate; (h) absorbents such as kaolin and bentonite clay, and (i) lubricating agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, nutriceuticals and mixtures thereof. In the case of capsules, tablets and pills dosage forms may also include buferiruemoi agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin ka is Sul, using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like

Solid dosage forms as tablets, pills, capsules, pills and granules can be obtained with coatings and shells, such as gastric coatings and other coatings well known in the field of production of pharmaceutical forms. They may not necessarily contain shielding agents and can also be a composition, which emit only the active ingredient (the ingredient), or predominantly, in certain parts of the gastrointestinal tract, optionally, with some delay. Examples of compositions with the inclusion that can be used include polymeric substances and waxes. Tablets contain the compound in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for preparing tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and loosening agents, for example corn starch or alginic acid; binding agents, for example corn starch, gelatin or resin of acacia, and lubricating agents such as magnesium stearate or stearic acid or talc. Tablets can be b the h coverage, or they can be coated by known methods to slow the breakdown and absorption in the gastrointestinal tract and thereby provide a slow prolonged action. For example, you can use delaying the allocation of material, such as glycerylmonostearate or glycerylmonostearate. Compositions for oral administration may be presented as hard gelatin capsules where the compound is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents which are usually used by professionals, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed oil, peanut oil, corn oil, oil the germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids sorbitan and mixtures thereof. Besides inert diluents, compositions for oral administration can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, sweeteners, flavoring agents and fragrances.

The water suspension containing the compound in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone resin tragakant and resin acacia; dispersing or wetting agents may be natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids, such as hexitol, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters of fatty acids and anhydrides hexitol, e.g. the measures polyethyleneterphthalate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more of the sweeteners, such as sucrose or saccharin.

Oil suspensions can be obtained by suspension of the compounds in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Can be added sweeteners, such as described hereinafter, and flavoring agents to provide drugs for oral administration with a pleasant taste. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for obtaining aqueous slurry by adding water, contain the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or wetting agents and suspendresume agents are those that have already been disclosed above. May also contain additional excipients, for example the EP sweeteners, flavoring agents.

The present compounds can also be in the form of emulsions of the type oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural resins such as resin acacia or resin tragakant, natural offidani, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and anhydrides hexitol, such as servicemonitor and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs can be prepared with a sweetener, such as glycerol, sorbitol or sucrose. Such compositions may also contain a softener, a preservative and flavoring agent, and a dye.

In one embodiment, compounds are prepared in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form, in the sense here used, the term refers to a physically discrete unit suitable as a single dosage form to be treatment of the subject; each of which shall contain a therapeutically effective amount of the compounds and, at least one pharmaceutical excipient. Drug product will include a unit dosage form within a container that is labeled or accompanied by a label that lists the proposed method of treatment, such as treatment of amyloid diseases, such as amyloidosis, such as Alzheimer's disease, or disease associated with the formation of α-synuclein/NAC fibril formation, such as in Parkinson's disease. Compositions for rectal or vaginal injection are preferably suppositories which can be obtained by mixing the present compound with suitable not irritating excipients or carriers such as cocoa butter, polyethylene glycol or wax, for suppositories, which are solid at room temperature but become liquid at body temperature and therefore melt in rectum or vaginal cavity and release the active compound.

The present compounds can also be led in the form of liposomes. Methods of obtaining liposomes known in the art (Ed Prescott. Methods in Cell Biology. 1976, Volume XIV, Academic Press, New York, N.Y.) As known in the art, liposomes are usually derived from phospholipids or other lipid substances. Liposomes are formed from mono - or pallamallawa of hydrated liquid crystals that are dispersed in water with the food. You can use any non-toxic, physiologically acceptable and metabolisable lipids capable of forming liposomes. Consider composition in liposomal form may contain in addition to the present compounds, stabilizers, preservatives, excipients and the like, the Preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithins).

The present compounds can also be entered in the form of prodrugs”, where the active pharmaceutical ingredients, represented by formulas 1-3, are highlighted in vivo after exposure to the organism with hydrophilic enzymes such as esterase and phosphatase. The term "pharmaceutically acceptable proletarienne form" in the sense used here, is proletarienne form presented here of connections in the volume of medical knowledge are suitable for use in contact with tissues without unwanted toxicity, irritation, allergic response and the like, commensurate with a reasonable ratio of benefit/risk and are effective for the intended use. Detailed studies proposed by T. Higuchi and V. Stella (T. Higuchi and Stella V. Pro-drugs as Novel Delivery Systems. V. 14 of the A.C.S. Symposium Series; Edward B. Roche, Ed. Bioreversible Carriers in Drug Design, 1987, American Pharmaceutical Association and Pergamon Press), which is included here for reference.

Presents is here compounds or their pharmaceutically acceptable derivatives can also be prepared this way, so they were directed to a particular tissue, receptor, or other parts of the body to be treated of the subject. All such methods of targeting are discussed here for use in the present compositions. For limitiruesh examples of methods of targeting, see, for example, U.S. patents№6316652, 6274552, 6271359, 6253872, 6139865, 6131570, 6120751, 6071495, 6060082, 6048736, 6039975, 6004534, 5985307, 5972366, 5900252, 5840674, 5759542 and 5709874.

In one embodiment, liposomal suspensions, including those directed on the fabric of the liposomes, such as those aimed at the tumor liposomes, may also be suitable as pharmaceutically acceptable carriers. Such suspensions can be obtained in accordance with well-known experts in this field means. For example, liposomal compositions can be obtained, as disclosed in U.S. patent No. 4522811. Briefly, liposomes, such as paramelhania bubbles (MLV's), can be obtained by drying of egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) on the inner side of the flask. Add the solution presented here join in phosphate buffered saline, containing no divalent cations (PBS), and the flask is shaken up until the lipid film is dispersed. The resulting bubbles are washed to remove not encapsulated compounds precipitated by centrifugation and then SN the VA suspended in PBS.

Product

The compounds or pharmaceutically acceptable derivatives may be packaged as articles containing packaging material, a compound or presents here its pharmaceutically acceptable derivatives, which are effective for the treatment, prevention or improvement of one or more of the symptoms of amyloidosis and synucleinopathies diseases, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable derivative used for the treatment, prevention or improvement of one or more of the symptoms of amyloidosis and synucleinopathies disease.

The articles shown here contain packing materials. Packaging materials used for packaging pharmaceutical products, well known to specialists in this field. See, for example, U.S. patent No. 5323907, 5052558 and 5033252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected form and the intended route of administration and processing. Accept a wide range of forms represented here by the compounds and compositions, as well as different ways of treatment is amyloidogenic and synuclein diseases.

Compositions with delayed release

Also proposed compositions with delayed release for the delivery of compounds to the desired target (i.e. in the brain or systemic organs) with high circulating levels (between 10-9up to 10-4M). In some embodiments, for the treatment of Alzheimer's disease or Parkinson's disease circulating levels of connections to support up to 10-7M. Such levels or circulating in the body of the patient systemically, or in one of the variants present in the tissues of the brain, and in other embodiments, localized deposits of amyloid or α-synuclein fibrils in the brain or in other tissues.

Note that the levels of connections are maintained for a required period of time, and it can easily identify the person skilled in the art. In one embodiment, the introduction of the composition with delayed allocation carried out in such a way as to maintain constant the concentration of therapeutic content connectivity from 10-8up to 10-6M during the time interval from 48 to 96 hours.

Such compositions with delayed release and/or release time can be obtained by using devices for delivery, providing delayed release, which is well known to specialists in this field, that is them as those what are disclosed in U.S. patents№3845770; 3916899; 3536809; 3598123; 4008719; 4710384; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556 and 5733566, the disclosure of which is included here for reference. These pharmaceutical compositions can be used to provide slow release or release with a delay of one or more of the active compounds using, for example, hypromellose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres or other Suitable compositions with delayed release, known to specialists in this field, including those disclosed here, you can easily choose to use presented here pharmaceutical compositions. So, here you can use the unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel capsules, tablets in capsules, powders and the like, which are adapted for slow release.

In one embodiment, the composition with delayed release contains the active compound and one or more excipients, such as, without limitation, microcrystalline cellulose, maltodextrin, ethylcellulose and magnesium stearate. As disclosed above, can be used all izvestnyakovye encapsulate, compatible with the properties of the disclosed compounds. Compositions with delayed release encapsulation, coating the particles or granules presented here pharmaceutical compositions of different thickness slowly soluble polymers or by using microencapsulation. In one embodiment, the composition with delayed release encapsulate using covering materials of different thickness (for example, from about 1 micron to 200 microns), which provides for the dissolution of a pharmaceutical composition for from about 48 hours to about 72 hours after administration to a mammal. In another embodiment, a covering material is allowed to use a nutritional Supplement.

In another embodiment, the composition with delayed release is a matrix dissolving device, which is produced by extruding the drug with a slowly dissolving polymer carrier in the form of tablets. In one embodiment, the particles coated with dimensions in the range of from about 0.1 to about 300 microns, as disclosed in U.S. patent No. 4710384 and 5354556, which is included here for your reference in its entirety. Each particle exists in the form of chips, and the active ingredient is evenly distributed throughout the polymer.

Compositions with delayed release, such as disclosed in U.S. patent No. 4710384 to the th is included here for your reference in its entirety, contain a relatively high percentage of plasticizer in the coating in order to provide flexibility and to prevent further degradation during the specified compaction process. A specific amount of plasticizer varies depending on the nature of the coating and the concrete used plasticizer. These amounts can easily be determined empirically by testing the characteristics of the allocation of the resulting tablets. If the drug released too quickly, then use large amounts of plasticizer. Allocations are also a function of coating thickness. If you use significant amounts of plasticizer, the ability of slow release through the coating decreases. Thus, the coating thickness can be slightly increased to compensate for the increased amount of plasticizer. Typically, the plasticizer in such a variant is present in amount from about 15% to 30% of the material is delayed selection in the floor, in one embodiment, from 20 to 25%, and the amount of coating is from 10 to 25% by weight of active material and in other embodiments from 15 to 20% by weight of the active material. In such coatings may include any conventional pharmaceutically acceptable plasticizers.

The present compounds may be in the form of a composition with delayed release and/whom do with release time. All pharmaceutical products with slow release is a common goal of improving drug therapy compared with that achieved using conventional compositions without delayed allocation. Ideally, the use of optimally selected delayed allocation, can be achieved with therapeutic treatment, characterized by a minimum of medicinal substances which are used for the treatment or control condition. Advantages of the compositions with delayed release may include: 1) prolonged activity of the composition, 2) a reduction in the frequency of doses and 3) improvement of convenience for the patient. In addition, the composition with delayed release can be used to influence the time of onset of action or other characteristics, such as levels of composition in the blood, and, thereby, affect the occurrence of side effects.

The compositions with delayed release created for the initial allocation of a certain amount of a therapeutic composition, which immediately causes the desired therapeutic effect, and gradually and constant release other amounts of the composition to maintain the achieved level of therapeutic effect over a prolonged period of time. In order to maintain this constant is the level in the body, therapeutic composition should be released from the dosage form at a rate that will compensate for the amount of the composition, which is metabolized and excreted from the body.

Slow release of the active ingredient can be stimulated in various ways, such as pH, temperature, enzymes, water, or other physiological conditions or compounds.

Preparations for oral administration can be formulated accordingly to provide controlled release of the active compounds. In one embodiment, the compounds prepared in the form of powders with controlled-release, consisting of discrete particles that are readily available in liquid form. Powder with a slow release includes particles containing the active ingredient and not necessarily excipient with at least one non-toxic polymer.

The powder can be atomized or suspended in a liquid carrier, and it will retain its slow release characteristics for a sufficient period of time. Such dispersions or suspensions possess both chemical stability and stability from the viewpoint of the dissolution rate. The powder may contain excipient comprising a polymer, which may be soluble, nerator the most permeable, impermeable or biodegradable. Such polymers can be polymers or copolymers. Polymers can be natural or synthetic polymers. Natural polymers include polypeptides (e.g., Zein), polysaccharides (e.g. cellulose and alginic acid. Representatives synthetic polymers disclosed include, but are not limited to those listed in column 3 at lines 33-45 U.S. patent No. 5354556, which is included here for your reference in its entirety. Particularly suitable polymers include those that are disclosed, but are not limited to those listed in column 3, line 46, column 4, line 8 of U.S. patent No. 5354556, which is included here for your reference in its entirety.

Presented here is a song with a slow release can be created for parenteral administration, such as intramuscular injection or as an implant for subcutaneous tissues and various body cavities and for transdermally devices. In one embodiment, the preparations for intramuscular injection is prepared in the form of aqueous or oil suspensions. In the case of aqueous suspensions, the effect of slow release partly due to the decrease of the solubility of the active compound in the complexation or associated with a reduction in the dissolution rate. A similar approach is valid for oil suspensions, and RA is solutions, where the release rate of the active compound is determined by the selection of active compounds from the oil into the surrounding aquatic environment. Suitable only those active compounds which are soluble in oil and have the necessary characteristics of discharge from the oil. Oils that can be used for intramuscular injection include, but are not limited to, sesame, olive, peanut, corn, almond, soy, cotton, and castor oil.

Well-developed method of drug delivery, which is a slow release over time from several days to several years, is cheek implants containing drug and polymer devices subcutaneously or in various body cavities. Polymeric materials used for implants, which must be biocompatible and non-toxic, include, but are not limited to, hydrogels, silicones, polyethylene, copolymers of ethylene and vinyl acetate or biodegradable polymers.

