1-oxa-3-azadibenzoazulenes as inhibitors of producing tumor necrosis factor and intermediate compounds for their preparing

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein X represents heteroatom, such as oxygen (O) or sulfur (S) atoms; X and Z mean independently of one another one or some identical or different substitutes bound any available carbon atom and they can represent hydrogen atom or halogen atom; R1 represents a substitute of the formula (II): , wherein R2 and R3 can represent simultaneously or independently of one another hydrogen atom or (C1-C4)-alkyl, or R1 can represent hydrogen, halogen atom, (C1-C7)-alkyl, -CHO, -(CH2)2COOH, -(CH2)2CO2Et, (CH2)mL wherein L means -OH or bromine atom (Br); m represents a whole number from 1 to 3; n represents a whole number from 0 to 3; Q1 and Q2 represent independently of one another oxygen atom or group of the formula: wherein substitutes y1 and y2 represent hydrogen atom, and to their pharmacologically acceptable salts. Also, invention relates to use of these compounds as intermediate substances used in synthesis of novel compounds of dibenzoazulene class, and to their using for preparing drugs.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 tbl, 13 ex

 

The technical field

The present invention relates to a derived class of the 1-oxa-3-sedimentation, to their pharmacologically acceptable salts and solvate, to methods and intermediate products for their production and to their anti-inflammatory effects, particularly to the inhibition of the production of tumor necrosis factor-α (TNF-α) and to inhibition of production of interleukin-1 (IL-1), and their analgesic action.

Prior

To date in the literature have been disclosed derivatives of 1-tidimensional, substituted in position 2 stands, a ketone, a nitrogroup, or derived from a carboxyl group (Cagniant PG, C.R. Hebd. Sceances Acad. Sci., 1976, 283:683-686). Some derivatives of 1,3-deazaguanosine and their salts known as a new class of compounds possessing anti-inflammatory activity (U.S. patent No. 3711489, 4198421 and Canada No. 967573). Derivatives of 1-tidimensional with alkyloxyalkyl in position 2 (WO 01/878990), also possess strong anti-inflammatory action.

Of dibenzazepine class oksazolov known compounds with heteroatoms only oxazoline ring, namely their dihydrobromide 2-phenyl substituent (Schoshichiro K et al., Yakugaki Zasshi 1967, 87:861-866 and JP 45006811) and 2-amino derivatives (ZA 6801411), whereas the currently received raskryty other for the first time fully unsaturated (aromatic) dibenzoxazepine class oksazolov with the heteroatom (oxygen, sulfur or nitrogen) in cycloheptanol part of the molecule, which is the subject of the present invention.

In accordance with the authors information and available literature data up to the present time it was not known that such compounds may have anti-inflammatory action (inhibitors of secretion of TNF-α and IL-1) or an analgesic effect.

In 1975, TNF-α was defined as a serum factor, induced by endotoxin and causes tumor necrosis in vitro and in vivo (Carswell EA, et al., Proc. Natl. Acad. Sci. U.S.A., 1975, 72:3666-3670). In addition to the antitumor activity of TNF-α also has other numerous biological actions, which are important in the homeostasis of organisms and pathophysiological conditions. The main sources of TNF-α represent monocytes-macrophages, T-lymphocytes and mast cells.

The discovery that antibodies anti-TNF-α (Ca2) have effect in the treatment of patients with rheumatoid arthritis (RA) (Elliott M, et al., Lancet, 1994, 344:1105-1110), has led to heightened interest in finding new inhibitors of TNF-α as a possible potent medicines for RA. Rheumatoid arthritis is an autoimmune chronic inflammatory disease characterized by irreversible pathological changes in the joints. In addition to the use ol the RA antagonists of TNF-α can also be used in numerous pathological conditions and diseases such as spondylitis, osteoarthritis, gout and other arthritic condition, sepsis, septic shock, toxic shock, atopic dermatitis, contact dermatitis, psoriasis, glomerulonephritis, systemic lupus erythematosus, scleroderma, asthma, cachexia, chronic obstructive pulmonary disease, heart failure, insulin resistance, lung fibrosis, multiple sclerosis, Crohn's disease, ulcerative colitis, viral infection and AIDS (AIDS).

The biological evidence of the importance of TNF-α was obtained in the in vivo tests carried out on mice, in which iactiveaware genes of mice, responsible for TNF-α or its receptor. These animals were resistant to induced collagen arthritis (Mori L, et al., J. Immunol., 1996, 157:3178-3182) and induced endotoxin shock (Pfeffer K. et al., Cell, 1993, 73:457-467). When in animal tests the level of TNF-α rose, manifested chronic inflammatory polyarthritis (Georgopoulos S, et al., J. Inflamm., 1996, 46:86-97; Keffer J. et al., EMBO J. 1991, 10:4025-4031) and its pathological picture was softened by inhibitors of the production of TNF-α. The treatment of such inflammatory and pathological conditions usually includes the use of nonsteroidal anti-inflammatory drugs, and in more severe cases, injected gold salts, D-penicillin is in or methotrexate. These medicines act symptomatically, but they do not stop the disease process. New approaches in the treatment of rheumatoid arthritis based on drugs, such as tenidap, Leflunomide, cyclosporine, FK-506, and biomolecules, neutralizing the action of TNF-α. Currently, there are commercially available etanercept (Enbrel, Immunex/Wyeth), a fused protein of soluble receptor of TNF-αand infliximab (Remicade, Centocor) is a chimeric monoclonal antibody human and mouse. Except for use in the treatment of RA etanercept and infliximab registered as medicines for the treatment of Crohn's disease (Exp. Opin. Invest. Drugs, 2000, 9:103).

In addition to inhibiting the secretion of TNF-α in the treatment of RA is very important also the inhibition of the secretion of IL-1, since IL-1 is an important cytokine in the regulation and immune regulation of cells, as well as in pathophysiological conditions such as inflammation (Dinarello CA, et al., Rev. Infect. Disease, 1984, 6:51). Well-known types of biological activity of IL-1 are: activation of T-lymphocytes, inducing elevated temperature, stimulation of secretion of prostaglandin or collagenase, chemotaxis of neutrophils and a decrease in plasma iron (Dinarello CA, J. Clinical Immunology, 1985, 5:287). Two of the receptor, which may be associated IL-1, are well known: the IL-1RI and IL-1RII. While IL-1RI before the em signal intracellularly, IL-1RII is located on the cell surface and does not transmit the signal inside the cell. Because IL-1RII binds IL-1 and IL-1RI, it can act as a negative regulator of the activity of IL-1. In addition to the mechanism of the regulation of signal transmission in cells is another natural receptor antagonist IL-1 (IL-1ra). This protein binds to IL-1RI, but does not transmit any signal. However, its effectiveness in stopping the transmission signal is low and its concentration to achieve a break in the signal transmission must be 500 times greater than the concentration of IL-1. Recombinant human IL-1ra (Amgen) was clinically tested (Bresnihan B, et al., Arthrit. Rheum., 1996, 39:73) and the results showed improvement of the clinical picture in 472 patients with RA compared with placebo. The results show the importance of inhibiting the activity of IL-1 in the treatment of diseases, such as RA, in which impaired production of IL-1. Since there is a synergistic effect of TNF-α and IL-1, 1-oxa-3-sedimentable can be used in the treatment of conditions and diseases associated with increased secretion of TNF-α and IL-1.