E. evaluation of the activity of compounds

Biological activity of compounds represented here as the disruptors/inhibitors of β-fibrils of amyloid protein (Aβ) of Alzheimer's disease, IAPP fibrils of type 2 diabetes and NAC fibrils Parkinson's estimate, determining the effectiveness of the compounds as the ability of the de is ontage/destruction of previously formed amyloid fibrils of Alzheimer's disease (i.e. consisting of Aβ 1-42 fibrils), IAPP fibrils and NAC fibrils of Parkinson's disease. In one study using fluorometry of thioflavin T to determine the effects of compounds and EDTA (as negative control). In this analysis tioflavin T binds specifically to fibrillar amyloid, and as a result of this binding occurs, the increased fluorescence at 485 nm, which is directly proportional to the amount present of the fibrils. The more intense fluorescence, the more there is of fibrils (Naki et al., Lab. Invest. 65:104-110, 1991; Levine III, Protein Sci. 2:404-410, 1993; Amyloid: Int. J. Exp.Clin. Invest. 2:1-6, 1995). The destruction of Aβ 1-42, even in their Monomeric form, confirmed by research, including the use of the method SDS-PAGE and Western blotting.

In the analysis of the binding of Congo red, the ability of a specific test compound to alter amyloid (Aβ 1-42 fibrils, IAPP fibrils or NAC fibrils) quantify the binding of Congo red. In this analysis of Aβ 1-42 fibrils, IAPP fibrils or NAC fibrils and the test compounds are incubated for 3 days and then carry out vacuum filtration through a 0.2 μm filter. The amount of Aβ 1-42 fibrils, IAPP fibrils or NAC fibrils remaining on the filter, then quantitatively determine the subsequent staining of the filter Congo red. After appropriate washing, any weakening of the color of the Congo is Krasnogo on the filter in the presence of the test compound (compared with Congo red staining of amyloid protein without the test compound) is indicative of the ability of test compounds to reduce/modify the number of aggregated and congophilic Aβ 1-42 fibrils, IAPP fibrils or NAC fibrils.

F. Combination therapy

In another embodiment, compounds can be introduced in combination, or sequentially with other therapeutic agent. Such other therapeutic agents include those that are known for treating, preventing or improving one or more symptoms of amyloidosis and synucleinopathies disease. Such therapeutic agents include, but are not limited to, donepezil hydrochloride (Aracept), rivastigmine tartrate (Exelon), TakingITGlobal (Cognex) and galantamine hydrobromide (Reminyl).

G. Methods of using compounds and compositions.

The present compounds and compositions can be used in methods of treatment, prevention or improvement of one or more of the symptoms of amyloid diseases or disorders, including, but not limited to, diseases associated with the formation, deposition, accumulation, or persistence of amyloid fibrils. In one embodiment, the fibrils of amyloid protein selected from the group of Aβ amyloid, AA amyloid, AL amyloid, IAPP amyloid, PrP amyloid, α2-macroglobulinemia amyloid, transthyretin, prealbumin and procalcitonin. In some embodiments, the amyloid protein fibrils represent Aβ amyloid and IAPP am is laid. In some embodiments, the present compounds and compositions used for the treatment, prevention or improvement of one or more of the symptoms of the disease, including, but not limited to, Alzheimer's disease, down's syndrome, Boxing dementia, multiple system athey, myositis with inclusions of Taurus, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, disease Niemann-pick type C, cerebral β-amyloid angiopathy, dementia associated with cortical basal degeneration, the amyloidosis of type 2 diabetes, the amyloidosis of chronic inflammation, the amyloidosis malignancy and familial Mediterranean fever, the amyloidosis of multiple myeloma and b-cell dyscrasia, amyloidosis Pranovich diseases, disease Creutzfeldt-Jakob syndrome of Gerstman-Straussler, Kuru, scrapie, the amyloidosis associated with carpal tunnel syndrome, senile cardiomyocytes, family amyloidotic polyneuropathy and the amyloidosis associated with endocrine diseases. In some embodiments, the disease is Alzheimer's disease or type 2 diabetes.

Also suggested ways to inhibit or prevent α-synuclein/NAC fibril formation, methods of inhibiting or preventing growth of α-synuclein/NAC fibrils and methods of dismantling, destruction and/or the disaggregation previously formed α-synuclein/NAC fibrils and related α-synuclein/NAC protein deposits.

In some embodiments sinucleanse disease or synucleinopathies that treat, prevent prophylactically or symptoms which weaken represented here by the compounds and compositions include, but are not limited to, diseases associated with the formation, deposition, accumulation or persistence synuclein fibrils, including fibrils of α-synuclein. In some embodiments, such diseases include Parkinson's disease, familial Parkinson's disease, variant Alzheimer's disease with calves Levi, dementia with calves Levi, multiple system atrophy and complex parkinsonism-dementia of GUAM island.

The following not limiting examples are presented only to illustrate and not be considered as limiting the subject matter of the invention, many apparent variations of which are possible without going beyond its essence and scope.

EXAMPLES

General experimental procedures

All the solvents distilled before use and removed using a rotary evaporator at temperatures up to 35°. For flash chromatographie on silica gel using Merck silica gel 60, 200-400 mesh, 40-63 μm. TLC carried out using Merck DC•plastikfoiien Kieselgel 60 F254first visualizing with UV lamp, and then immersing in a solution of vanillin (1% vanillin, 1% H2SO 4in EtOH) and heating. Mass spectra were recorded on a device Kratos MS-80. NMR spectra were recorded at 25°, at a frequency of 500 or 300 MHz for1H and 125 or 75 MHz for13C spectrophotometer Varian INOVA-500 or VXR-300. Chemical shifts are expressed in parts per million scale (relative to the values of the peaks of the comparative compounds CHCl3at 7.25 and CDCl3on of 77.0 ppm, or (CH3)2CO 2,15 and (CD3)2CO 30.5 ppm, or CH3OD at 3.30, and CD3OD on 39,0 h/million

Conditions of HPLC

Equipment for analytical HPLC consists of an automatic sampler Waters 717, 600 pump and controller, and a 2487 UV detector, managed software Omega for method 2, and an automatic sampler Waters 717, 600 pump and controller, and 490 UV detector, managed software Millennium for method 1. Samples analyzed using RP-18 prepreparation column (Phenomenex Prodigy 5 mm C18 100A, 250×4.6 mm) (Phonomenex SecurityGuard cartridge containing C18 ODS 4×3 mm, 5 mm column)filled at 30°C. Samples (5 ml) was analyzed using a flow rate of the mobile phase of 5.0 ml/min, with UV detection at a wavelength of 280 nm.

Solvent A - CH3CN

Solvent B - H2O containing 0.1% TFA

Method 1

Time (minutes)Solvent A Solvent B
01189
201189
301000
311189
401189

HPLC (method 2) (for connections DC-0051-B1 - DC-0051-B4)

Method 2 is carried out, using a C18 column with dimensions of 2.1×50 mm running Time set for 7 minutes. The mobile phase contains (A) acetonitrile with 0.05% of TFA and (B) distilled water with 0.05% of TFA. In all runs of method 2 using a gradient elution from 10% to 90% solvent A.

Example 1

Synthesis of 3,4-dihydroquinoline 3 methanesulfonamido-4-hydroxybenzoic acid (DC-0051-S1; referred to as DC-0051-CB)

Education methanesulfonylaminoethyl derived amide DC-0051 exercise, getting the first known 3-nitro-4-methoxybenzoic acid, then getting anilide using 3,4-methylenedioxyaniline, receiving the 3-nitro-4-methoxime. In the catalytic reduction followed by immediate metilirovaniem get ethylamin, which will Demetriou, just interacting with tribromide boron, resulting in the 3,4-dihydroxymandelic 3 methanesulfonamido-4-hydroxybenzoic acid

(DC-0051-S1; also referred to as DC-0051-CB)).

A) 3-nitro-4-methoxybenzoic acid.

To a suspension of p-anise acid (3 g) in acetic anhydride (20 ml) at 0°C is added dropwise concentrated nitric acid (6 ml). The obtained clear solution is allowed to warm to room temperature, then stand for 30 minutes. The resulting mixture was poured on ice (100 ml) and the resulting solid white color is filtered off, then washed with a large quantity of ice water, resulting in the product (2.8 g, 72%).

1H NMR ((CD3)2CO) 8,44 (1H, d, J=2 Hz), 8,29 (1H, DD, J=2, 8 Hz), 7,51 (1H, d, J=8 Hz) and of 4.11 (3H, s).

(B) 3,4-methylenedioxyaniline 3-nitro-4-methoxybenzoic acid.

A suspension of 3-nitro-4-methoxybenzoic acid (1.4 g) in thionyl chloride (10 ml) is refluxed for 1 hour. The solvent is removed in vacuum, obtaining the acid chloride in a solid white color, which is again dissolved in dry dichloromethane (20 ml) and added dropwise a mixture of pyridine (1 ml) and 3,4-methylenedioxyaniline (1 g) in dichloromethane (5 ml). The resulting mixture is left at room temperature for 24 hours, then add another dichloro the'étang (50 ml) and hydrochloric acid (1 M, 50 ml) and the precipitate filtered and washed with water getting in the 3,4-methylenedioxyaniline 3-nitro-4-methoxybenzoic acid (1,72 g, 72%).

1H NMR ((CD3)2CO) 9,79 (1H, Sirs, NH), 8,58 (1H, d, J=2 Hz), to 8.41 (1H, DD, J=2, 8 Hz), 7,63 (1H, d, J=2 Hz), a 7.62 (1H, d, J=8 Hz), 7,35 (1H, DD, J=2, 8 Hz), of 6.96 (1H, d, J=8 Hz), x 6.15 (2H, s) and 4,22 (3H, s).

(C) 3,4-methylenedioxyaniline 3 methanesulfonamido-4-methoxybenzoic acid.

A suspension of 3,4-methylenedioxyaniline 3-nitro-4-methoxybenzoic acid (0,44 g) in methanol (20 ml) with formic acid (1 ml) is stirred under an atmosphere of hydrogen with palladium hydroxide-on-coal (10%, 200 mg) for 5 hours. The resulting mixture was filtered through cotton wool and the solvent removed in vacuum. In the chromatographic purification on a column of silica gel performing a gradient elution from 20 to 100% ethyl acetate in dichloromethane, get pure amine (270 mg, 68%). It immediately dissolved in pyridine (5 ml) and added dropwise to methanesulfonanilide (0.2 ml), then the resulting mixture is left at room temperature overnight. Add hydrochloric acid (1 M, 100 ml) and ethyl acetate (100 ml)then the organic layer is dried and evaporated in vacuo, resulting in the crude product. As a result of crystallization from dichloromethane receive 3,4-methylenedioxyaniline 3 methanesulfonamido-4-methoxybenzoic acid in the form of Cristallo is white (155 mg, 47%).

1H NMR ((CD3)2CO) 9,62 (1H, Sirs, NH), 8,07 (1H, d, J=2 Hz), of 7.97 (1H, Sirs, NH), 7,87 (1H, DD, J=2, 8 Hz), 7,55 (1H, d, J=2 Hz), 7,22 (1H, DD, J=2, 8 Hz), 7,21 (1H, d, J=8 Hz), 6,83 (1H, d, J=8 Hz), 6,13 (2H, C)to 4.14 (3H, s) and of 3.16 (3H, s).

D) 3,4-dihydroxymandelic 3 methanesulfonamido-4-hydroxybenzoic acid (DC0051-S1), see J. van Alphen. Rec. trav. Chim. 1929, 48, 1112-23.

To a stirred suspension of 3,4-methylenedioxyaniline 3 methanesulfonamido-4-methoxybenzoic acid (100 mg) in dry CH2Cl2(20 ml) under nitrogen atmosphere add trichromacy boron (0.2 ml), then stirring is continued for another 20 hours. Carefully add methanol (50 ml), then the solvent is evaporated in vacuum to a volume of 1 ml, repeat this 2 more times. In the treatment using crystallization from methanol receive 3,4-dihydroxymandelic 3 methanesulfonamido-4-hydroxybenzoic acid

(DC0051-A1) (45 mg, 47%) as crystals pale brown color.

1H NMR ((CD3)2CO) 9,68 (1H, Sirs, NH), 927 (1H, Sirs, NH), 8,03 (1H, d, J=2 Hz), 8,02 (1H, Sirs, OH), to $ 7.91 (1H, Sirs, OH), 7,76 (1H, DD, J=2, 8 Hz), of 7.75 (1H, Sirs, OH), 7,49 (1H, d, J=2 Hz), 7,10 (1H, DD, J=2, 8 Hz), to 7.09 (1H, d, J=8 Hz), 6,79 (1H, d, J=8 Hz) and 3.05 (3H, s).

M/z 337 (M-H), 100%).

HPLC (method 1) to 21.1 minutes

Example 2

3-hydroxy-4-methanesulfonamido-N-(3,4-dihydroxyphenyl)benzamide (DC0051-S8; also referred to as DC-0051-DB).

Education anilide 3-methoxy-4-Latrobe what sainoi acid with 3,4-methylenedioxyaniline leads to the production of 3-nitro-4-methoxyamino. In the recovery by the catalytic hydrogenation followed by immediate metilirovaniem get mesalamine. It will Demetriou, interacting with tribromide boron, receiving the 3-hydroxy-4-methanesulfonamido-N-(3,4-dihydroxyphenyl)benzamide (DC-0051-S8; also referred to as DC0051-BD).

A) 3-methoxy-4-nitro-N-(3,4-methylenedioxyphenyl)benzamide.

A suspension of 3-methoxy-4-nitrobenzoic acid (0.5 g) in thionyl chloride (10 ml) is refluxed for one hour. The solvent is removed in vacuum, obtaining the resulting acid chloride in a solid white color. The obtained acid chloride was dissolved in dry dichloromethane (10 ml) and added dropwise a mixture of pyridine (0.5 ml) and 3,4-methylenedioxyaniline (0.4 g) in dichloromethane (5 ml). The resulting mixture is left at room temperature for 24 hours, then added dichloromethane (50 ml) and hydrochloric acid (1 M, 50 ml), the precipitate filtered and washed with water, resulting in the 3-methoxy-4-nitro-N-(3,4-methylenedioxyphenyl)benzamide (0,43 g, 54%).