The invention

The present invention relates to 1-oxa-3-sedimentation formula I

where X may be a heteroatom such as O, S, S(=O), S(=O) 2or NRawhere Rarepresents hydrogen or a protective group;

Y and Z independently of one another mean one or more identical or different substituents associated with any available carbon atom, and may represent hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, halogen-C1-C4-alkyl, hydroxy, C1-C4-alkoxy, trifluoromethyl, triptoreline,1-C4-alkanoyl, amino, amino-C1-C4-alkyl, N-(C1-C4-alkyl)amino, N,N-di(C1-C4-alkyl)amino, thiol,1-C4-alkylthio, sulfonyl,1-C4-alkylsulfonyl, sulfinil,1-C4-alkylsulfonyl, carboxy, C1-C4-alkoxycarbonyl, cyano, nitro;

R1can represent hydrogen, C1-C7-alkyl, Cho, (CH2)2COOH, (CH2)2CO2Et, (CH2)mL, where m is 1 or 3 and L means HE or Br;

or Deputy formula II

in which R2and R3at the same time or independently of one another can be hydrogen, C1-C4is alkyl, aryl or together with the N means optionally substituted heterocycle or heteroaryl;

m is an integer from 1 to 3;

n represents the FDS is th integer from 0 to 3;

Q1and Q2independently of one another represent oxygen, sulphur or the group:

where the substituents y1and y2independently of one another can be hydrogen, halogen, C1-C4is alkyl or aryl, hydroxy, C1-C4-alkoxy, C1-C4-alkanoyl, thiol, C1-C4-alkylthio, sulfonyl, C1-C4-alkylsulfonyl, sulfinil, C1-C4-alkylsulfonyl, cyano, nitro, or together form a carbonyl or aminogroup;

and their pharmacologically acceptable salts and solvate.

Preferred are the compounds:

a) where X is S or O; (b) Y and/or Z denote H, Cl; (c) R1means H, CH3, SNO, (CH2)2COOH, (CH2)2CO2Et; (d) R1means (CH2)mL; (e) the symbol m is 1 or 3; (f) L means HE or Br; g) R1means the formula II; (h) m is 1, n is 1 or 2, Q1means O Q2means of CH2and R1and R2mean CH3.

The term "halo", "Gal" or "halogen" refers to a halogen atom, which may be a fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to alkyl groups with a value of alkanes, of which produced radicals, which may be straight, branched or cyclic, or may present with the Oh combination of direct and cyclic radical and branched and cyclic radical. Preferred straight or branched alkilani are, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. Preferred cyclic alkilani are, for example, cyclopentyl or cyclohexyl.

The term "halogenated" refers to alkyl groups that need to be substituted by at least one halogen atom. Most often halogenoalkane represent, for example, chloromethyl, dichloromethyl, trifluoromethyl or 1, 2-dichloropropyl.

The term "alkenyl" refers to alkenyl groups relevant hydrocarbon radicals which may be straight, branched or cyclic, or may be a combination of direct and cyclic radical or a branched and cyclic radical, but you have at least one carbon-carbon double bond. Most often, alkenyl are ethynyl, propenyl, butenyl or cyclohexenyl.

The term "quinil" refers to alkynylaryl groups relevant hydrocarbon radicals are straight or branched and contain at least one and not more than two carbon-carbon triple bond. Most often alkinyl represent, for example, ethinyl, PROPYNYL or butynyl.

The term "alkoxy" refers to straight or branched chains CNS GRU is dust. Examples of such groups are methoxy, propoxy, propyl-2-oxy, butoxy, butyl-2-hydroxy or methylpropyl-2-oxy.

The term "aryl" refers to groups having the value of the aromatic ring, such as phenyl, and condensed aromatic rings. The aryl contains one ring with at least 6 carbon atoms or two rings containing a total of 10 carbon atoms, and the rings have alternating double (resonance) relationship between carbon atoms. The most commonly used arily represent, for example, phenyl or naphthyl. Aryl groups can be usually linked to the rest of the molecule via any available carbon atom via a simple link or via1-C4-alkylenes group, such as methylene or ethylene.

The term "heteroaryl" refers to groups having the value of aromatic and partially aromatic groups are monocyclic or bicyclic ring with 4-12 atoms, at least one of which is a heteroatom such as O, S or N, and available nitrogen atom or a carbon atom is the site linking group with the rest of the molecule, or via a simple link or through defined above With1-C4-alkylenes group. Examples of groups of the specified type are thiophenyl, pyrrolyl, imidazolyl, pyridinyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, Piri is idini, pyrazinyl, chinoline or triazinyl.

The term "heterocycle" refers to a five-membered or six-membered fully saturated or partially unsaturated heterocyclic groups containing at least one heteroatom such as O, S or N, and available nitrogen atom or a carbon atom is the site linking group with the rest of the molecule, or via a simple link or through defined above With1-C4-alkylenes group. The most common examples of such groups are morpholinyl, piperidinyl, piperazinil, pyrrolidinyl, pyrazinyl or imidazolyl.

The term "alcoolica" group refers to a straight chain acyl group such as formyl, acetyl or propanole.

The term "Carolina" group refers to an aromatic acyl groups such as benzoline.

The term "optionally substituted alkyl" refers to alkyl groups which may be optionally additionally substituted with one, two, three or more substituents. Such substituents may be a halogen atom (preferably fluorine, chlorine or bromine), hydroxy, C1-C4-alkoxy (preferably methoxy or ethoxy), thiol,1-C4-alkylthio (preferably methylthio or ethylthio), amino, N-(C1-C4)alkylamino (preferably N-methylamino or N-ethylamino), N,N-di(C 1-C4alkyl)amino, preferably dimethylamino or diethylamino), sulfonyl,1-C4-alkylsulfonyl (preferably methylsulphonyl or ethylsulfonyl), sulfinil,1-C4-alkylsulfonyl (preferably methylsulfinyl).

The term "optionally substituted of alkenyl" refers to alkenyl groups, optionally additionally substituted with one, two or three halogen atoms. Such substituents may represent, for example, 2-chloranil, 1,2-dichlorethane or 2-bromopropane-1-yl.

The term "optionally substituted aryl, heteroaryl or a heterocycle" refers to an aryl, heteroaryl or heterocyclic groups, which may be optionally additionally substituted by one or two substituents. The substituents may be a halogen (preferably chlorine or fluorine)1-C4-alkyl (preferably methyl, ethyl or isopropyl), cyano, nitro, hydroxy, C1-C4-alkoxy (preferably methoxy or ethoxy), thiol,1-C4-alkylthio (preferably methylthio or ethylthio), amino, N-(C1-C4)alkylamino (preferably N-methylamino or N-ethylamino), N,N-di (C1-C4-alkyl)amino (preferably N,N-dimethylamino or N,N-diethylamino), sulfonyl,1-C4-alkylsulfonyl (preferably methylsulphonyl or tilsley), sulfinil,1-C4-alkylsulfonyl (preferably methylsulfinyl).

When X is NRaand Rameans a protective group, then Rarefers to such groups as alkyl (preferably methyl or ethyl), alcoolica (preferably acetyl), alkoxycarbonyl (preferably methoxycarbonyl or tert-butoxycarbonyl), armletaccessory (preferably benzyloxycarbonyl), Carolina (preferably benzola), arylalkyl (preferably benzyl), alkylsilane (preferably trimethylsilyl) or alkyltrimethylenedi (preferably trimethylsilylamodimethicone).

When R2and R3together with N mean heteroaryl or a heterocycle, this means that such heteroaryl or heterocycles have at least one carbon atom substituted by a nitrogen atom through groups that are associated with the rest of the molecule. Examples of such groups are morpholine-4-yl, piperidine-1-yl, pyrrolidin-1-yl, imidazol-1-yl or piperazine-1-yl.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of formula I include, for example, salts with1-C4-alkylhalogenide (preferably bromide, methyl chloride) (Quaternary ammonium salt), inorganic acids (such as chloridometer is DNA, Hydrobromic, phosphoric, metaphosphoric, nitric or sulphuric acid) or organic acids (such as tartaric, acetic, citric, maleic, lactic, fumaric, benzoic, succinic, methanesulfonate or p-toluensulfonate acid).

Some compounds of formula I can form salts with organic or inorganic acids or bases and they are also included in the present invention.

The object of the present invention are also solvate (most frequently hydrates), which can form compounds of the formula I or their salts.

Depending on the specific nature of the substituents of the compounds of formula I can have geometric isomers and one or more chiral centers, so that can exist enantiomers or diastereoisomers. The present invention relates also to such isomers and their mixtures, including the racemates.

The present invention relates to all possible tautomeric forms of specific compounds of formula I.

Another aim of the present invention relates to the production of compounds of formula I in accordance with the methods, including

a) to obtain compounds of the formula I, the cyclization of the compounds of formula III

where a represents-O - or-NH-;

b) for compounds of formula I, where Q1OSN which denotes-O-,

interaction of alcohols of the formula IV

with compounds of the formula V

where R4means remove the group;

(C) to obtain the compounds of formula I, where Q1means-O-, -NH-, -S - or- With-,

the interaction of compounds of formula IVa

where L means the deleted group, with compounds of the formula Va

d) for compounds of formula I, where Q1means heteroatom-O-, -NH-or-S-,

the interaction of compounds of formula IVb

with compounds of the formula V, where R4means remove the group;

e) for compounds of formula I, where Q1means-C=C-,

the interaction of compounds of formula IVb, where Q1means carbonyl, phosphorous ylides.

Ways to get:

a) the Cyclization of compounds of the formula III is performed by the methods disclosed for obtaining similar compounds. For example, the compounds of formula III, where a represents-NH-, can be cyklinowanie reaction with POCl3in an organic solvent (preferably benzene or toluene) at boiling point for a time from 1 to 5 hours (Lombardino J.G., J. Heterocyclic Chem., 1974, 11:17-21), whereas the cyclization of compounds of formula III, the de And means, carried out in the presence of ammonium acetate in acetic acid at the boiling temperature for 5 to 10 hours. Received tetracyclic products can be separated by chromatography on a column of silica gel or by recrystallization from a suitable solvent.

The source of the substance to obtain the compounds of formula III, ketones of formula VI

where R5means H is already known or obtained by the methods disclosed for obtaining similar compounds. As a result of interaction of sodium nitrite in ethanol hydrochloric acid with a ketone of formula VI, where R5means H is formed corresponding oxime, which when recovering a metal, such as zinc in acetic acid, forms aminosidine formula VI, where R5means the group of NH2. This reaction path is disclosed in U.S. patent No. 4191421. As a result of interaction of formic acid (Romo D, et al., J. Am. Chem. Soc., 1998, 120:12237-12254) or anhydrides of the acids in accordance with normal Protocol formed the compounds of formula III, where a represents a group-NH-. In the result of alloxylon the corresponding ketone of formula VI, where R5means atom N, using Pb(OAc)4(Cavill GWK, Organic Oxidation Processes; 1955, 4:4426-4429) are compounds of formula III, where a represents-O-.

b) Compounds of the formula I according nastojasim method can be obtained by the interaction of the alcohols of formula IV and compounds of the formula V, where R4means delete the group, which may be a halogen atom (most often bromine, iodine or chlorine) or sulfonyloxy (the most tripterocalyx or p-toluensulfonate). The condensation reaction can be carried out in accordance with the methods disclosed for obtaining similar compounds (Menozzi G, et al., J. Heterocyclic Chem., 1997, 34:963-968 or WO 01/87890). The reaction is carried out at a temperature of from 20 to 100°during the time from 1 to 24 hours in the two-phase system (preferably using a mixture of 50% NaOH/toluene) in the presence of a phase transfer catalyst (preferably benzyltriethylammonium, benzyltriethylammonium, cetyltrimethylammonium). After treatment of the reaction mixture formed products produce by recrystallization or by chromatography on a column of silica gel.

The original substance representing the alcohols of formula IV can be obtained from compounds of the formula I, in which R1means suitable functional group. Thus, the alcohols of formula IV can be obtained by reduction of alkanoyloxy group (for example, formyl or allyloxycarbonyl group (for example, methyloxycarbonyl or ethoxycarbonyl) using metal hydrides, such as alumalite lithium or sodium borohydride. In addition, the alcohols form the s IV can be obtained by hydrolysis of the corresponding esters in an alkaline or acidic environment.

The initial compounds of formula V are already known, or receive them in accordance with the methods disclosed for obtaining similar compounds.

C) the compounds of formula I in accordance with the present method can be obtained by the interaction of the compounds of formula IVa, in which L means delete the group defined above for R4and compounds of the formula Va, in which Q1means oxygen, nitrogen, sulfur or- With-. The most suitable the condensation reaction is a reaction of nucleophilic substitution at a saturated carbon atom disclosed in the literature.

The initial compounds of formula IVa (most often halides) can be obtained by halogenoalkanes (for example, bromirovanii or chlorination) alcohols of the formula IV conventional halogenation agents (for example, Hydrobromic acid, PBr3, SOCl2or PCl5) by the methods disclosed in the literature. The compounds obtained can be isolated or can be used without isolation as intermediate products suitable for producing compounds of formula I.

The parent compound of formula Va is already known, or receive them in accordance with the methods disclosed for obtaining similar compounds.

d) the compounds of formula I in which Q1means-O-, -NH - or-S-, can be obtained Conde is sacia compounds of the formula IVb and compounds of the formula V, in which R4means remove the group defined above. The reaction can be carried out under the reaction conditions disclosed in method b), or under conditions of nucleophilic substitution, disclosed in the literature. The original alcohols, amines and thiols can be obtained by the interaction of water, ammonia or hydrogen sulphide compounds IVa in accordance with the methods disclosed in the literature.

e) Alcohol of structural formula IV can be oxidized into the corresponding compounds of formula IVb, where Q1means a carbonyl, as a result of subsequent interactions with relevant ilide reagents is the lengthening of the chain and education alkenylphenol Deputy with carbonyl or ester groups, as disclosed in the patent application of Croatia No. 20000310.

The compounds of formula I, in addition to the above reactions can be obtained by transformation of other compounds of formula I, and it should be understood that the present invention also includes such compounds, and methods. A special example of changes in the functional groups is the reaction of the aldehyde group with the selected phosphorous ylides leading to the lengthening of the chain and the formation of alkenylphenol Deputy with carbonyl or ester group, which is disclosed in the patent application of Croatia No. 20000310. The above reaction is carried out in dissolve the fir-trees, such as benzene, toluene or hexane, at a high temperature (most often at boiling point).

The compounds of formula I in which Q1is a- -Receive interaction of compounds of formula IVa with 1-Alcina in an alkaline environment (such as sodium amide in ammonia). The reaction conditions of this method are disclosed in the literature. Under exactly the same conditions of reaction (nucleophilic substitution) can be obtained by a variety of simple derivatives of ether, simple tiefer and Amin.

Formirovanie compounds of the formula I by means of, for example, acylation on Vilsmeier or the reaction of n-BuLi and N,N-dimethylformamide, is a more General example of the transformation. The conditions of the reactions in these ways well known in the literature.

As a result of hydrolysis of the compounds of formula I, having a nitrile, amide or ester groups, can be obtained compound with a carboxyl group, which are suitable intermediates for other compounds with novel functional groups, such as, for example, esters, amides, halides, anhydrides, alcohols or amines.

Oxidation reaction or recovery are additional possibility of changing the substituents in the compounds of formula I. the Most commonly used otiliaobradbalcu a peroxides (hydrogen peroxide, m-chloroperbenzoic acid or benzoyl peroxide or permanganate ions, chromate or perchlorate. Thus, as a result, for example, oxidation of the alcohol group pyridinediamine or pyridinylamino formed aldehyde group which can be converted into a carboxyl group by additional oxidation. Oxidation of compounds of the formula I, in which R1means alkyl, leads to compounds, which lead in acetic acid or N-bromosuccinimide using a catalytic amount of benzoyl peroxide, is obtained the corresponding carbonyl derivative.

Selective oxidation of ancilliary can be obtained alkylsulfonyl or alkylsulfonyl group.

In the recovery of the compounds of the nitrogroup it is possible to obtain amino compounds. The reaction is carried out in the usual conditions of catalytic hydrogenation or electrochemically. Catalytic hydrogenation using palladium on coal alkeneamine substituents can be converted into alkyl or nitrile group can be converted into aminoalkyl.