1H NMR ((CD3)2CO) 9,79 (1H, Sirs, NH), 8,03 (1H, d, J=8 Hz), 7,98 (1H, d, J=2 Hz), 7,78 (1H, DD, J=2, 8 Hz), 7,63 (1H, d, J=2 Hz), 7,32 (1H, DD, J=2, 8gts), 6,93 (1H, d, J=8 Hz), 6,11 (2H, s) and 4.17 (3H, s).

B) 3-methoxy-4-methanesulfonamido-N-(3,4-methylenedioxyphenyl)benzamide.

A suspension of 3-methoxy-4-nitro-N-(3,4-methylenedioxyphenyl)b is samida (100 mg) in methanol (20 ml) is stirred under an atmosphere of hydrogen with palladium-on-coal (10%, 50 mg) for 18 hours.

The solvents are removed in vacuo, resulting in the resin brown. The residue is dissolved in pyridine (0.5 ml) and cooled to 0°C, then add methanesulfonanilide (0.1 ml), the mixture was incubated at 0°C for 30 minutes, then brought to room temperature for 1 hour. Add diluted hydrochloric acid (10 ml, 1 M) and dichloromethane, the organic layer emit, dried and evaporated in vacuo, resulting in the product in the form of a brown resin. In the chromatographic purification on a column of silica gel performing a gradient elution (0-100%) ethyl acetate in dichloromethane, to obtain 3-methoxy-4-methanesulfonamido-N-(3,4-methylenedioxyphenyl)benzamide (65 mg, 55%) as a solid white color.

1H NMR ((CD3)2CO) 9,52 (1H, Sirs, NH), 8,13 (1H, Sirs, NH), 7,74 (1H, d, J=2 Hz), 7,72 (1H, DD, J=2, 8 Hz), to 7.64 (1H, d, J=8 Hz), a 7.62 (1H, d, J=2 Hz), 7,26 (1H, DD, J=2,8 Hz), 6,91 (1H, d, J=8 Hz), 6,09 (2H, s), 4,07 (3H, s) and of 3.16 (3H, s).

C) 3-hydroxy-4-methanesulfonamido-N-(3,4-dihydroxyphenyl)benzamide

(DC0051-S8).

To a stirred suspension of 3-methoxy-4-methanesulfonamido-N-(3,4-methylenedioxyphenyl)benzamide (200 mg) in dry CH2Cl2(20 ml) under nitrogen atmosphere add trichromacy boron (0.3 ml), and then stirring is continued for another 20 hours. Carefully add methanol (5 ml), then the solvent is evaporated in vacuum to a volume of 1 ml, repeat this 2 more times. In the chromatographic purification on a column of silica gel performing a gradient elution of 10-20% methanol in chloroform, to obtain 3-hydroxy-4-methanesulfonamido-N-(3,4-dihydroxyphenyl)benzamide (DC51-DB) (65 mg, 34%) as crystals pale brown color.

1H NMR (CD3OD) 7,45 (1H, d, J=8 Hz), 7,40 (1H, d, J=2 Hz), was 7.36 (1H, DD, J=2, 8 Hz),

7,20 (1H, d, J=2 Hz), to 6.88 (1H, DD, J=2, 8 Hz), 6.73 x (1H, d, J=8 Hz) and 2,98 (3H, s).

M/z 337(M-H)-; 100%)

HPLC (method 1) 29,2 minutes

Example 3

N-(3-methanesulfonamido-4-hydroxyphenyl)-3,4-dihydroxybenzamide (DC0051-S6; also referred to as DC-0051-AE)

As a result of processing commercial 2-methoxy-5-nitroaniline by methanesulfonamido get mesalamine. Then in the catalytic reduction of the nitro group get the desired aniline, which when interacting with 3,4-methylenedioxyphenethylamine forms anilide. Then after removal of methoxy, methylenedioxy groups using trichromate boron receive N-(3-methanesulfonamido-4-hydroxyphenyl)-3,4-dihydroxybenzamide (DC0051-S6; also referred to as DC0051-AE).

A) 2-methoxy-5-nitratecontaminated.

To a solution of 2-methoxy-5-nitroaniline (5 g) in pyridine (25 ml) at 0°C is added dropwise methanesulfonanilide (3.5 m is), then add pyridine (0.5 ml). The resulting mixture was left at 0°C for 1 hour, then brought to room temperature for 2 hours. The resulting mixture was poured on ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the resulting solid product is filtered off, then washed with water, receiving the 2-methoxy-5-nitratecontaminated (5,2 9,71%) as a crystalline solid is not quite white.

1H NMR (CDCl3) 8,39 (1H, d, J=2 Hz), 8,05 (1H, DD, J=2, 8 Hz), of 6.99 (1H, d, J=8 Hz) and 6,98 (1H, Sirs, NH).

B) 2-methoxy-5-aminoethylethanolamine.

A solution of 2-methoxy-5-nitratecontaminated (1 g) in methanol (20 ml)containing palladium-on-coal (10%, 100 mg), stirred at room temperature for 48 hours in an atmosphere of hydrogen. The resulting mixture was filtered through celite and then evaporated, to deliver 2-methoxy-5-aminomethylpyrimidine in the form of a brown resin. The specified resin used in the next reaction without further purification.

C) N-(3-methanesulfonamido-4-methoxyphenyl)-3,4-methylenedioxybenzene.

A suspension of 3,4-methylenedioxybenzene acid (300 mg) in thionyl chloride (10 ml) is refluxed for one hour. The solvent is removed in vacuum, obtaining the resulting acid chloride in the form of a solid substance is logo color. 2-methoxy-5-aminomethylpyrimidine (from the previous reaction) was dissolved in pyridine (20 ml) and added dropwise to the acid chloride. The resulting mixture is left at room temperature for 24 hours, then poured onto ice (50 g) and hydrochloric acid (3M, 100 ml) and the precipitate filtered and washed with water, resulting in the

N-(3-methanesulfonamido-4-methoxyphenyl)-3,4-methylenedioxybenzene (1,37 g, 93%).

1H NMR ((CD3)2CO) 9,52 (1H, Sirs, NH), 7,88 (1H, DD, J=2, 8 Hz), 7,87 (1H, d, J=2 Hz), 7,71 (1H, DD, J=2, 8 Hz), to 7.59 (1H, d, J=2 Hz), 7,14 (1H, d, J=8 Hz),? 7.04 baby mortality (1H, d, J=8 Hz), of 6.20 (2H, s), of 4.00 (3H, s) and of 3.10 (3H, s).

D) N-(3-methanesulfonamido-4-hydroxyphenyl)-3,4-dihydroxybenzamide.

To a stirred suspension of N-(3-methanesulfonamido-4-methoxyphenyl)-3,4-methylenedioxybenzene (200 mg) in dry CH2Cl2(20 ml) under nitrogen atmosphere add trichromacy boron (0.3 ml), and then stirring is continued for another 20 hours. Carefully add methanol (50 ml), then the solvent is evaporated in vacuum to a volume of 1 ml, repeat this 2 more times. In the chromatographic purification on a column of silica gel performing a gradient elution (10-20%) of methanol in chloroform, to obtain N-(3-methanesulfonamido-4-hydroxyphenyl)-3,4-dihydroxybenzamide (62 mg, 33%) as crystals pale brown color.

1H NMR ((CD3)2CO) 7,87 (1H, d, J=2 is C), of 7.70 (1H, DD, J=2, 8 Hz), the 7.65 (1H, d, J=2 Hz), 7,05 (1H, d, J=8 Hz), 7,00 (1H, d, J=8 Hz) and 3.12 (3H, s).

M/z 337(M-H)-, 100%)

HPLC (method 1) to 22.1 minutes

Example 4

N-(3-hydroxy-4-methanesulfonylaminoethyl)-3,4-dihydroxybenzamide (DC-0051-S7; also referred to as DC-0051-AF)

As a result of processing commercial 2-methoxy-4-nitroaniline by methanesulfonamido get mesalamine. Then the restoration of the nitro group using catalytic hydrogenation leads to the production of the desired aniline, which, after condensation with 3,4-methylenedioxybenzyl the acid chloride results in annelid. Remove methoxy, methylenedioxy groups using trichromate boron leads to the production of N-(3-hydroxy-4-methanesulfonylaminoethyl)-3,4-dihydroxybenzamide (DC-0051-S7; also referred to as DC-0051-AF).

A) 2-methoxy-4-nitratecontaminated.

To a solution of 2-methoxy-4-nitroaniline (5 g) in pyridine (25 ml) at 0°C is added dropwise methanesulfonanilide (3.5 ml), then pyridine (0.5 ml). The resulting mixture was left at 0°C for 1 hour, then brought to room temperature for 2 hours. The resulting mixture was poured on ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the resulting solid product is filtered off, then washed with water, receiving the 2-methoxy-4-nitratecontaminated (7,32 g, 98%) as cu is Starichenko solids not quite white.

1H NMR (CDCl3) 7,92 (1H, DD, J=2, 8 Hz), 7,78 (1H, d, J=2 Hz), to 7.64 (1H, d, J=8 Hz) and 7.23 percent (1H, Sirs, NH).

B) 2-methoxy-4-aminoethylethanolamine.

A solution of 2-methoxy-4-nitratecontaminated (1 g) in methanol (20 ml)containing palladium-on-coal (10%, 100 mg), stirred at room temperature in an atmosphere of hydrogen for 48 hours. The resulting mixture was filtered through celite and then evaporated, to deliver 2-methoxy-4-aminoethylethanolamine in the form of a brown resin. It is used without additional purification in the next reaction.

C) N-(3-methoxy-4-methanesulfonylaminoethyl)-3,4-methylenedioxybenzene.

A suspension of 3,4-methylenedioxybenzene acid (300 mg) in thionyl chloride (10 ml) is refluxed for one hour. The solvent is removed in vacuum, obtaining the acid chloride in a solid white color. 2-methoxy-4-aminoethylethanolamine (from previous stage) is dissolved in pyridine (20 ml) and added dropwise to the acid chloride. The resulting mixture is left at room temperature for 24 hours, then poured onto ice (50 g) and hydrochloric acid (3M, 100 ml), the precipitate filtered and washed with water, receiving N-(3-methoxy-4-methanesulfonylaminoethyl)-3,4-methylenedioxybenzene (1,37 g, 93%).

1H NMR (CDCl3) 7,81 (1H, d, J=2 Hz), of 7.70 (1H, Sirs, NH), 7,47 (1H, is, J=8 Hz),

7,38 (1H, DD, J=2, 8 Hz), 7,34 (1H, d, J=2 Hz), to 6.88 (1H, d, J=8 Hz), 6,79 (1H, DD, J=2, 8 Hz), 6,63 (1H, Sirs, NH), the 6.06 (2H, s) to 3.92 (3H, s), and only 2.91 (3H, s).

D) N-(3-hydroxy-4-methanesulfonylaminoethyl)-3,4-dihydroxybenzamide.

To a stirred suspension of N-(3-methoxy-4-methanesulfonylaminoethyl)-3,4-methylenedioxybenzene (200 mg) in dry CH3Cl2(20 ml) under nitrogen atmosphere add trichromacy boron (0.3 ml), and then stirring is continued for another 20 hours. Carefully add methanol (50 ml), then the solvent is evaporated in vacuum to a volume of 1 ml and this was repeated twice. In the chromatographic purification on a column of silica gel performing a gradient elution with methanol (10-20%) in chloroform, receive N-(3-hydroxy-4-methanesulfonylaminoethyl)-3,4-dihydroxybenzamide (62 mg, 33%) as crystals pale brown color.

1H NMR ((CD3)2CO) 7,86 (1H, d, J=2 Hz), 7,60 (1H, d, J=2 Hz), 7,51 (1H, DD, J=2, 8 Hz), 7,40 (1H, d, J=8 Hz), 7,30 (1H, DD, J=2, 8 Hz), 7,00 (1H, d, J=8 Hz), 3.06 (3H, s).

M/z 337(M-H)-,100%)

HPLC (method 1) to 29.5 minutes

Example 5

3,4-dimethanesulfonate-N-(3,4-dimethanesulfonate)benzamide (also referred to as DC0051-GH)

Acid catalyzed formation of methyl ester of 3,4-diaminobenzoic acid with subsequent metilirovaniem gives dimethylaminobenzoate. Then, as a result of delacherois get the desired 3,4-dimethanesulfonate acid. Metilirovanie 4-nitro-1,2-phenylenediamine results in dimethylamino product, which, after catalytic hydrogenation gives the desired aniline. Then by condensation of the acid with the amine in the presence of DCC get tetramethylsilane.

A) methyl-3,4-diaminobenzoate.

In dry methanol (20 ml) was carefully added thionyl chloride (1 ml) dropwise with stirring. Added by portions at room temperature 3,4-diaminobenzoic acid (1 g) under stirring, then the mixture is refluxed for 3 hours. Add a saturated solution of sodium bicarbonate until then, until the mixture becomes alkaline, and then the resulting mixture was extracted with chloroform containing 25% methanol. The obtained extract is dried and evaporated in vacuo, resulting in the product (0.88 g, 81%) as a crystalline solid brown color.

1H NMR (CDCl3) 7,46 (1H, DD, J=2, 8 Hz), 7,40(1H, d, J=2 Hz), to 6.67 (1H, d, J=8 Hz) and of 3.84 (3H, s).

B) Methyl-3,4-dimethanesulfonate.