In the compounds of formula I by standard substitution reactions or regular replacement of individual functional groups can be introduced by various substituents of the aromatic structure. Examples of such reactions are aromatic substitution, Ala the regulation, halogenoalkane, hydroxylation, and oxidation or restoration of deputies. Reagents and reaction conditions known from the literature. So, for example, aromatic substitution in the presence of concentrated nitric acid and sulfuric acid is introduced nitrogroup. Using allelochemical or alkylhalogenide possible the introduction of the acyl group or alkyl group. The reaction is carried out in the presence of Lewis acids, such as trichloride aluminum or iron, in the conditions of the reaction, Friedel -. The restoration of the nitro group are amino group, which through reaction of diazotization turn into a suitable source group which may be substituted by one of the following groups: H, CN, OH, halogen.

To prevent unwanted interactions in chemical reactions, it is often necessary to protect certain groups, such as, for example, hydroxy, amino, thio or carboxy. For this purpose, can be used a number of protective groups (Green T. W, Wuts PGH, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999) and their selection, use and destruction carried out using methods generally accepted in chemical synthesis.

Traditional protection for the amino - or alkylamino are, for example, such groups as alcoolica (acetyl), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl or t is et-butoxycarbonyl); armletaccessory (benzyloxycarbonyl), Carolina (benzola) or alkylsilane (trimethylsilyl or trimethylsilylamodimethicone) group. Conditions for removal of the protective group depend on the choice and properties of this group. So, for example, acyl groups such as alcoolica, alkoxycarbonyl or arolina, can be removed by hydrolysis in the presence of a base (sodium hydroxide or potassium hydroxide), tert-butoxycarbonyl or alkylsilane (trimethylsilyl) group can be removed by treatment with a suitable acid (hydrochloric, sulfuric, phosphoric or triperoxonane acid), whereas armletaccessory group (benzyloxycarbonyl) can be removed by hydrogenation using a catalyst such as palladium on coal.

Salts of compounds of formula I can be obtained by well-known methods, such as the interaction of the compounds of formula I with an appropriate base or acid in a suitable solvent or solvent mixture, for example in ethers (diethyl ether) or alcohols (ethanol, propanol or isopropanol).

Another objective of the present invention is the use of the claimed compounds in the treatment of inflammatory diseases and conditions, especially all the diseases and conditions caused by excessive secretion of f is O-α and IL-1.

Inhibitors of the production of cytokines or inflammatory mediators, which is the object of the present invention, or their pharmaceutically acceptable salts can be used in the production of pharmaceuticals for the treatment and prevention of a pathological condition or disease caused by excessive unregulated production of cytokines or inflammatory mediators, this medicinal product must contain an effective dose of these inhibitors.

The present invention particularly relates to an effective dose of an inhibitor of TNF-α, which can be determined by conventional methods.

The present invention relates also to a pharmaceutical preparation containing an effective non-toxic dose of the compounds of the present invention and pharmaceutically acceptable carriers or diluents.

The preparation of medicines may include mixing, granulating, tableting and dissolution of the ingredients. Chemical carriers may be solid or liquid. Solid media can be represented as lactose, sucrose, talc, gelatin, agar, pectin, magnesium stearate, fatty acids, etc. Liquid carriers may include syrups, oils, such as olive oil, sunflower oil or soybean oil, water, etc. Similarly, the carrier may also contain the AMB component for prolonged release of the active component, such as glycerylmonostearate or glycerylmonostearate. Can be used in different forms of medications. Thus, if you are using solid media, the above form can be a tablet, hard gelatin capsules, powder or granules, which can be put into capsules for oral administration. The amount of solid carrier may vary, but it typically ranges from 25 mg to 1 g If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsules, sterile injectable solutions, such as ampoules or nonaqueous liquid suspension.

Compounds in accordance with the present invention can be used orally, parenterally, topically, vnutripuzarno, vnutriuretrale and intrawaginalno. Parenteral in this description means intravenous, intramuscular and subcutaneous use. Corresponding preparations of the present compounds can be used for the prevention and treatment of various diseases and pathological inflammatory conditions caused by excessive unregulated production of cytokines or inflammatory mediators, in particular TNF-α. They include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic pathological conditions and diseases, eczema, PS is RIAs and other inflammatory skin conditions, such as burns caused by ultraviolet radiation (sun rays and similar UV sources), inflammatory eye diseases, Crohn's disease, ulcerative colitis and asthma.

The inhibitory activity of the compounds of the present invention on the secretion of TNF-α and IL-1 was determined by the following tests in vitro and in vivo.

In vivo secretion of TNF-α and IL-1 in mononuclear cells of human peripheral blood

Mononuclear cells from human peripheral blood (RVMS) received from heparinization whole blood after separation RVMS on Ficoll-Paque™ Plus (Amersham-Pharmacia). To determine the level of TNF-α 3,5-5×104cells in a total volume of 200 ál were grown in a period of time from 18 hours to 24 hours in tablets for micrometrology with a flat bottom (96 wells, Falcon) in RPMI 1640 to which was added 10% FBS (fetal (embryonic) bovine serum, Biowhittaker), previously inactivated at 54°C/30 min, 100 units/ml penicillin, 100 mg/ml streptomycin and 20 mm HEPES (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid) (GIBCO). Cells were incubated at 37°C in an atmosphere containing 5% CO2with 90%humidity. Negative control cells were grown only in the environment (NC), whereas positive control the secretion of TNF-α was initiated by adding 1 ng/ml lipopolysaccharide (LPS, serological type E. coli 0111:B4, SIGMA(PC). The effect of the tested compounds on the secretion of TNF-α investigated after adding them to the culture of cells stimulated by LPS (TS). The level of TNF-α in the cell supernatant was determined by the method of TYPHUS (enzyme-linked immunosorbent analysis (ELISA) according to the manufacturer's recommendations (R&D Systems). Sensitivity testing was <3 PG/ml TNF-α. The level of IL-1 was determined in the analysis carried out under the same conditions and with the same number of cells and the same stimulus concentration, method of TYPHUS (R&D Systems). The percentage of inhibition of production of TNF-α or IL-1 was calculated according to the equation:

% inhibition = [1-(TS-NC)/(PC-NC)]×100.

The value of the IC 50 was determined as the concentration of the substance which was 50% inhibition of production of TNF-α.

Compounds having the value of IC-50 at concentrations of 20 μm or lower, are active.

Determination of in vitro secretion of TNF-α and IL-1 in peritoneal macrophages of mice

To obtain peritoneal macrophages mice-male Balb/C age from 8 to 12 weeks were injected intraperitoneally with 300 µg zymosan (SIGMA)dissolved in phosphate buffer (PBS), the total of which amounted to 0.1 ml/mouse. After 24 hours, mice were killed, in accordance with the Act on the protection of laboratory animals (Laboratory Animal Welfare Act). The peritoneal cavity was rinsed with sterile is ideologicheskim solution (5 ml). Received peritoneal macrophages washed twice with sterile saline solution and after the last centrifugation (350 g/10 min), re-suspended in RPMI 1640 to which was added 10% portion of FBS. To determine the secretion of TNF-α 5×104cells/well total volume of 200 ál were grown in a period of time from 18 hours to 24 hours in tablet titration with a flat bottom (96 wells, Falcon) in RPMI 1640 to which was added 10% FBS (fetal bovine serum, Biowhittaker), inactivated by heat, 100 units/ml penicillin, 100 mg/ml streptomycin, 20 mm HEPES and 50 μm 2-mercaptoethanol (all from GIBCO). Cells were incubated at 37°C in an atmosphere containing 5% CO2with 90%humidity. Negative control cells were grown only in the environment (NC), whereas the positive control was initiated by the secretion of TNF-α by adding 10 ng/ml lipopolysaccharide (LPS, serological type E. coli 0111:B4, SIGMA)(PC). The effect of substances on the secretion of TNF-α investigated after adding them to the culture of cells stimulated by LPS (TS). The level of TNF-α in the cell supernatant was determined by the method of TYPHUS (R&D Systems, Biosource). The level of cells was determined in the analysis is identical to the analysis of TNF-α - implemented method of TYPHUS (R&D Systems). The percentage of inhibition of production of TNF-α or IL-1 was calculated according to the equation:

% inhibition = [1-(TS-NC)/(C-NC)]× 100.

The value of the IC 50 was determined as the concentration of the substance which was 50% inhibition of production of TNF-α.

Compounds having values of IC-50 at concentrations of 10 μm or lower, are active.

Model excessive secretion of TNF-α or IL-1 in mice caused by LPS in vivo

The secretion of TNF-α or IL-1 in mice was induced in accordance with the known method (Badger AM, et al., J.Pharmac. Env. Therap., 1996, 279:1453-1461). Used male Balb/C mice aged 8 to 12 weeks groups of 6-10 animals. Animals were treated orally or only the solvent (negative or positive control) or solutions of substances for 30 minutes prior to intraperitoneal LPS treatment (serological type E. Coli 0111:B4, Sigma) at a dose of 25 μg/animal. After 2 hours the animals were killed by intraperitoneal injection of Romana (Bayer) and ketanest (Parke-Davis). A sample was taken of the blood of each animal in a microcentrifuge tube (Becton Dickinson) and the separated plasma in accordance with the manufacturer's instructions. The level of TNF-α plasma was determined by the method of TYPHUS (Biosource, R&D Systems) according to the manufacturer's instructions. Sensitivity testing was <3 PG/ml TNF-α. The level of IL-1 was determined by the method of TYPHUS (R&D Systems). The percentage of inhibition of production of TNF-α or IL-1 was calculated in accordance with urav is the group of:

% inhibition = [1-(TS-NC)/(PC-NC)]×100

The compounds exhibiting 30% or greater inhibition of production of TNF-α at the dose of 10 mg/kg, are active.

Analysis of analgesic activity by the number of cramps (cramps)

In this analysis caused pain by injection of irritating tools most frequently acetic acid, in the peritoneal cavity of mice. Animals responded with characteristic cramps (spasms), which gave the name of the analysis (Collier HOJ et al., Pharmac. Chemother., 1968, 32:295-310; Fukawa K et al., J. Pharmacol. Meth., 1980, 4:251-259; A Schweizer et al., Agents Actions, 1988, 23:29-31). The analysis is useful for determining the activity of compounds. Methodology: we used mice male Balb/C (Charles River, Italy) aged 8 to 12 weeks. The control group received oral methylcellulose 30 minutes prior to intraperitoneal administration of acetic acid with a concentration of 0.6%, whereas the experimental group received standard oral (acetylsalicylic acid) or subjects substances in methylcellulose 30 minutes before the intraperitoneal injection of 0.6% acetic acid (volume 0.1 ml/10 g). Mice were placed individually under a glass funnel and within 20 minutes we registered the number of cramps (spasms) for each animal. The percentage inhibition of writhing (convulsions) was calculated according to the equation:

% inhibition = (mean number of writhing (convulsions) in to trolley group the number of cramps (cramps) in the experimental group)/number of cramps (cramps) in the control group × 100.

Compounds showing the same analgesic activity as acetylsalicylic acid or higher, are active.

Model shock in mice caused by LPS in vivo

Used mice male Balb/C mice (Charles River, Italy) aged 8 to 12 weeks. Selected from Serratie marcessans LPS (Sigma, L-6136) was diluted in sterile saline. The first injection of LPS was performed intradermally dose of 4 µg/mouse. After 18-24 hours of LPS was administered intravenous dose of 200 μg/mouse. The control group received two injections of LPS, as described above. The experimental group received the substance orally half an hour before each injection of LPS. After 24 hours was observed survival of animals.

Substances, in the presence of which survival at doses of 30 mg/kg 40% or more are active.

The compounds of examples 7 and 9 show the activity of at least two research analyses, although these results are only an illustration of the biological activity of compounds and do not limit the invention in any way.

Methods of obtaining examples

The present invention is illustrated by the following examples, which in no way limit.

Example 1

1-oxa-8-thia-3-sediment[e,h]azulene (1; table 1)

To a solution of POCl3(0,137 g, 0,892 mmol) in anhydrous toluene (5 ml) was added N-(11-oxo-10,11-dihydrobenzo[b,f]thiepin-10-yl) formamide (III; X=S, Y=Z=H, A=NH, R1=H) (0.06 g, 0,223 mmol)dissolved in toluene (10 ml). The reaction mixture is boiled under reflux for 2 hours. Then dry evaporated toluene, was added water and was extracted with ethyl acetate. The organic extract was washed with saturated solution of NaHCO3and water and dried over anhydrous Na2SO4. The solvent evaporated and after purification by chromatography on a column of allocated oily product.

Following the procedure of example 1 using as starting products in the following connections:

N-(11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-yl)formamide (III; X=O, Y=Z=H, A=NH, R1=H);

ethyl ester of N-(11-oxo-10,11-dihydrobenzo[b,f]thiepin-10-yl)succinamic acid (III; X=S, Y=Z=H, A=NH, R1=(CH2)2CO2Et);

ethyl ester of N-(11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-yl)succinamic acid (III; X=O, Y=Z=H, A=NH, R1=(CH2)2CO2Et);

got connection:

1,8-dioxa-3-sediment[e,h]azulene;

ethyl ester of 3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propionic acid;

ethyl ester of 3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propionic acid (table 1, compound 2-4).

When is EP 2

2-Methyl-1-oxa-8-thia-3-sediment[e,h]azulene (5; table 1)

To a solution of 11-oxo-10,11-dihydrobenzo[b,f]thiepin-10-silt ether acetic acid (III; X=S, Y=Z=H, A=O, R1=CH3) (0.910 g, 3,204 mmol) in acetic acid (25 ml) was added ammonium acetate (2,47 g, 32,04 mmol). The reaction mixture is boiled under reflux for 12 hours and then it was diluted with water (50 ml), neutralized with ammonia and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of isolated product in the form of a yellow powder.

Following the procedure of example 2, using as initial products of the following connections:

ether 11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-luxusni acid (III; X=O, Y=Z=H, A=O, R1=CH3);

ether 2-chloro-11-oxo-10,11-dihydrobenzo[b,f]thiepin-10-luxusni acid (III; X=S, Y=H, Z=2-Cl, A=O, R1=CH3);

ether 2-chloro-11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-luxusni acid (III; X=Oh, Y=H, Z=2-Cl, A=O, R1=CH3);

got connection:

2-methyl-1,8-dioxa-3-sediment[e,h]azulene;

5-chloro-2-methyl-1-oxa-8-thia-3-sediment[e,h]azulene in a mixture of 11-chloro-2-methyl-1-oxa-8-thia-3-sediment[e,h]azulene;

5-chloro-2-methyl-1,8-dioxa-3-sediment[e,h]azulene in a mixture of 11-chloro-2-methyl-1,8-dioxa-3-sediment[e,h]azulene (table 1, compounds 6-10).

PR is measures 3

1-oxa-8-thia-3-sediment[e,h]azulene-2-carbaldehyde (11; table 1)

To a solution of compound 1 (0,334 g 1,331 mmol) in anhydrous tetrahydrofuran (15 ml), cooled to -78°slowly dropwise added n-BuLi (0,256 g 3,985 mmol)dissolved in hexane (2.4 ml). The reaction mixture was stirred for 15 minutes at the same temperature and then was added anhydrous dimethylformamide (0,243 g 3,328 mmol). The reaction mixture was heated to room temperature and stirred for another hour, and then thereto was added water and was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of isolated product in the form of yellow crystals.

Example 4

3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propionic acid (12; table 1)

Connection 3 (0,280 g, 0,798 mmol) and KOH (0,067 g, 1,197 mmol) was dissolved in ethanol (10 ml) and the reaction mixture is boiled under reflux for 2 hours. After completion of the reaction the solvent evaporated to a dry residue was added water and was extracted with dichloromethane. The aqueous extract was acidified with HCl and the precipitated white crystals were filtered and washed with water.

Following the procedure of example 4 using the quality of the original product compound 4 was obtained 3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propy the OIC acid (13; table 1).