A solution of diamine (0.88 g) in pyridine (10 ml) at 0°C is treated with methanesulfonamide (2 ml). The resulting mixture is left at room temperature for 12 hours, then poured onto ice and hydrochloric acid (3M, 50 ml) and the resulting mixture is filtered, resulting in the product in the form of crystalline t is ejogo substance white (0.54 g, 32%).

1H NMR ((CD3)2CO) 9,39 (2H, Sirs), 8,11 (1H, d, J=2 Hz), 7,95(1H, DD, J=2, 8 Hz), of 7.75 (1H, d, J=8 Hz), of 3.97 (3H, s), or 3.28 (3H, s) and 3,17 (3H, s).

(C) 3,4-dimethanesulfonate acid.

A suspension of ester (0.5 g) in acetone (25 ml) is treated with sodium hydroxide solution (3 M, 5 ml) and the resulting orange solution left at room temperature for 2 hours. Aqueous hydrochloric acid (3M) add up until the solution becomes acidic, then extracted with ethyl acetate containing 25% methanol, getting acid in a solid brown color (0.36 g, 75%).

1H NMR ((CD3)2CO) of 9.30 (2H, Sirs), 8,10 (1H, d, J=2 Hz), to 7.93 (1H, DD, J=2, 8 Hz), 7,72 (1H, d, J=8 Hz), with 3.27 (3H, s) and 3,17 (3H, s).

D) 3,4-dimethanesulfonate.

A solution of the diamine (2 g) in pyridine (10 ml) at 0°C is treated with methanesulfonamide (3 ml). The resulting mixture is left at room temperature for 12 hours, then poured onto ice and hydrochloric acid (3M, 50 ml) and the resulting mixture is filtered, resulting in the product in the form of a crystalline solid, white (1,21 g, 30%).

1H NMR ((CD3)2CO) of 8.37 (1H, d, J=2 Hz), 8,24 (1H, DD, J=2, 8 Hz), 7,86 (1H, d, J=8 Hz), to 3.34 (3H, s) or 3.24 (3H, s).

E) 3,4-dimethanesulfonate.

A suspension of 3,4-dimethanesulfonate (1.2 g) in methanol (50 ml) and utilized is those (50 ml) is stirred in hydrogen atmosphere in the presence of palladium-on-coal (10%, 10 mg) for 18 hours. The catalyst was removed by filtration through celite and the solvent is removed in vacuo, resulting in the amine (1.0 g) as a brown resin. It is used without additional purification.

F) N-(3,4-dimethanesulfonate)-3,4-dimethanesulfonate (called DC0051-GH).

A suspension of acid (1.5 g) and amine (1.5 g) with DCC (1.5 g) in dry THF (100 ml) is stirred together for 12 hours, then the solvent is removed in vacuum. Methanol (50 ml) is added to the residue and filtered off the solid white color. The suspension of the residue in the additional amount of methanol (50 ml) followed by filtration gives a remainder of the crude product in the form of solid substances not quite white. This substance is suspended in acetone (4×50 ml), filtered and the solvent is removed in vacuum, obtaining the pure product in the filtrate in the form of a solid white color.

1H NMR ((CD3)2CO) there is a 10.03 (1H, Sirs), to 8.45 (2H, Sirs), of 8.28 (1H, d, J=2 Hz)to 8.12 (1H, d, J=2 Hz), of 8.09 (1H, DD, J=2, 8 Hz), to 7.93 (1H, DD, J=2, 8 Hz), a 7.85 (1H, d, J=8 Hz), 7,63 (1H, d, J=8 Hz), 3,24 (3H, s), 3,23 (3H, s), 3,19 (3H, s) and 3,17 (3H, s).

HPLC of 30.3 minutes

Example 6

4-hydroxy-3-methanesulfonamido-N-(3-hydroxy-4-methanesulfonylaminoethyl)benzamide (referred to as DC0051-CF)

As a result of processing commercial 2-methoxy-4-nitroaniline, methansulfonate the ohms get mesalamine. Then in the catalytic reduction of the nitro group get the desired aniline, which is condensed with 4-methoxy-3-nitrobenzotrifluoride, deliver anilide. Restore using catalytic hydrogenation followed by immediate metilirovaniem gives methylamin. It will Demetriou, interacting with tribromide boron, receiving the 4-hydroxy-3-methanesulfonamido-N-(3-hydroxy-4-methanesulfonylaminoethyl)benzamide (DC0051-CF).

A) 2-methoxy-4-nitratecontaminated.

To a solution of 2-methoxy-4-nitroaniline (5 g) in pyridine (25 ml) at 0°C is added dropwise methanesulfonanilide (3.5 ml). The resulting mixture was left at 0°C for 1 hour, then brought to room temperature for 2 hours. The resulting mixture was poured on ice (100 g) and diluted hydrochloric acid (3 M, 100 ml), the resulting solid product is filtered off, then washed with water and dried, resulting in the 2-methoxy-4-nitratecontaminated (7,32 g, 98%) as a solid crystalline substances not quite white.

1H NMR (CDCl3) to 7.93 (1H, DD, J=2, 8 Hz), 7,78 (1H, d, J=2 Hz), the 7.65 (1H, d, J=8 Hz), 7.23 percent (1H, Sirs), of 4.00 (3H, s), and to 3.09 (3H, s).

B) 2-methoxy-4-aminoethylethanolamine.

A solution of 2-methoxy-4-nitratecontaminated (1 g) in methanol (20 ml)containing palladium-on-the where (10%, 100 mg), stirred at room temperature for 48 hours in an atmosphere of hydrogen. The resulting mixture was filtered through celite and then evaporated, to deliver 2-methoxy-4-aminoethylethanolamine in the form of a brown resin. It is used without purification in the next reaction.

C) 4-methoxy-3-nitro-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide.

A suspension of 4-methoxy-3-nitrobenzoic acid (1 g) in thionyl chloride (20 ml) is refluxed for two hours. The excess thionyl chloride is removed in vacuum, obtaining the resulting acid chloride in a solid white color. The specified acid chloride dissolved in dry dichloromethane (25 ml) and added dropwise to a mixture of pyridine (1 ml) and 2-methoxy-4-aminomethylenemalonate (0.4 g) in dichloromethane (5 ml).

The resulting mixture is left at room temperature for 24 hours, then added dichloromethane (50 ml) and hydrochloric acid (1 M, 50 ml), the precipitate filtered and washed with water, resulting in the 4-methoxy-3-nitro-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide (0,43 g, 54%).

1H NMR ((CD3)2CO) to 8.57 (1H, d, J=2 Hz), to 8.41 (1H, DD, J=2, 8 Hz), 7,89 (1H, d, J=2 Hz), to 7.61 (1H, d, J=8 Hz), 7,47 (1H, d, J=8 Hz), 7,40 (1H, DD, J=2, 8 Hz), 4,18 (3H, s), was 4.02 (3H, s) and 3,03 (3H, s).

D) 4-methoxy-3-methanesulfonamido-N-(3-methoxy-4-methanesulfonylaminoethyl)benzamide.

is uspension 4-methoxy-3-nitro-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide (100 mg) in methanol (20 ml) is stirred in hydrogen atmosphere in the presence of palladium-on-coal (10%, 50 mg) for 18 hours. The solvents are removed in vacuo, resulting in the resin brown. The residue is dissolved in pyridine (0.5 ml) and cooled to 0°C, then add methanesulfonanilide (0.1 ml), the mixture was incubated at 0°C for 30 minutes, then brought to room temperature for 1 hour. Add diluted hydrochloric acid (10 ml, 1 M) and dichloromethane, the organic layer emit, dried and evaporated in vacuo, resulting in the product in the form of a brown resin. In the chromatographic purification on a column of silica gel performing a gradient elution dichloromethane,

contains (0-100%) ethyl acetate, receive 3-methanesulfonamido-4-methoxy-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (65 mg, 56%) as a solid white color.

1H NMR ((CD3)2CO) being 9.61 (1H, Sirs, NH), 8,11 (1H, d, J=2 Hz), of 7.96 (1H, Sirs, NH), of 7.90 (1H, DD, J=2, 8 Hz), a 7.85 (1H, d, J=2 Hz), to 7.67 (1H, Sirs, NH), 7,39 (1H, d, J=8 Hz), 7,34 (1H, DD, J=2, 8 Hz), 7.23 percent (1H, d, J=8 Hz), was 4.02 (3H, s), of 3.94 (3H, s), 3.04 from (3H, s) and 2.95 (3H, s).

E) 4-hydroxy-3-methanesulfonamido-N-

(3-hydroxy-4-methanesulfonylaminoethyl)benzamide.

To a stirred suspension of 3-methanesulfonamido-4-methoxy-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (200 mg) in dry CH2Cl2(20 ml) under nitrogen atmosphere add trichromacy boron (0.3 ml), then p is remesiana continue for another 20 hours. Carefully add methanol (50 ml), then the solvent is evaporated in vacuum to a volume of 1 ml, repeat this 2 more times. In the chromatographic purification on a column of silica gel performing a gradient elution with chloroform containing methanol (10-20%), receive a 4-hydroxy-3-methanesulfonamido-N-(3-hydroxy-4-methanesulfonylaminoethyl)benzamide (62 mg, 33%) as crystals pale brown color.

1H NMR (CD3OD) 7,92 (1H, d, J=2 Hz), to 7.68 (1H, DD, J=2, 8 Hz), 7,51 (1H, d, J=2 Hz), 7,26 (1H, d, J=8 Hz), of 6.99 (1H, DD, J=2, 8 Hz), 6,98 (1H, d, J=8 Hz), 2,99 (3H, s) and of 2.92 (3H, s).

HPLC (method 1) 29,0 minutes

Example 7

3-hydroxy-4-methanesulfonamido-N-(4-hydroxy-3-methanesulfonylaminoethyl)benzamide (called DC0051-DE)

As a result of processing commercial 2-methoxy-5-nitroaniline by methanesulfonamido get mesalamine. Then in the catalytic reduction of the nitro group get the desired aniline, which is condensed with 3-methoxy-4-nitrobenzofurazan, deliver anilide. In the restore using catalytic hydrogenation followed by immediate metilirovaniem get mesalamine. It will Demetriou, interacting with tribromide boron, resulting in the low yield of 3-hydroxy-4-methanesulfonamido-N-(4-hydroxy-3-methanesulfonamido the Nile)benzamide (DC0051-DE), together with a large number of stable borate complex.

A) 2-methoxy-5-nitratecontaminated.

To a solution of 2-methoxy-5-nitroaniline (5 g) in pyridine (25 ml) at 0°C is added dropwise methanesulfonanilide (3.5 ml), then pyridine (0.5 ml). The resulting mixture was left at 0°C for 1 hour, then brought to room temperature for 2 hours. The resulting mixture was poured on ice (100 g) and diluted hydrochloric acid (3 M, 100 ml), the resulting solid product is filtered off, then washed with water, receiving the 2-methoxy-5-nitratecontaminated (5.2 g, 71%) as a crystalline solid is not quite white.

1H NMR (DCl3) 8,39 (1H, d, J=2 Hz), with 8.05 (1H, DD, J=2, 8 Hz), of 6.99 (1H, d, J=8 Hz), 6,97 (1H, Sirs, NH), to 4.01 (3H, s) and of 3.07 (3H, s).

B) 2-methoxy-5-aminoethylethanolamine.

A solution of 2-methoxy-5-nitratecontaminated (1 g) in methanol (20 ml)containing palladium-on-coal (10%, 100 mg), stirred at room temperature for 48 hours in an atmosphere of hydrogen. The resulting mixture was filtered through celite and then evaporated, to deliver 2-methoxy-5-aminomethylpyrimidine in the form of a brown resin. The above resin is used without purification in the next reaction.

C) 3-methoxy-4-nitro-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide.

Suspensio-methoxy-4-nitrobenzoic acid (1.5 g) in thionyl chloride (25 ml) is refluxed for two hours. The excess thionyl chloride is removed in vacuum, obtaining the acid chloride in a solid white color. The specified acid chloride dissolved in dry dichloromethane (50 ml), then added dropwise to a mixture of pyridine (1.5 ml) and 4-methoxy-3-methanesulfonylaminoethyl (1.8 g) in dichloromethane (50 ml). The resulting mixture is left at room temperature for 24 hours, then added dichloromethane (100 ml) and hydrochloric acid (1 M, 100 ml), the precipitate filtered and washed with water, resulting in the 3-methoxy-4-nitro-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (2,41 g, 80%).

1H NMR ((CD3)2CO) 9,88 (1H, Sirs, NH), 8,03 (1H, d, J=8 Hz), to 7.99 (1H, d, J=2 Hz), 7,87 (1H, DD, J=2, 8 Hz), 7,86 (1H, d, J=2 Hz), 7,81 (1H, DD, J=2, 8 Hz), 7,19 (1H, d, J=8 Hz), 4,17 (3H, s), was 4.02 (3H, s) and the 3.11 (3H, s).

D) 3-methoxy-4-methanesulfonamido-N-

(3 methanesulfonamido-4-methoxyphenyl)benzamide.

A suspension of 3-methoxy-4-nitro-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (1.4 g) in methanol (20 ml) is stirred in hydrogen atmosphere in the presence of palladium-on-coal (10%, 50 mg) for 18 hours. The solvents are removed in vacuo, resulting in the resin brown. The residue is dissolved in pyridine (5 ml) and cooled to 0°C, then add methanesulfonanilide (0.5 ml), the mixture was incubated at 0°C for another 2 hours, then brought to room temperature for 1 casabalance mixture was poured onto ice (50 g) and hydrochloric acid (3 M, 50 g)obtained solid brown color filtered and washed with water, resulting in the 4-methanesulfonamido-3-methoxy-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (1.26 g, 86%) as a solid brown color.