Table 1

Compounds of structure I

ConnectionXYZR1MS

(m/z)
1H NMR (ppm, CDCl3)
1SHHH252,0 (MH+)of 7.36-7,9l (m, 8H); of 8.06 (s, 1H)
2OHHH236,1 (MH+)7,07-8,02 (m, 8H); 8,03 (s, 1H)
3SHH(CH2)2CO2Et352,2 (MH+)1,26-of 1.30 (t, 3H); 2.93 which are 2.98 (t, 2H); 3.24 in-3,29 (t, 2H); 4,17-4,24 (q, 2H); 7,31-7,86 (m, 8H)
4OHH(CH2)2CO2Et358,0 (MNa+)1,26-of 1.30 (t, 3H); 2,97-to 3.02 (t, 2H); 3,30-to 3.35 (t, 2H); 4,14-4,22 (q, 2H); 7.29 trend is 7.85 (m, 8H)
5SHHCH3266,1 (MH+)of 2.66 (s, 3H); 7,33-7,87 (m, 8H)
6OHHCH3250,0 (MH+)to 2.65 (s, 3H); 7,19-7,79 (m, 8H)
7S5-ClH300,1 (MH+)of 2.68 (s, 3H); 7,31-7,88 (m, 7H)
8SH11-ClCH3300,1 (MH+)of 2.68 (s, 3H); 7,30-7,87 (m, 7H)
9O5-C1HCH3284,2 (MH+)of 2.58 (s, 3H);7,11 to 7.75 (m, 7H)
10OH11-ClCH3284,2 (MH+)at 2.59 (s, 3H); 7,12-7,72 (m, 7H)
11SHHCHO7,15-of 7.97 (m, 8H); to 9.91 (s, 1H)
12SHH(CH2)2CO2H324,0 (MH+)3,02-of 3.07 (t, 2H); 3,29-to 3.33 (t, 2H); 7,33-7,87 (m, 8H)
13OHH(CH2)2CO2H308,1 (MH+)

Example 5

1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)methanol (14; table 2)

To a solution of compound 11 (of 0.081 g, 0,290 mmol) in methanol (5 ml) was slowly added NaBH4(0,016 g, 0,435 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then neutralized with acetic acid. Evaporated races is varicel to the dry residue, was added a saturated solution of NaHCO3and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of isolated product in the form of light yellow powder.

Following the procedure of example 5, using as initial products of esters 3-4, got alcohols:

3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propan-1-ol;

3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propan-1-ol (table 2, compounds 15-16).

Example 6

2-methyl bromide-1-oxa-8-thia-3-sediment[e,h]azulene (17; table 2)

To a solution of compound 5 (0,110 g, 0,415 mmol) in carbon tetrachloride (5 ml) was added N-bromosuccinimide (0,259 g, 1,453 mmol) and a catalytic amount (PhCO)2O2. The reaction mixture was heated at 77°C for 3 hours, after which it was cooled and filtered besieged succinimide, the solvent evaporated to a dry residue, was added to her water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4. The solvent evaporated and after purification by chromatography on a column of allocated connection in the form of a yellow powder.

Following the procedure of example 6, using as initial products of compounds 6-10, got bromine compounds:

2-methyl bromide-1,8-dioxa-3-sediment[e,h]azulene;

2-methyl bromide-5-CHL is R-1-oxa-8-thia-3-sediment[e,h]azulene;

2-methyl bromide-11-chloro-1-oxa-8-thia-3-sediment[e,h]azulene;

2-methyl bromide-5-chloro-1,8-dioxa-3-sediment[e,h]azulene;

2-methyl bromide-11-chloro-1,8-dioxa-3-sediment[e,h]azulene (table 2, compounds 18-22).

Table 2

Compounds of structure I

20
ConnectionXYZR1MS

(m/z)
1H NMR (ppm, CDCl3)
14SHHCH2OH304,2 (MNa+)and 5.30 (s, 2H); 7,35-7,88 (m, 8H)
15SHH(CH2)3OH310,0 (MH+)
16OHH(CH2)3OH294,0 (MH+)
17SHHCH2Brto 4.62 (s, 2H); 7,38-8,10 (m, 8H)
18OHHCH2Brof 4.57 (s, 2H); 7,16-7,76 (m, 8H)
19S5-ClHCH2Brto 4.62 (s, 2H); 7,35-7,88 (m, 7H)
SH11-ClCH2Br379,9 (MH+)br4.61 (s, 2H); 7,33-a 7.85 (m, 7H)
21O5-ClHCH2Br4,59 (s, 2H); 7,20 for 7.78 (m, 7H)
22OH11-ClCH2Br4,59 (s, 2H); 7,16 to 7.75 (m, 7H)

Example 7

a)Dimethyl-[2-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]amine (I; X=S; Y=Z=H, R1=(CH3)2N(CH2)2OCH2)

To a solution of the hydrochloride of 2-diethylaminoethylamine (0,718 g 4,984 mmol) in 50% sodium hydroxide (3.9 ml) was added a catalytic amount of a chloride of benzyltriethylammonium and a solution of alcohol 14 (0,100 g, 0,356 mmol) in toluene (15 ml). The reaction mixture is boiled under reflux with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated oily product.

MC (m/z; MeOH): 353,2 MH+

b)Dimethyl-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]amine (I; X=S; Y=Z=H, R1=(CH3) 2N(CH2)3OCH2)

As a result of interaction of alcohol 14 (0,070 g, 0,249 mmol) and hydrochloride 3-dimethylaminopropylamine (0,551 g 3,486 mmol) was obtained colorless oily product.

MC (m/z; MeOH): 367,2 MH+, 389,2 MNa+.

Example 8

a)Dimethyl-{2-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propoxy]ethyl}amine (I; X=S; Y=Z=H, R1=(CH3)2N(CH2)2O(CH2)3)

To a solution of the hydrochloride of 2-diethylaminoethylamine (1,010 g 7,014 mmol) in 50% sodium hydroxide (6.2 ml) was added a catalytic amount of a chloride of benzyltriethylammonium and a solution of alcohol 15 (0,155 g, 0,501 mmol) in toluene (20 ml). The reaction mixture is boiled under reflux with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated yellow oily product.

MC (m/z; MeOH): 380,9 MH+, 402,9 MNa+.

b)Dimethyl-{3-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propoxy]propyl}amine (I; X=S; Y=Z=H, R1=(CH3)2N(CH2)3O(CH2)3)

As a result of interaction of alcohol 15 (0,155 g, 0,501 IMO the ü) hydrochloride and 3-dimethylaminopropylamine (1,11 g, 7,014 mmol) was obtained yellow oily product.

MC (m/z; MeOH): 395,1 MH+.

Example 9

a){2-[3-(1,8-Dioxa-3-sediment[e,h]azulene-2-yl)propoxy]ethyl}dimethylamine (I; X=O; Y=Z=H, R1=(CH3)2N(CH2)2O(CH2)3)

To a solution of the hydrochloride of 2-diethylaminoethylamine (0,653 g 4,536 mmol) in 50% sodium hydroxide (4.0 ml) was added a catalytic amount of a chloride of benzyltriethylammonium and a solution of alcohol 16 (0,095 g, 0,324 mmol) in toluene (15 ml). The reaction mixture is boiled under reflux with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated yellow oily product.

MC (m/z; MeOH): 365,0 MH+, 386,9 MNa+.

b){3-[3-(1,8-Dioxa-3-sediment[e,h]azulene-2-yl)propoxy]propyl}dimethylamine (I; X=O; Y=Z=H, R1=(CH3)2N(CH2)3O(CH2)3)

As a result of interaction of alcohol 16 (0,095 g, 0,324 mmol) and hydrochloride 3-dimethylaminopropylamine (determined as 0.720 g, 4,536 mmol) was obtained yellow oily product.

MC (m/z; MeOH): to 379.2 MH+.

Example 10

a)Dimethyl-[2-(1-oxa-8-thia-3-azadienes is[e,h]azulene-2-ylethoxy)ethyl]amine (I; X=S; Y=Z=H, R1=(CH3)2N(CH2)2OCH2)

To a solution of 2-dimethylaminoethanol (to 0.127 g, 1,425 mmol) in 50% sodium hydroxide (2.5 ml) was added a solution of bromide 17 (0,070 g, 0,204 mmol) in toluene (12 ml). The reaction mixture is boiled under reflux with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated yellow oily product.