1H NMR ((CD3)2CO) to 9.66 (1H, Sirs, NH), 8,11 (1H, Sirs, NH), 7,88 (1H, DD, J=2, 8 Hz), 7,87 (1H, d, J=2 Hz), to 7.84 (1H, Sirs, NH), 7,79 (1H, d, J=2 Hz), 7,76 (1H, DD, J=2, 8 Hz), the 7.65 (1H, d, J=8 Hz), 7,17 (1H, d, J=8 Hz), 4,08 (3H, s)to 4.01 (3H, s), and 3.16 (3H, s), and the 3.11 (3H, s).

E) 3-hydroxy-4-methanesulfonamido-

N-(3-methanesulfonamido-4-hydroxyphenyl)benzamide.

To a stirred suspension of 4-methanesulfonamido-3-methoxy-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (1.25 g) in dry CH2Cl2(50 ml) under nitrogen atmosphere add trichromacy boron (1.5 ml), and then stirring is continued for another 20 hours. Carefully add methanol (50 ml), then the solvent is evaporated in vacuum to a volume of 1 ml, repeat this 2 more times. In the chromatographic purification on a column of silica gel performing a gradient elution with chloroform containing methanol (10-20%), receive 3-hydroxy-4-methanesulfonamido-N-(3-methanesulfonamido-4-hydroxyphenyl)benzamide (143 mg, 15%) as a solid substance not quite white.

1H NMR ((CD3)2CO) of 9.55 (1H, Sirs), 8,82 (1H, Sirs), 7,87 (1H, d, J=2 Hz), 7,73 (1H, DD, J=2, 8 Hz), 7,69 (1H, d, J=2 Hz), to 7.64 (1H, d is, J=2, 8 Hz), to 7.59 (1H, d, J=8 Hz),? 7.04 baby mortality (1H, d, J=8 Hz), and 3.16 (3H, s) and 3.12 (3H, s).

HPLC (method 1) to 29.5 minutes

Example 8

3-hydroxy-4-methanesulfonamido-N-(3-hydroxy-4-methanesulfonylaminoethyl)benzamide (called DC0051-DF)

As a result of processing commercial 2-methoxy-4-nitroaniline by methanesulfonamido get mesalamine. Then in the catalytic reduction of the nitro group get the desired aniline, which is condensed with 3-methoxy-4-nitrobenzofurazan, deliver anilide. In the restore using catalytic hydrogenation followed by immediate metilirovaniem get mesalamine. It will Demetriou, interacting with tribromide boron, receiving the 3-hydroxy-4-methanesulfonamido-N-(3-hydroxy-4-methanesulfonylaminoethyl)benzamide (DC0051-DF).

A) 2-methoxy-4-nitratecontaminated.

To a solution of 2-methoxy-4-nitroaniline (5 g) in pyridine (25 ml) at 0°C is added dropwise methanesulfonanilide (3.5 ml). The resulting mixture was left at 0°C for 1 hour, then brought to room temperature for two hours. The resulting mixture was poured on ice (100 g) and diluted hydrochloric acid (3 M, 100 ml), the resulting solid product is filtered off, then washed with water and dried, resulting in the 2-methox the-4-nitratecontaminated (7,32 g, 98%) as a solid crystalline substances not quite white.

1H NMR (CDCl3) to 7.93 (1H, DD, J=2, 8 Hz), 7,78 (1H, d, J=2 Hz), the 7.65 (1H, d, J=8 Hz), 7.23 percent (1H, Sirs), of 4.00 (3H, s), and to 3.09 (3H, s).

B) 2-methoxy-4-aminoethylethanolamine.

A solution of 2-methoxy-4-nitratecontaminated (1 g) in methanol (20 ml)containing palladium-on-coal (10%, 100 mg), stirred at room temperature for 48 hours in an atmosphere of hydrogen. The resulting mixture was filtered through celite and then evaporated, to deliver 2-methoxy-4-amino-methanesulfonylaminoethyl in the form of a brown resin. It is used without purification in the next reaction.

C) 3-methoxy-4-nitro-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide.

A suspension of 3-methoxy-4-nitrobenzoic acid (1.5 g) in thionyl chloride (20 ml) is refluxed for two hours. The excess thionyl chloride is removed in vacuum, obtaining the resulting acid chloride in a solid white color. A solution of the obtained acid chloride (1.64 g) in dichloromethane (50 ml) are added to a suspension of 4-methylamino-3-methoxyaniline (1.75 g) in dichloromethane (50 ml) and then added pyridine (1.5 ml). The resulting mixture was refluxed for 2 hours, then leave at room temperature overnight. The resulting mixture was added to dichloromethane (100 ml) and hydrochloric KIS the OTE (3 M, 50 ml), the precipitate filtered off, washed with water (100 ml), then dried, obtaining as a result of 3-methoxy-4-nitro-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide (2,03 g, 67%).

1H NMR ((CD3)2CO) to 9.91 (1H, Sirs, NH), with 8.05 (1H, d, J=8 Hz), 7,98 (1H, d, J=2 Hz), of 7.90 (1H, d, J=2 Hz), 7,81 (1H, Sirs, NH), 7,80 (1H, DD, J=2, 8 Hz), to 7.50 (1H, d, J=8 Hz), 7,39 (1H, DD, J=2, 8 Hz), 4,18 (3H, C)was 4.02 (3H, s) and 3.04 (3H, s).

D) 4-methanesulfonamido-3-methoxy-N-

(4 methanesulfonamido-3-methoxyphenyl)benzamide.

A suspension of 3-methoxy-4-nitro-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide (2,03 g) in methanol (50 ml) and ethyl acetate (50 ml) is stirred in hydrogen atmosphere in the presence of palladium-on-coal (10%, 50 mg) for 18 hours. The solvents are removed in vacuo, resulting in the resin brown. The residue is dissolved in pyridine (5 ml) and cooled to 0°C, then add methanesulfonanilide (1 ml), the mixture was incubated at 0°C for another 2 hours, then brought to room temperature for 1 hour. The resulting mixture was poured onto ice (50 g) and hydrochloric acid (3 M, 50 g)obtained brown solid product is filtered off and washed with water, resulting in the 4-methanesulfonamido-3-methoxy-N-(4-methanesulfonamido-3-methoxyphenyl)benzamide (2.1 g, 100%) as a solid pale brown color.

1H NMR ((CD3)2CO) RS 9.69 (1H, Sirs, N), of 8.15 (1H, Sirs, NH), to 7.93 (1H, d, J=2 Hz), 7,78 (1H, d, J=2 Hz), 7,76 (1H, Sirs, NH), 7,74 (1H, DD, J=2, 8 Hz), 7,66 (1H, d, J=8 Hz), 7,47 (1H, d, J=8 Hz), 7,40 (1H, DD, J=2, 8 Hz), 4.09 to (3H, s)that was 4.02 (3H, s), 3,17 (3H, s) and 3,03 (3H, s).

E) 4-methanesulfonamido-3-hydroxy-N-

(4 methanesulfonamido-3-hydroxyphenyl)benzamide.

To a stirred suspension of 4-methanesulfonamido-3-methoxy-N-(3-methanesulfonamido-4-methoxyphenyl)benzamide (2 g) in dry CH2Cl2(50 ml) under nitrogen atmosphere add trichromacy Bor (2 ml) and the resulting orange suspension is left for 3 hours. Carefully add methanol (50 ml) and the solution stand overnight. The solvent is evaporated in vacuum to a volume of 1 ml, then add methanol (50 ml), repeat this 2 more times. In the chromatographic purification on a column of silica gel performing a gradient elution with chloroform containing methanol (10-20%), receive a 4-methanesulfonamido-3-hydroxy-N-(4-methanesulfonamido-3-hydroxyphenyl)benzamide (DC0051-DF) (0.74 g, 40%) as a brown resin.

1H NMR ((CD3)2SO) 10,37 (1H, Sirs, NH), of 10.21 (1H, Sirs, NH), of 10.01 (1H, Sirs, NH), 9,05 (1H, Sirs, OH), 8,76 (1H, Sirs, OH), to 7.68 (1H, Sirs), 7,53 (1H, Sirs), 7,51 (1H, DD, J=2, 8 Hz), was 7.45 (1H, d, J=8 Hz), 7,21 (2H, Sirs), 3,14 (3H, s) and 3,03 (3H, s).

HPLC (method 1) of 29.4 min

Example 9

2-oxo-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,3-dihydro-1H-benzo[d]imidazol-5-carboxamide (referred to as DC-0051-B1)

Amide synthesized through reaction of 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid with 5-amino-2,3-dihydro-1H-benzoimidazol-5-one in the presence of 1,3-N,N-diisopropylcarbodiimide and 1-hydroxybenzotriazole.

1,3-N,N-diisopropylcarbodiimide (0,504 g, 4 mmol) are added to a solution of 2-oxo-2,3-dihydro-1H-benzoimidazol-5-carboxylic acid (0,448 g, 2.5 mmol), 5-amino-2-oxo-2,3-dihydro-1H-benzimidazole and 1-hydroxybenzotriazole (0.34 g, 2.5 mmol) in anhydrous N,N-dimethylformamide (10 ml). The reaction mixture was stirred at 40°C for 12 hours. Phase precipitate the product produce by filtration of the reaction mixture with subsequent three-time washing with N,N-dimethylformamide (3 ml). The product is dissolved in dimethyl sulfoxide (5 ml) and precipitated by adding a solution of acetonitrile (60 ml). After filtration and drying under vacuum to obtain 2-oxo-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2,3-dihydro-1H-benzo[d]imidazol-5-carboxamid (also referred to as DC-0051-B1) (0,22 g, 28%).

1H NMR ((CD3)2SO to 10.62 (1H, s, NH), 10,53 (1H, s, NH), 9,98 (1H, s, NH), the 7.65 (1H, d, J=8 Hz), 7,55 (2H, Sirs), of 7.23 (1H, d, J=8 Hz), 7,05 (1H, d, J=8 Hz), a 7.85 (1H, d, J=8 Hz).

Example 10

N-(3,4-dihydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxamide (referred to as DC-0051-B2).

3,4-dihydroxy-1-nitrobenzene benzylium using boiling reverse Kholodilin the ball benzylbromide with potassium carbonate as the base, in acetone, after recovery detonator sodium leads to the production of 3,4-dibenzoylacetylene. Its attached to 2-oxo-2,3-dihydro-1H-benzoimidazol-5-carboxylic acid using N,N-1,3-diisopropylcarbodiimide in the presence of 1-hydroxybenzotriazole, to obtain the amide. Then the obtained amide dibenzyline, Giriraja in the presence of palladium-on-charcoal grill.

A) 3,4-dimensions-1-nitrobenzene.

Potassium carbonate (4,14 g; 30 mmol) are added to a solution of 3,4-dihydroxy-1-nitrobenzene (1.55 g; 10 mmol) and benzylbromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture is refluxed for 12 hours. After removal of the solvent under reduced pressure the residue is divided between ethyl acetate (150 ml) and water (50 ml). An ethyl acetate layer washed with water (100 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure to obtain 2.37 g of 3,4-dimensions-1-nitrobenzene. (Yield=70%.)

1H NMR (CDCl3) a 7.85 (1H, d, J=8 Hz), and 7.8 (1H, s), 7,28-to 7.50 (m, 10H), to 6.95 (1H, d, J=8 Hz), of 5.24 (s,2H), total of 5.21 (s,2H).

(B) 3,4-dibenzalacetone.

Dithionite sodium (2 g) are added to a solution of 3,4-dimensions-1-nitrobenzene (2.37 g) in methanol (30 ml)/aqueous ammonia (5 ml). After stirring for 12 hours at room temperature the solvent is removed under reduced pressure. The residue is divided between ethyl acetate (75 ml) and water (75 ml An ethyl acetate layer washed with water (25 ml), brine (25 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. In the purification using flash chromatography on a column of silica gel by elution with a mixture of ethyl acetate/hexane (1:1)obtain 1.0 g of 1-benzyloxy-2-methoxy-5-aminobenzoate. (Yield=47%.)

1H NMR (CDCl3) 7,27-7,47 (10H, m), 6,8 (1H, d, J=8 Hz), 6,37 (1H, s), from 6.22 (1H, d, J=8 Hz), 5,13 (2H, s), is 5.06 (2H, s), 3,49 (2H, Sirs, NH2).

C) 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxyl(1-N-3,4-dibenzalacetone)amide

1,3-N,N-diisopropylcarbodiimide (0,412 g of 3.27 mmol) are added to a solution of 2-oxo-2,3-dihydro-1H-benzoimidazol-5-carboxylic acid (0,584 g of 3.27 mmol), 3,4-dibenzoylacetylene (1.0 g, of 3.27 mmol) and 1-hydroxybenzotriazole (0,442 g of 3.27 mmol) in anhydrous N,N-dimethylformamide (15 ml). After stirring for 16 hours at room temperature the reaction mixture was poured into water (150 ml). the pH of the resulting mixture adjusted to 2 using 1 n hydrochloric acid, and stirred for 30 minutes. After filtering and washing the product with ethyl acetate (3×10 ml) receive 1.12 grams of 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxyl(1-N-3,4-dibenzalacetone)amide.

Output=73,6%.

1H NMR (CD3)2SO to 10.5 (1H, s, NH), the 7.65 (1H, d, J=8 Hz), and 7.6 (1H, s), 7,2-7,6 (m, 12H), 7,0 (2H, d, J=8 Hz), 5,15 (4H, s).

D) N-(3,4-dihydroxyphenyl)-2-oxo-2,3-Digi the ro-1H-benzo[d]imidazol-5-carboxamid

A solution of 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxyl(1-N-3,4-dibenzalacetone)amide (1.10 g) in a mixture of acetic acid (100 ml) and N,N-dimethylformamide (25 ml) hydronaut at 40 psi in the presence of 10% palladium-on-coal for 12 hours at room temperature. After removal of catalyst by filtration, the solvent is removed under reduced pressure. The residue is dissolved in N,N-dimethylformamide (15 ml) and the product precipitated by diluting with a mixture of hexane/ethyl acetate (1:1) (100 ml). After filtration receive 0,550 g of N-(3,4-dihydroxyphenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide. Yield 81%.