MC (m/z; MeOH): 353,0 MH+, 374,9 MNa+.

b)Dimethyl-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]amine (I; X=S; Y=Z=H, R1=(CH3)2N(CH2)3OCH2)

As a result of interaction of bromide 17 and 3-dimethylaminopropan-1-ol was obtained yellow oily product.

MC (m/z; MeOH): 367,3 MH+, 389,3 MNa+.

Example 11

a)[2-(1,8-Dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine (I; X=O; Y=Z=H, R1=(CH3)2N(CH2)2OCH2)

To a solution of 2-dimethylaminoethanol (0,190 g, 2,134 mmol) in 50% sodium hydroxide (3,7 ml) was added a solution of bromide 18 (0,100 g 0,305 mmol) in toluene (15 ml). The reaction mixture was heated to reverse the fridge with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated yellow oily product.

MC (m/z; MeOH): 337,2 MH+, 359,1 MNa+.

b)[3-(1,8-Dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine (I; X=O; Y=Z=H, R1=(CH3)2N(CH2)3OCH2)

As a result of interaction of bromide 18 and 3-dimethylaminopropan-1-ol was obtained yellow oily product.

MC (m/z; MeOH): to 351.3 MH+, 373,3 MNa+.

Example 12

a) [2-(5-Chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine (I; X=S; Y=5-Cl, Z=H, R1=(CH3)2N(CH2)2OCH2)

To a solution of 2-dimethylaminoethanol (0,122 g, 1,370 mmol) in 50% sodium hydroxide (2.4 ml) was added a solution of bromide 19 (0,074 g, 0,196 mmol) in toluene (12 ml). The reaction mixture is boiled under reflux with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated yellow oily product.

MC (m/z; MeOH): 38,9 MH +.

b)[3-(5-Chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine (I; X=S; Y=5-Cl, Z=H, R1=(CH3)2N(CH2)3OCH2)

As a result of interaction of bromide 19 and 3-dimethylaminopropan-1-ol was obtained yellow oily product.

MC (m/z; MeOH): 403,1 MH+.

(C)[2-(11-Chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine (I; X=S; Y=H, Z=11-Cl, R1=(CH3)2N(CH2)2OCH2)

As a result of interaction of bromide 20 and 2-dimethylaminoethanol received a yellow oily product.

MC (m/z; MeOH): 387,0 MH+.

Example 13

a)[2-(5-Chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine (I; X=O; Y=5-Cl, Z=H, R1=(CH3)2N(CH2)2OCH2)

To a solution of 2-dimethylaminoethanol (0,112 g, 1,253 mmol) in 50% sodium hydroxide (2.2 ml) was added a solution of bromide 21 (0,065 g, 0,179 mmol) in toluene (10 ml). The reaction mixture is boiled under reflux with vigorous stirring for 4 hours. Then it was cooled to room temperature, diluted with water and was extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of allocated yellow oily PR the product.

MC (m/z; MeOH): 373,0 MH+, 395,0 MNa+.

b)[3-(5-Chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine (I; X=O; Y=5-Cl, Z=H, R1=(CH3)2N(CH2)3OCH2)

As a result of interaction of bromide 21 and 3-dimethylaminopropan-1-ol was obtained yellow oily product.

MC (m/z; MeOH): 387,0 MH+, 409,0 MNa+.

(C)[2-(11-Chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine (I; X=Oh; Y=H, Z=11-Cl, R1=(CH3)2N(CH2)2O(CH2)

As a result of interaction of bromide 22 and 2-dimethylaminoethanol received a yellow oily product.

MC (m/z; MeOH): 373,1 MH+, 395,1 MNa+.

Obtain the original substance

Method And

Monooxime dibenzo[b,f]thiepin-10,11-dione

11N-Dibenzo[b,f]thiepin-10-he (2.0 g, 8,8 mmol) was dissolved with stirring and heating to 75°With 3 M HCl in ethanol (36,4 ml). NaNO2(0,818 g, up 11,86 mmol) was dissolved in minimum amount of water and ethanol (1 ml) and the resulting solution was added to an ethanolic solution of HCl. The reaction mixture was heated for 2.5 hours and then cooled and neutralized with 10% NaOH solution (pH˜7-8). Partially, the solvent evaporated and the precipitated product (green crystals) was filtered and washed with water.

Using the above methodology used is eaten as a source of product 11N-dibenzo[b,f]oxepin-10-she received monooxime dibenzo[b,f]oxepin-10,11-dione.

Method In

Hydrochloride 11-amino-11N-dibenzo[b,f]thiepin-10-it

To a solution of monooxime dibenzo[b,f]thiepin-10,11-dione (of 2.06 g, 8,078 mmol) in acetic acid (25,8 ml), cooled to 0°With added zinc (0,792 g, 12.1 mmol). The reaction mixture was stirred for 30 minutes at the same temperature, after which the precipitate was filtered and evaporated acetic acid to the dry residue. The obtained oily product was dissolved in minimum amount of ethanol, then it was cooled to and acidified with HCl, precipitated the product which was then filtered and washed with ether.

Using the above method, method B, using as starting product monooxime dibenzo[b,f]oxepin-10,11-dione, was obtained the hydrochloride of 11-amino-11N-dibenzo[b,f]oxepin-10-it.

Way

N-(11-Oxo-10,11-dihydrobenzo[b,f]thiepin-10-yl) formamide (III; X=S; Y=Z=H, A=NH, R1=H)

To a suspension of formic acid to 27.2 μl, 0,721 mmol) and dichloromethane (5 ml), cooled to 0°With, in a stream of nitrogen was added a solution of hydrochloride of 11-amino-11N-dibenzo[b,f]thiepin-10-she (0,200 g, 0,721 mmol) in dichloromethane (10 ml) and triethylamine (50 μm, 0,357 mmol) and catalyst 1-hydroxybenzotriazole (of € 0.195 g, 1,442 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,580 g, 3,028 mmol). The reaction mixture is PE is amasyali at room temperature for 24 hours. After completion of the reaction the solvent evaporated, added water and was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column of white solid was isolated product.

Following the procedure of method using as starting product hydrochloride 11-amino-11N-dibenzo[b,f]oxepin-10-she received N-(11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-yl)formamide (III; X=S; Y=Z=H, A=NH, R1=H).

Method D

Ethyl ester of N-(11-oxo-10,11-dihydrobenzo[b,f]thiepin-10-yl)succinamic acid (III; X=S; Y=Z=H, A=NH, R1=(CH2)2CO2Et)

To a solution of hydrochloride of 11-amino-11N-dibenzo[b,f]thiepin-10-she (strength of 0.159 g, 0,540 mmol) in pyridine (640 μl), cooled to 0°C, was added a solution of ethylsuccinate (0,098 g, 0,594 mmol) in chloroform (220 ml). The reaction mixture was stirred for another 2.5 hours at room temperature, evaporated the solvent to the dry residue was added water and was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4and evaporated. After purification by chromatography on a column were isolated yellow solid product.

Following the procedure of method D, using as starting product hydrochloride 11-amino-11N-dibenzo[b,f]oxepin-10-she's got a complex of ethyl N-(11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-yl)succinamic acid (III; X=O; Y=Z=H, A=NH, R1=(CH2)2CO2Et).

Method E

11-Oxo-10,11-dihydrobenzo[b,f]thiepin-10-silt ether acetic acid (III; X=S; Y=Z=H, A=O, R1=CH3)

To a suspension of the acetate of lead (IV) (3,9 g, 8,8 mmol) in acetic acid solution was added to 11N-dibenzo[b,f]thiepin-10-she (2.0 g, 8,8 mmol) in acetic acid (5 ml). The reaction mixture is boiled under reflux for several hours, and during this was filtered acetic acid using stills of Hickmann, and then added water and was extracted with ethyl acetate. The organic extract was washed with saturated solution of NaHCO3and water, dried over anhydrous Na2SO4and evaporated to a dry residue. After purification by chromatography on a column were isolated yellow solid product.