1H NMR (CD3)2SO 10,94 (1H, Sirs), 9,86 (1H, s), cent to 8.85 (1H, Sirs), to 7.61 (1H, d, J=8 Hz), to 7.59 (1H, s), and 7.3 (1H, s)to 7.0 (1H, d, J=8 Hz), of 6.96 (1H, d, J=8 Hz), of 6.66 (1H, d, J=8 Hz).

HPLC (method 2) 3,256 minutes

Example 11

3,4-dihydroxy-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzamide (referred to as DC-0051-B3).

3,4-dihydroxybenzoic acid is converted into its methyl ester by boiling under reflux in the presence of acid. Dihydroxy group protects as its benzyl ether, processing benzylbromide and potassium carbonate. As a result of hydrolysis of ester with sodium hydroxide receive acid, which is added to 5-amino-2,3-dihydro-1H-benzoimidazol-5-ONU, using N,N-1,3-diisopropylcarbodiimide in the presence of 1-hydroxybenzo is rezola to obtain the amide. Specified amide dibenzyline, by hydrogenation in the presence of palladium-on-charcoal grill.

A) Methyl ester of 3,4-dihydroxybenzoic acid.

A solution of 3,4-dihydroxybenzoic acid (2.8 g) in methanol (150 ml) is refluxed in the presence of concentrated hydrochloric acid (0.5 ml) within 12 hours. After concentration under reduced pressure the residue is dissolved in ethyl acetate (150 ml) and washed with water (50 ml), 10% sodium bicarbonate solution (50 ml), brine (50 ml) and dried over anhydrous magnesium sulfate. Removing the solvent under reduced pressure, to obtain 2.64 g of methyl ester of 3,4-dihydroxybenzoic acid. (Output=86,5%.)

1H NMR (CDCl3) and 7.7 (1H, s), 7,63 (1H, d, J=8 Hz), 6,92 (1H, d, J=8 Hz), 5,7(2H, Sirs), to 3.92 (3H, s).

B) Methyl ester of 3,4-dibenzalacetone acid.

Potassium carbonate (6.5 g; 47 mmol) are added to a solution of methyl ester of 3,4-dihydroxybenzoic acid (2.6 g; 15.7 mmol) and benzylbromide (lower than the 5.37 g; of 31.4 mmol) in acetone (100 ml). The reaction mixture is refluxed for 12 hours. After removal of the solvent under reduced pressure the residue is divided between ethyl acetate (150 ml) and water (50 ml). An ethyl acetate layer washed with water (50 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure get to 3.36 g metrov the th ether 3,4-dibenzalacetone acid. (Output=86,6%.)

1H NMR (CDCl3) to 7.67 (1H, s), the 7.65 (1H, d, J=8 Hz), 7,28-to 7.50 (m, 10H), to 6.95 (1H, d, J=8 Hz), of 5.24 (s, 2H), total of 5.21 (s, 2H), with 3.89 (s, 3H).

(C) 3,4-dibenzalacetone acid.

A solution of sodium hydroxide (1.2 g) in methanol (100 ml) was added to a solution of methyl ester of 3,4-dibenzalacetone acid (with 4.64 g) in methanol (50 ml) and refluxed for 4 hours. After removal of methanol under reduced pressure the residue is dissolved in water (100 ml) and washed with ethyl acetate (2×50 ml). The aqueous layer was acidified with 2 n hydrochloric acid to pH 2. Precipitated precipitated product is collected by filtration and after drying in the vacuum receiving 2.4 g of 3,4-benzyloxybenzyl acid. (Yield=74%.)

1H NMR CDCl3to 7.7 (2H, Shir., C), 7,27-to 7.5 (10H, m), 6,98 (1H, d, J=8 Hz), of 5.26 (2H, s), with 5.22 (2H, s).

D) 3,4-dimensions-(5-N-2-oxo-2,3-dihydro-1H-benzoimidazolyl)benzamide.

1,3-N,N-diisopropylcarbodiimide (0,945 g, 7.5 mmol) are added to a solution of 3,4-dibenzalacetone acid (1,67 g, 5 mmol), 5-amino-2,3-dihydro-1H-benzoimidazol-5-it (0,745 g, 5 mmol) and 1-hydroxybenzotriazole (0,675 g, 5 mmol) in anhydrous N,N-dimethylformamide (20 ml). After stirring for 16 hours at room temperature the reaction mixture was poured into water (100 ml). the pH of the mixture was adjusted to 2 using 1 n hydrochloric acid, and stirred for 30 minutes. After filtering and washing the product with ethyl acetate (3 the 10 ml) receive 1.06 grams of 3,4-dimensions-(5-N-2-oxo-2,3-dihydro-1H-benzoimidazolyl)benzamide. (Output=45.7 per cent.)

1H NMR (CD3)2SO 9,94 (1H, s), 7,65-7,2 (14H, m), to 7.09 (2H, d, J=8 Hz), 5,1 (4H, s).

E) 3,4-dihydroxy-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzamide.

A solution of 3,4-dimensions-(5-N-2-oxo-2,3-dihydro-1H-benzoimidazolyl)benzamide (1.06 g; 2.28 mmol) in acetic acid (120 ml) hydronaut at 40 psi in the presence of 10% palladium-on-coal for 12 hours at room temperature. After removal of catalyst by filtration, the solvent is removed under reduced pressure. The residue is dissolved in N,N-dimethylformamide (15 ml) and the product precipitated by diluting with a mixture of hexane/ethyl acetate (1:1) (100 ml). After filtration receive 0,334 g of 3,4-dihydroxy-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzamide. Output=50%.

1H NMR (CD3)2SO 10,54 (1H, Sirs), 9,78 (1H, s), 9,41 (1H, Sirs), 7,54 (1H, s), 7,37 (1H, s), 7,32 (1H, d, J=8 Hz), 7.23 percent (1H, d, J=8 Hz), 6,85 (1H, d, J=8 Hz), to 6.80 (1H, d, J=8 Hz).

HPLC (method 2) 2,34 minutes

Example 12

3-hydroxy-N-(3-hydroxy-4-methoxyphenyl)-4-methoxybenzamide (called

DC-0051-B4).

3-hydroxy-4-methoxy-1-nitrobenzene benzylium by boiling under reflux with benzylbromide, with potassium carbonate as the base in acetone, after recovery dithionite sodium gives 3-benzyloxy-4-methoxyaniline. 4-hydroxy-3-methoxybenzoic acid is converted into its methyl ester in the boiling from about ATiM refrigerator in methanol in the presence of acid. The resulting hydroxyl benzylium using benzylbromide and potassium carbonate. The obtained ester hydrolyzing using sodium hydroxide and receiving acid. Carry out the reaction of the accession of aniline and acid using N,N-1,3-diisopropylcarbodiimide in the presence of 1-hydroxybenzotriazole and receiving amide. Finally, the benzyl group is removed using hydrogenation in the presence of palladium-on-charcoal grill.

A) 1-benzyloxy-2-methoxy-5-nitrobenzene.

Potassium carbonate (1.65 g; 12 mmol) are added to a solution of 2-methoxy-5-NITROPHENOL (1,69 g; 10 mmol) and benzylbromide (1,71 g; 10 mmol) in acetone (60 ml). The reaction mixture is refluxed for 12 hours. The solvent is removed under reduced pressure and the residue is divided between ethyl acetate (150 ml) and water (50 ml). An ethyl acetate layer emit, washed with water (2×50 ml), dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure to obtain 2.5 g of 1-benzyloxy-2-methoxy-5-nitrobenzene. (Output=96,5%.)

1H NMR (CDCl3) to 7.95 (1H, d, J=8 Hz), 7,81 (1H, s), 7,3-7,5 (5H, m), 6,92 (1H, d, J=8 Hz), further 5.15 (2H,s), of 3.95 (3H, s).

B) 1-Benzyloxy-2-methoxy-5-aminobenzo.

Dithionite sodium (1.5 g) are added to a solution of 1-benzyloxy-2-methoxy-5-nitrobenzene (2.5 g) in methanol (20 ml)/aqueous ammonia (4 ml). After stirring for 12 hours at room temperature the solvent is removed is under reduced pressure. The residue is divided between ethyl acetate (75 ml) and water (50 ml). An ethyl acetate layer washed with water (25 ml), brine (25 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After purification using flash chromatography on a column of silica gel, elwira a mixture of ethyl acetate/hexane

(1:1), receive 0,771 g of 1-benzyloxy-2-methoxy-5-aminobenzoate. (Yield=35%.)

1H NMR (CDCl3) of 7.25 and 7.5 (5H, m), is 6.78 (1H, d, J=8 Hz), 6.35mm (1H, s), 6,28 (1H, d, J=8 Hz), a 5.1 (2H, s), and 3.8 (3H, s).

C) Methyl ester of 4-hydroxy-3-methoxybenzoic acid.

A solution of 4-hydroxy-3-methoxybenzoic acid (7.2 g) in methanol (150 ml) is refluxed in the presence of concentrated hydrochloric acid (0.5 ml) within 12 hours. After concentration under reduced pressure the residue is dissolved in ethyl acetate (200 ml) and washed with water (50 ml), 10% sodium bicarbonate solution (2×50 ml), water (50 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure gain of 7.25 g of methyl ester of 4-hydroxy-3-methoxybenzoic acid. (Output=91,5%.)

1H NMR (CDCl3) the 7.65 (1H, d, J=8 Hz), 7,55 (1H, s), to 6.95 (1H, d, J=8 Hz), x 6.15 (1H, Sirs, -OH), of 3.95 (3H, s)of 3.9 (3H, s).

D) Methyl ester of 4-benzyloxy-3-methoxybenzoic acid.

Potassium carbonate (3,45 g; 25 mmol) are added to a solution of methyl ester 4-hydroxy-3-methoxybenzoic the acid (3.6 g; 20 mmol) and benzylbromide (3.42 g; 20 mmol) in acetone (100 ml). The reaction mixture is refluxed for 12 hours. After removal of the solvent under reduced pressure the residue is divided between ethyl acetate (150 ml) and water (50 ml). An ethyl acetate layer washed with water (50 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure get with 4.64 g of methyl ester of 4-benzyloxy-3-methoxybenzoic acid. (Output=86,6%.)

E) 4-benzyloxy-3-methoxybenzoic acid.

A solution of sodium hydroxide (2.0 g) in methanol (50 ml) was added to a solution of methyl ester 4-benzyloxy-3-methoxybenzoic acid (with 4.64 g) in methanol (50 ml) and refluxed for 4 hours. After removal of methanol under reduced pressure the residue is dissolved in water (150 ml) and washed with ethyl acetate (2×50 ml). The aqueous layer was acidified using 2 N. hydrochloric acid to pH 2. Precipitated precipitated product is collected by filtration and after drying it in vacuum get to 4.17 g of 4-benzyloxy-3-methoxybenzoic acid. (Yield=74%.)

1H NMR (CDCl3) and 7.7 (1H, d, J=8 Hz), 7,63 (1H, s), 7,3-7,5 (5H, m), 6,92 (1H, d, J=8 Hz), a 5.25 (2H, s), 3,98 (3H, s).

F) 4-benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide.

N N-1,3-diisopropylcarbodiimide (0.40 g, to 3.36 mmol) are added to a solution of 1-benzyloxy-2-methoxy-5-aminobenzoate (0,771 g, to 3.36 mmol who), 4-benzyloxy-3-methoxybenzoic acid (0.87 g, to 3.36 mmol) and 1-hydroxybenzotriazole (0,454 g, to 3.36 mmol) in N,N-dimethylformamide (15 ml) and stirred for 12 hours. The product is precipitated by adding a mixture of ethyl acetate/hexane (1:1) (120 ml). In the filtration of the reaction mixture obtain 1.12 g of 4-benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide. Yield=69%.

1H NMR (CD3)2SO to 9.93 (1H, s), 7,29-to 7.59 (14H, m), 7,16 (1H, d, J=8 Hz), of 6.96 (1H, d, J=8 Hz), is 5.18 (2H, s), is 5.06 (2H, s), 3,85 (3H, s), 3,76 (3H, s).

G) 3-hydroxy-N-(3-hydroxy-4-methoxyphenyl)-4-methoxybenzamide.

A solution of 4-benzyloxy-3-methoxy-N-(3-benzyloxy-4-methoxyphenyl)benzamide (1,05 g) in a mixture of N,N-dimethylformamide/methanol (1:5, 120 ml) hydronaut in the presence of 10% palladium-on-the angle at 40 psi at room temperature for 12 hours. After removal of catalyst by filtration and purification using flash chromatography on a column of silica gel, elwira a mixture of 65% ethyl acetate/hexane to obtain 0.26 g of 3-hydroxy-N-(3-hydroxy-4-methoxyphenyl)-4-methoxybenzamide. Output=41,6%.

1H NMR (CD3)2SO 9,73 (1H, s), 9,62 (1H, Sirs), 8,99 (1H, Sirs), and 7.5 (1H, s), 7,45 (1H, d, J=8 Hz), 7,29 (1H, s), to 7.09 (1H, d, J=8 Hz), 6,85 (1H, d, J=8 Hz), of 3.84 (3H, s), 3,74 (3H, s).

M/z 290 (M+H+), 312 (M+Na+), 100%).

HPLC (method 2) 3,86 minutes

Example 13

The following connections will be received, using methods similar to described here:

i) DC-0051-A2, so named the e DC-0051-S2

ii) DC-0051-A3, also referred to as DC-0051-S3

iii) DC-0051-A4, also referred to as DC-0051-S4

iv) DC-0051-A5, also referred to as DC-0051-S5

v)

2,4-bis(3,4-dihydroxybenzyl)-8-methyl-8-azabicyclo[3.2.1]Octan-3-one

Example 14

Borate complex of 4-hydroxy-3-methanesulfonamido-N-(4-hydroxy-3-methanesulfonylaminoethyl)benzamide (hereinafter referred to as borate complex DC0051-CE).

As a result of processing commercial 2-methoxy-5-nitroaniline by methanesulfonamido get mesalamine. Then in the catalytic reduction of the nitro group get the desired aniline, which is condensed with 4-methoxy-3-nitrobenzotrifluoride, deliver anilide. After the restoration, carried out by catalytic hydrogenation, followed by immediate metilirovaniem get mesalamine. In demethylation in normal conditions are stable form borate complex of the desired product.

Example 15

The present compounds are effective RA is rosielee fibrils of Alzheimer's Aβ 1-42.

It was found that obtained in the preceding examples, the compounds are effective disruptors/inhibitors of Aβ fibrils of Alzheimer's disease. In a number of studies have analyzed the effectiveness of some proposed here compounds for their ability to cause removal/destruction of previously formed fibrils of Alzheimer's disease (i.e. consisting of Aβ 1-42 fibrils).

Part a - the Results of fluorimetry of Thioflavin T

In one study, a fluorometry of thioflavin T are used to determine the effects of compounds and EDTA (as negative control). In this analysis tioflavin T specifically binds to fibrillar amyloid, and this binding is increased fluorescence at a wavelength of 485 nm, which is directly proportional to the number formed amyloid fibrils. The more intense fluorescence, the greater the number of amyloid fibrils formed (Naki et al., Lab. Invest. 65:104-110, 1991; Levine III, Protein Sci. 2:404-410, 1993; Amyloid:Int. J. Exp.Clin. Invest. 2:1-6, 1995).

In this study, 25 μm of pre-fibrillating Aβ 1-42 (Bachem Inc) incubated at 37°C for three days, or separately, or in the presence of one of the compounds or EDTA (at a weight ratio of Aβ:test compound

1:1, 1:0,1, 1:0,01 or 1:0,001). After 3 days of co-incubation with 50 μl each of inkubiruemykh mixtures p is rinoseat in 96-well microtiter plate, containing 150 ál of distilled water and 50 μl of a solution of thioflavin T (i.e. 500 mm thioflavin T in 250 mm phosphate buffer, pH 6,8). The values of fluorescence read at a wavelength of 485 nm (444 nm wavelength excitation)using ELISA tablet fluorimeter after subtraction of values for a single buffer or a single connection as a control.

The results obtained after 3-day incubation, presented next. For example, whereas EDTA does not cause significant inhibition/destruction of Aβ 1-42 fibrils at all tested concentrations, the compounds (DC-0051, DC-0051-S1, S3, S4, S5, S6, S7, S8 and S9) all cause dose-dependent disruption/disassembly of previously formed Aβ 1-42 fibrils to some extent (table 1). For example, compound DC-0051-S8 causes a significant (p<0,01) 87,9+/-0,78% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:0,1, and visible

56,0+/-11,32% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:0,01 (table 1). In the same conditions (i.e. with weight./weight. the ratio of Aβ:test compound 1:0.01) compound DC-0051 calls to 89.5+/-3,26% destruction, compound DC-0051-S5 causes 80,0+/-0,63% destruction and compound DC-0051-S9 causes 84,1+/-4,28% destruction. A study shows that the present compounds are disruptors/inhibitors of Aβ fibrils of type of disease, Alzhe the measure and usually manifest their effect dose-dependent manner.

Table 1
The results of fluorimetry of thioflavin T - Destruction of Aβ 1-42 fibrils of the tested compounds (% inhibition of Aβ; for the weight./weight. relations Aβ:test compound)

Part B: Results of SDS-PAGE/Western blotting

The destruction of Aβ 1-42, even in their Monomeric form, highlight research involving the use of SDS-PAGE and Western blotting (not shown). In this last study has been prepared in triplicate samples prefabrication Aβ 1-42 (25 μm) incubated at 37°C for 3 days, separately or in the presence of the compounds or EDTA. Then five micrograms of each sample was filtered through a 0.2 μm filter. Then a protein isolated from the filtrate, load and render in 10-20% Tris-tricin SDS-PAGE, printed on nitrocellulose, and detected using Aβ-antibody (clone 6E10; Senetek). In this study, Aβ 1-42 detected as a band of ~4 kilodaltons (i.e. Monomeric Aβ) followed by incubation alone or in the presence of EDTA for 3 days. For example, Aβ 1-42 monomers are not detected after incubating Aβ 1-42 with connections DC-0051, DC-0051-S1, DC-0051-S5, DC-OO51-S8 and DC-0051-S9, which dovetails nicely with fluorimetric data for thioflavin T (disclosed to enter is) and suggests, these compounds are able wyswietl disappearance of Monomeric Aβ 1-42. This study confirms that these compounds are able to cause the destruction/removal of Monomeric Aβ 1-42.

Part C: results of the binding of Congo red

In the analysis of the binding of Congo red to quantitatively determine the ability of test compounds to alter amyloid (in this case, Aβ), associating with Congo red. In this assay, Aβ 1-42 and test compounds are incubated for 3 days and then carry out vacuum filtration through a 0.2 μm filter. Quantitatively determine the amount of Aβ 1-42, remaining on the filter with subsequent staining with Congo red. After appropriate washing, any reduction in the color of Congo red on the filter in the presence of the test compound (compared with Congo red staining of amyloid protein in the absence of the test compound) is indicative of the ability of test compounds to reduce/change the number of aggregated and congophilic Aβ. This particular analysis is probably more accurate than fluorometry of thioflavin T, and more difficult to remove Congo red, is associated with Aβ 42 fibrils, rather than to evaluate with other analyses, so that the % inhibition observed even with effective compounds are usually lower than % and is generowania, observed when using other tests, such as fluorometry for thioflavin T.

In one study, determine the capacity of β to connect with Congo red in the absence or in the presence of increasing amounts of the compounds or EDTA (at the weight./weight. relations Aβ:test compound 1:0,001, 1:0,01, 1:0,1 1:1). The results obtained after 3 days of incubation, presented below in table 2. If EDTA does not cause significant inhibition of binding of A(1-42 fibrils with Congo red, connection (DC-0051, DC-0051-S1, S3, S4, S5, S6, S7, S8 and S9) cause dose-dependent inhibition of A(binding of Congo red (table 2). For example, compound DC-0051-S5 causes noticeable to 82.3+/-0,59% inhibition of binding of Congo red with Aβ 1-42 fibrils, if it is used for weight./weight. the ratio of Aβ:test compound 1:1, and 40.3+/-5,81%if it is used for weight./weight. the ratio of Aβ:test compound 1:0,1 (table 2). Other good inhibitors when compared with the weight./weight. relations with Aβ:test compound 1:0,1, apparently, are DC-0051-S1 (19,7+/-2,97% inhibition), DC-0051 (40,3+/-5,81% inhibition), DC-0051-S6 (17,1+/-4,94% inhibition), DC-0051-S8 (19,8+/-2,43% inhibition) and DC-0051-S9 (17,4+/-6,11% inhibition).

Table 2
Results binding of Congo red - Destruction of Aβ 1-42 fibrils under test, the compounds (% inhibition of Aβ; for a specific weight./weight. relations Aβ:test compound)

Example 16

Presented here further connections are effective destroyers of Aβ 1-42 fibrils of Alzheimer's disease.

It was found that obtained in the preceding examples, the compounds are effective disruptors/inhibitors of Aβ fibrils in Alzheimer's disease. In another group of studies have analyzed the effectiveness of some compounds represented here (and referred to as DC-0051-B2, DC-0051-B3 and DC-0051-B4) to cause the removal/destruction of previously formed amyloid fibrils in Alzheimer's disease (i.e. consisting of Aβ 1-42 fibrils).

The results obtained in fluorimetry of thioflavin T

In one study, a fluorometry of thioflavin T are used to determine the effect of compounds and EDTA (as negative control). In this analysis tioflavin T binds specifically to fibrillar amyloid, and this binding is increased fluorescence at a wavelength of 485 nm, which is directly proportional to the number formed amyloid fibrils. The more intense fluorescence, the greater the number of amyloid fibrils formed (Naki et al., Lab. Invest. 65:104-110, 1991; Levine III, Protein Sci. 2:404-410,1993; Amyloid: Int. J. Exp.Clin. Invest. 2:1-6, 1995).

This research is the training of 25 μm of pre-hybridisierung Aβ 1-42 (Bachem Inc) incubated at 37°C for 3 days either alone or in the presence of one of the compounds (DC-0051-B2, DC-0051-B3 or DC-0051-B4). After 3 days of co-incubation 50 μl of each incubation mixtures are transferred into 96-well microtiter plate containing 150 μl of distilled water and 50 μl of a solution of thioflavin T (i.e. 500 mm thioflavin T in 250 mm phosphate buffer, pH 6,8). The intensity of the fluorescence read at a wavelength of 485 nm (wavelength of 444 nm excitation)using ELISA tablet fluorimeter, after subtraction of values for a single buffer or connection separately, as a control).

The results obtained after 3-day incubation, presented next. For example, if EDTA does not cause significant inhibition/destruction of Aβ 1-42 fibrils at all tested concentrations, the compounds (DC-0051-B2, DC-0051-B3 and DC-0051-B4) all cause dose-dependent disruption/disassembly of previously formed Aβ 1-42 fibrils to some extent (table 3). The most effective compound against the destruction of previously formed Aβ 1-42 fibrils according to the fluorimetric analysis of thioflavin T is, apparently, DC-0051-B2. For example, compound DC-0051-B2 causes a significant (p<0,01) 65,8+/-2,01% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound, and visible to 85.5+/-1,27% inhibition, if it is used for weight./weight. the ratio of Aβ: test compound 1:1 (table 3). This is the study shows, what is presented here further connections are disruptors/inhibitors of Aβ fibrils of the type found in Alzheimer's disease, and usually manifest their effect dose-dependent manner.

Table 3
The results of fluorimetry of thioflavin T - Destruction of Aβ 1-42 fibrils of the tested compounds (% inhibition of Aβ; specific weight./weight. relations Aβ:test compound)

Example 17

The present compounds are effective destroyers of IAPP fibrils of type 2 diabetes.

Obtained in the preceding examples, the compounds were found, are also affectinate disruptors/inhibitors of IAPP fibrils of type 2 diabetes. In the research group analyzed the effectiveness of some of these compounds dismantling/destruction of previously formed amyloid fibrils of type 2 diabetes (i.e. consisting of IAPP fibrils).

Part a - the Results of fluorimetry of thioflavin T

In one study, a fluorometry of thioflavin T is used to determine the efficacy of compounds and EDTA (as negative control). In this analysis tioflavin T binds specifically to fibrillar amyloid, and this tie is of is increased fluorescence at a wavelength of 485 nm, which is directly proportional to the number formed amyloid fibrils. The more intense fluorescence, the greater the number of amyloid fibrils formed (Naki et al., Lab. Invest. 65:104-110, 1991; Levine III, Protein Sci. 2:404-410, 1993; Amyloid: Int. J. Exp.Clin. Invest. 2:1-6, 1995).

In this study, 25 μm IAPP (Bachem Inc) incubated at 37°C for 3 days either alone or in the presence of one of the compounds or EDTA (at the weight./weight. relations Aβ:test compound 1:1, 1:0,1, 1:0,01 or 1:0,001). After 3 days of co-incubation 50 μl of each incubation mixtures are transferred into 96-well microtiter plate containing 150 μl of distilled water and 50 μl of a solution of thioflavin T (i.e. 500 mm thioflavin T in 250 mm phosphate buffer, pH 6,8). The values of fluorescence intensity read at 485 nm (wavelength of 444 nm excitation)using ELISA tablet fluorimeter after deduction of the separate buffer or separately compound as a control).

The results obtained after 3 days of incubation, presented next. For example, if EDTA does not cause significant inhibition/destruction of IAPP fibrils at all tested concentrations, the compounds (DC-0051, DC-0051-S1, S3, S4, S5, S6, S7, S8 and S9) all cause dose-dependent disruption/disassembly of previously formed Aβ 1-42 fibrils to some extent (table 4). For example, compound DC-0051-S8 causes a significant (p<0,01) 91,4+/-1,06% of ingibirovanie, if it is used for weight./weight. the ratio of Aβ:test compound 1:0,1, and significant 52,2+/-0,45% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:0,01 (table 4). In the same conditions (i.e. with weight./weight. the ratio of Aβ:test compound 1:0.01), and compound DC-0051 causes 63,9+/-0,56% destruction, compound DC-0051-S1 causes to 47.2+/-5,48% destruction and compound DC-0051-S3 causes of 49.3+/-0,65% destruction. This study shows that the present compounds are also effective disruptors/inhibitors of IAPP fibrils of type 2 diabetes and usually manifest their effect dose-dependent manner.

Table 4
The results of fluorimetry of thioflavin T - Destruction of IAPP fibrils of the tested compounds (% inhibition of Aβ; specific weight./weight. relations Aβ:test compound)

Part b: results of the binding of Congo red

In the analysis of the binding of Congo red to quantitatively determine the ability of test compounds to alter amyloid (in this case IAPP) binding to Congo red. In this analysis of IAPP and the test compounds are incubated for 3 days and then carry out vacuum filtration through a 0.2 μm filter. Soda is the content of IAPP, remaining on the filter was determined by Congo red staining. After appropriate washing, any weakening of the color of Congo red on the filter in the presence of the test compound (compared with Congo red staining of amyloid protein in the absence of the test compound) is indicative of the ability of compounds to reduce/change the number of aggregated and congophilic IAPP. This particular analysis is probably more accurate than fluorometry of thioflavin T, and more difficult to remove Congo red, associated with IAPP fibrils, rather than to evaluate with other analyses, so that the observed % inhibition even with effective compounds is generally lower than the % of inhibition observed when using other tests, such as fluorometry for thioflavin T.

In one study determined the ability of IAPP to connect with Congo red in the absence or in the presence of increasing amounts of the compounds or EDTA (at the weight./weight. relations IAPP:test compound 1:0,001, 1:0,01, 1:0,1 1:1). The results obtained after 3 days of incubation, presented below in Table 5. If EDTA does not cause significant inhibition of binding of IAPP fibrils with Congo red, connection (DC-0051, DC-0051-S1, S3, S4, S5, S6, S7, S8 and S9) cause dose-dependent inhibition of IAPP binding Quangocracy (table 5). For example, compound DC-0051-S8 causes noticeable 41,0+/-4,15% inhibition of binding of Congo red with IAPP fibrils, if it is used for weight./weight. against IAPP:test compound 1:1, and 26.7+/-0,82% inhibition, if it is used for weight./weight. against IAPP:test compound 1:0,1 (table 5). Other good inhibitors when compared with the weight./weight. relations IAPP:test compound 1:0,1, apparently, are

DC-0051 (51+/-0,63% inhibition), DC-0051-S1 (24,1+/-1,99% inhibition), DC-0051-S4 (22,0+/-0,26% inhibition) and DC-0051-S9 (21,2+/-2,70% inhibition).

Table 5
Results binding of Congo red - Destruction of IAPP fibrils of the tested compounds (% inhibition of IAPP; specific weight./weight. relations IAPP:test compound)

Example 18

The present compounds are effective destroyers of alpha-synuclein fibrils.

Obtained in the preceding examples, the compounds were found, are also affectinate disruptors/inhibitors of alpha-synuclein fibrils. In the research group analyzed the effectiveness of some of these compounds dismantling/destruction of previously formed amyloidogenic Feb the Fig Parkinson's disease (i.e. consisting of alpha-synuclein fibrils).

The results of fluorimetry of thioflavin T

In one study, a fluorometry of thioflavin T is used to determine the efficacy of compounds and EDTA (as negative control). In this analysis tioflavin T binds specifically to fibrillar amyloid, and this binding is increased fluorescence at a wavelength of 485 nm, which is directly proportional to the number formed amyloid fibrils. The more intense fluorescence, the greater the number of amyloid fibrils formed (Naki et al., Lab. Invest. 65:104-110, 1991; Levine III, Protein Sci. 2:404-410, 1993; Amyloid: Int. J. Exp.Clin. Invest. 2:1-6, 1995).

In this study, 25 μm of alpha-synuclein (recombinant peptide) initially incubated at 55°C for 2 days with heparin (Sigma)to induce aggregation of alpha-synuclein and the formation of fibrils. Heparin is a highly sulfated by glycosaminoglycans, which is known to cause aggregation of amyloid proteins. After the initial fibrillation of alpha-synuclein, alpha synuclein+heparin were incubated at 37°C for 3 days either alone or in the presence of one of the compounds or EDTA (at the weight./weight. relations Aβ:test compound 1:1, 1:0,1, 1:0,01 or 1:0,001). After 3 days of co-incubation 50 μl of each incubation mixtures transferred into a 96-hole of Microtiterwells the first tablet, containing 150 ál of distilled water and 50 μl of a solution of thioflavin T (i.e. 500 mm thioflavin T in 250 mm phosphate buffer, pH 6,8). The values of fluorescence intensity read at 485 nm (wavelength of 444 nm excitation)using ELISA tablet fluorimeter after deduction of the separate buffer or separate connections, as control).

The results obtained after 3 days of incubation, presented next. Connection (DC-0051, DC-0051-S1, S3, S4, S5, S6, S7, S8 and S9) all cause dose-dependent disruption/disassembly of the previously generated alpha-synuclein fibrils to some extent (table 6). For example, compound DC-0051-S1 causes a significant (p<0,01) 94,5+/-2,11% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:0,1, and significant of 99.1+/-0,12% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:1 (table 6). On the other hand, compound DC-0051-S8 causes a significant (p<0,01) 84,6+/ - 0.47% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:0,1, and significant 96,1+/-1,14% inhibition, if it is used for weight./weight. the ratio of Aβ:test compound 1:1 (table 6). This study shows that the present compounds are also effective disruptors/inhibitors of alpha-synuclein fibrils Parkinson's disease and usually have the proven action dose-dependent manner.

Table 6
The results of fluorimetry of thioflavin T - alpha synuclein fibrils of the tested compounds (% inhibition of Aβ; Aβ:test compound at a specific weight./weight. )

Example 19

The compositions presented here connections

Presented here are the links, as indicated above, preferably administered in the form of pharmaceutical compositions. Suitable pharmaceutical compositions and methods for their preparation are well known to specialists in this field and are disclosed in such treatises as Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

Representative compositions are given below:

Compositions for oral administration

The compositions of tablets for oral administration the compounds of the present invention is prepared as follows:

% weight./weight.
Presented here is the link10,0
Magnesium stearate0,5
Starch 2,0
The hypromellose1,0
Microcrystalline cellulose86,5

These ingredients are mixed to homogeneity, then granularit with water and the obtained granules are dried. Then, the resulting granules are compressed to the size of the tablets, receiving the appropriate dose of a compound. These pills do not necessarily cover the suspension of a film-forming agent (e.g. hypromellose), pigment (e.g. titanium dioxide) and plasticizer (for example, diethylphthalate) and dried film, viparita solvent. Film coating may be, for example, 2-6% by weight of the tablet.

Formulations capsules for oral administration

Pellets from the previous section this example is filled in hard gelatin capsules, size of which corresponds to the required dose. If desired, capsules ring to seal it.

Soft gel composition

Soft gel composition is prepared as follows:

% weight./weight.
Presented here is the link20,0
P is litlington 400 80,0

The compound is dissolved or dispersed in the polyethylene glycol, and optionally add a thickening agent. Then in a soft gel add such quantity of the composition which is sufficient to obtain the required dose for the connection.

The composition for parenteral administration

The composition for parenteral administration is prepared as follows:

% weight./weight.
Presented here is the connection1,0
Normal saline99,0

The compound was dissolved in saline solution and the resulting solution is sterilized and filled them with tubes, ampoules and pre-filled syringes.

The composition of the controlled release for oral administration

Composition with delayed release can be obtained using the method of U.S. patent No. 4710384, as follows.

1 kg presented here connections are coated with ethyl cellulose Dow Type 10 in modifitsirovannom Uni-Glatt powder device for coating. The solution spray consists of an 8% solution of ethyl cellulose in 90% acetone and 10% ethanol. As a plasticizer domovladelitsa oil in the quantity equal to 20% of ethyl cellulose present. Conditions applying spray the following: 1) the rate of 1 liter/hour; 2) flap, 10-15%; 3) water inlet temperature 50°C, 4) outlet temperature 30°C, 5) the coverage percentage, 17%. Coverts connection sieved to particle size of from 74 to 210 microns. Special attention should be paid to ensure good mixing of the particles with different sizes within the specified interval. Four hundred mg of the particles with the coating are mixed with 100 mg of starch and the resulting mixture is pressed into the hand pump creates a pressure of 1.5 tons, receiving 500 mg tablet with controlled selection.

The amount of the declared object of the invention is not limited to the disclosed specific options. Indeed, various modifications of the specific options in addition to the disclosed here will be apparent to experts in this field from previous descriptions. Such modifications fall within the scope of the attached claims. In the description cited various publications, the disclosure of which is included here for your reference in its entirety.

1. A compound selected from
,
,
where M represents S(O)2,
Rxmeans alkyl,
R1, R2, R3and R4each independently selected from HE-R 7S(O)2R8,
R5and R7each independently mean hydrogen or alkyl,
R8means alkyl;
or their pharmaceutically acceptable salts.

2. The compound according to claim 1, where R5represents isopropyl.

3. The compound according to claim 1, where Rxrepresents methyl.

4. The compound according to claim 1, selected from

,,
,,
,
,
,,

5. The compound according to any one of claims 1 to 4, showing inhibitory activity against β, IAPP amyloid fibrils or synuclein fibrils.

6. The compound according to claim 5, where sinucleanse fibrils are α-synuclein fibrils.

7. Pharmaceutical composition having inhibitory activity against β, IAPP amyloid fibrils or synuclein fibrils containing an effective amount of travel is according to any one of claims 1 to 4, or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

8. The product, including packaging material, a compound according to any one of claims 1 to 4, or its pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 7, having inhibitory activity against β, IAPP amyloid fibrils or synuclein fibrils enclosed within the packaging material, and a label that indicates that the compound or its pharmaceutically acceptable salt for use in the inhibition β, IAPP amyloid fibrils or synuclein fibrils.

9. A method of inhibiting the activity β, IAPP amyloid fibrils or synuclein fibrils, comprising introducing an effective amount of a compound according to any one of claims 1 to 4, or its pharmaceutically acceptable salt or pharmaceutical composition according to claim 7.

10. The method according to claim 9, where sinucleanse fibrils are α-synuclein fibrils.

11. The use of compounds according to any one of claims 1 to 4 for the preparation of drugs having inhibitory activity against β, IAPP amyloid fibrils or synuclein fibrils.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new 8-aza-bicyclo[3.2.1]octane derivatives of formula I or any its isomer or mixed isomers, or their pharmaceutically acceptable salt, where Ra represents hydrogen; X represents -O-; Rb represents aryl or heteroaryl group chosen from phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or quinazolinyl substituted with one or two substitutes independently chosen from group including: halogeno, trifluoromethyl, trifluoromethoxy, cyano, hydroxy and alkoxy provided that compound is not 3-(3-trifluoromethylphenoxy)-8-azabcyclo[3.2.1]octane, 3-(4-trifluoromethylphenoxy)-8-azabcyclo[3.2.1]octane, 3-(2-bromphenoxy)-8-azabcyclo[3.2.1]octane, 3-(4-chlorophenoxy)-8-azabcyclo[3.2.1]octane or 3-(4-fluorophenoxy)-8-azabcyclo[3.2.1]octane. Besides invention refers to pharmaceutical composition and application thereof.

EFFECT: production of new biologically active compounds characterised with monoamine recapture inhibiting activity.

6 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new hetero-aryl derivatives of 8-azabicyclo-[3.2.1]-octan-3-ol with general formula I where R-R4 represent hetero-aryl. The hetero-aryl is in form of a cyclic aromatic group with C5-C6 or a bicyclic group with C9-C10, which contain 1, 2 or 3 hetero atoms, independently O, S or N, or a residue of , R1-H, C1-C6-akyl, R2 and R3 independently CH3, -OCH3, F, Cl, Br, J, R4 - from 1 to 4 substitutes, -H, halogen, C1-C6alkyl, -CF3, -OCF3, -(CH2)n-OR5, -(CH2)n-NR5R6, -(CH2)n-NHSO2R5, -(CH2)n-NH(CH2)2NR5R6, -(CH2)n-NHC(O)NR5R7, -(CH2)n-NH(CH2)2OR5, or 1-piperazinyl; n - 0, 1, 2, 3; R5 and R6 - H, C1C3alkyl, R7-H, C1-C3alkyl, aminoalkyl C1-C3, or to their pharmaceutical salts. The compounds are antagonists of the nociceptin ORL-1 receptor.

EFFECT: obtaining of compounds that are useful in the treatment of cough.

10 cl, 22 ex, 1 tbl

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to a derivative (azetidin-1-illlil)lactams of the formula (I) and their pharmaceutically acceptable salts, where R - (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, aryl or het1and (C3-C7-cycloalkyl, optionally substituted with 1-2 substituents selected from (C1-C4)-alkyl and fluorine; R1is phenyl, optionally substituted by 1-2 halosubstituted; R2- -CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR3R4that gets3or a group of formula (a), (b), (C); X - (C1-C4-alkylene; X1- directional communication, X2- directional communication or CO; m = 1; used in the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- and NK3the receptor or in their combinations

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to compounds of formula (I) as inhibitor of phosphotyrosinphosphotase 1B, and to application thereof for making a based medical product. In general formula (I) X represents C-R2; Y represents O, R1 represents phenyl, 5-merous heterocycle with one sulphur atom with phenyl residue, and heterocyclic residue being mono-, twice- or trisubstituted with halogen, CN, -OH, -CF3, -(C1-C6)alkyl, -COOH, -(CH2)-COOH, phenyl, -O-phenyl with phenyl ring being substituted with halogen; R2, R3, R4, R5, R6, R7 and R8 represent H.

EFFECT: compounds can find application in treating adipose and carbohydrate metabolic disorders, including for controlling blood glucose.

3 cl, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: climed invention relates to method of obtaining 5-(4-(1,3,5-dithiazinan-5-sulfanyl)-phenyl)-1,3,5-dithiazinan, which finds application as radio protective, anti-tumor, diuretic means, and selective sorbent, and extragent of noble and precious metals. Essence of method lies in interaction of saturated with hydrogen sulfate water solution of formalin with water solution of n-anylin sulfamide (streptocide) with HCI with molar ratio streptocide: formaldehyde: hydrogen sulfate: HCl=1:6:4:4, at temperature 40°C, constant mixing during 2 hours and with further neutralisation with NaOH solution. Output of target product 5-[4-(1,3,5-dithiazinan-5-sulfanyl)-phenyl]-1,3,5- dithiazinan is 93%.

EFFECT: obtaining 5-(4-(1,3,5-dithiazinan-5-sulfanyl)-phenyl)-1,3,5-dithiazinan with high output.

1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

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