Following the procedure of method E, using as initial products of the following connections:

11N-dibenzo[b,f]oxepin-10-he;

8-chloro-11N-dibenzo[b,f]thiepin-10-he;

8-chloro-11N-dibenzo[b,f]oxepin-10-he;

got connection:

11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-silt ether acetic acid (III; X=O; Y=Z=H, A=O, R1=CH3);

2-chloro-11-oxo-10,11-dihydrobenzo[b,f]thiepin-10-silt ether acetic acid (III; X=S; Y=H, Z=2-Cl, A=O, R1=CH3).

2-chloro-11-oxo-10,11-dihydrobenzo[b,f]oxepin-10-silt ether acetic acid (II; X=Oh; Y=H, Z=2-Cl, A=O, R1=CH3).

Table 3

Compounds of structure III

ConnectionXYZR1MS (m/z)1H NMR (ppm, CDCl3)
SHNNHH292,0 (MNa+)6,72-6,74 (d, 1H);

7,19-of 7.69 (m, 8H);

compared to 8.26-8,29 (d, 1H);

of 8.47 (s, 1H)
ONNNHH276,0 (MNa+)6,33 to 6.35 (d, 1H);

7,16 to 7.62 (m, 8H);

8,07-8,10 (m, 1H);

8,54 (s, 1H)
SHNNH(CH2)2CO2Et370,2 (MH+)1,23 of 1.28 (t, 3H);

2,69 was 2.76 (m, 4H);

4,13-4,20 (kb, 2H);

of 6.66 (d, 1H);

7,19-to 7.67 (m, 8H);

compared to 8.26-8,29 (DD, 1H)
ONNNH(CH2)2CO2Et354,1 (MHa+)
SHNOCH3to 307.1 (MNa+)of 2.36 (s, 3H); 7,07 (s, 1H); 7,25 is 8.25 (m, 8H)
ONNO CH3of 2.38 (s, 3H); to 6.67 (s, 1H); 7,19-8,09 (m, 8H)
SN2-ClOCH3of 2.36 (s, 3H); was 7.08 (s, 1H); 7,26 is 8.25 (m, 7H)
ON2-ClOCH3325,1 (MNa+)2,38-2,39 (d, 3H); 6.73 x-6,74 (d, 1H); 7,12-8,08 (m, 7H)

Data for biological studies

In table 4 we present data confirming the biological activity of some compounds obtained in examples of the present invention, in the in vitro tests as described on p.24-26 above. Table 4 presents the values of % inhibition of production of TNF-α when the concentration of the compounds according to the invention 10 and 3 μm.

Table 4
The biological activity of the compounds obtained in examples of the present invention
Example No.The structural formulaConnection% inhibition of production of TNF-α in vitro (concentration 10 and 3 μm)
7aDimethyl-[2-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]amine14/7
Dimethyl-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]amine60/3
8ADimethyl-{2-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propoxy]ethyl}amine90/34
8bDimethyl-{3-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propoxy]propyl}amine100/38
9a{2-[3-(1,8-Dioxa-3-sediment[e,h]azulene-2-yl)propoxy]ethyl}dimethylamine73/26
9b3-[3-(1,8-Dioxa-3-sediment[e,h]azulene-2-yl)propoxy]propyl}dimethylamine87/23
10ADimethyl-[2-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]amine14/7

10bDimethyl-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]amine14/7
11a[2-(1,8-Dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]d is methylamine 0/14
11b[3-(1,8-Dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine22/15
12a[2-(5-Chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine100/39
12b[3-(5-Chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine100/23
12c[2-(11-Chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine100/59
13a[2-(5-Chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine44/9
13b[3-(5-Chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine100/33

13C[2-(11-Chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine98/22

1. The compound of the formula I

where X represents a heteroatom such as O, S;

Y and Z independently of one another mean one or more identical or different substituents associated with any available carbon atom, and may represent hydrogen or halogen;

R1is a Deputy of the formula II

in which R2and R3at the same time or independently of one another can represent hydrogen or C1-C4-alkyl;

m is an integer from 1 to 3;

n is an integer from 0 to 3;

Q1and Q2independently of one another represent oxygen or a group

where the substituents y1and I2represent hydrogen;

as well as its pharmacologically acceptable salt.

2. The compound according to claim 1, where Y and/or Z denotes H or Cl.

3. Connection and salt according to claim 2, where m is 1, n is 1 or 2, Q1means O Q2means of CH2and R2and R3mean CH3.

4. The compound of the formula I

where X can represent O or S;

Y and Z represent H or Cl;

R1can represent hydrogen, Galaga is, With1-C7-alkyl, Cho, (CH2)2COOH, (CH2)2CO2Et, (CH2)mL, where m has a value of 1 or 3 and L means HE or Br;

or its pharmacologically acceptable salt.

5. The compound or its pharmacologically acceptable salt according to claim 4, where R1means H, CH3, SNO, (CH2)2COOH, (CH2)2CO2Et, (CH2)mL, where m has a value of 1 or 3 and L means HE or Br.

6. Compounds according to claim 5, selected from among the following:

1-oxa-8-thia-3-sediment[e,h]azulene;

1,8-dioxa-3-sediment[e,h]azulene;

ethyl ester of 3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propionic acid;

ethyl ester of 3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propionic acid;

2-methyl-1-oxa-8-thia-3-sediment[e,h]azulene;

2-methyl-1,8-dioxa-3-sediment[e,h]azulene;

11-chloro-2-methyl-1-oxa-8-thia-3-sediment[e,h]azulene;

5-chloro-2-methyl-1-oxa-8-thia-3-sediment[e,h]azulene;

11-chloro-2-methyl-1,8-dioxa-3-sediment[e,h]azulene;

5-chloro-2-methyl-1,8-dioxa-3-sediment[e,h]azulene;

1-oxa-8-thia-3-sediment[e,h]azulene-2-carbaldehyde;

3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propionic acid;

3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propionic acid;

(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)methanol;

3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propan-1-ol;

3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propan-1-ol;

2-methyl bromide-1-oxa-8-thia-3-sediment[e,h]azulene;

2-methyl bromide-1,8-dioxa-3-sediment[e,h]azulene;

2-methyl bromide-5-chloro-1-oxa-8-thia-3-sediment[e,h]azulene;

2-methyl bromide-11-chloro-1-oxa-8-thia-3-sediment[e,h]azulene;

2-methyl bromide-5-chloro-1,8-dioxa-3-sediment[e,h]azulene;

2-methyl bromide-11-chloro-1,8-dioxa-3-sediment[e,h]azulene.

7. The compounds and salts according to claim 3, selected from among the following:

dimethyl-[2-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]amine;

dimethyl-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]amine;

dimethyl-{2-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propoxy]ethyl}amine;

dimethyl-{3-[3-(1-oxa-8-thia-3-sediment[e,h]azulene-2-yl)propoxy]propyl}amine;

{2-[3-(1,8-dioxa-3-sediment[e,h] azulene-2-yl)propoxy]ethyl}dimethylamine;

{3-[3-(1,8-dioxa-3-sediment[e,h]azulene-2-yl)propoxy]propyl}dimethylamine;

2-(1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine;

[3-(1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine;

2-[5-chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine;

[3-(5-chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine;

[2-(11-x is the PR-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine;

[3-(11-chloro-1-oxa-8-thia-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine;

[2-(5-chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine;

[3-(5-chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine;

[2-(11-chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)ethyl]dimethylamine;

[3-(11-chloro-1,8-dioxa-3-sediment[e,h]azulene-2-ylethoxy)propyl]dimethylamine.

8. The use of compounds of the formula I according to claim 5 as an intermediate product to obtain the new compounds of the class of dibenzazepines formula I according to claim 1, which have anti-inflammatory action.

9. The use of compounds of the formula I according to claim 3, having the properties of inhibitors of the production of TNF-α and inhibitors of the production of interleukin-1 (IL-1) to obtain medications for oral, parenteral or topical application in the treatment and prevention of diseases caused by excessive unregulated produced cytokines or inflammatory mediators.



 

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

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

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

22 cl, 3 tbl, 6 dwg, 7 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

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35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, pharmaceuticals.

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30 cl, 177 ex

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15 cl, 3 tbl, 80 ex

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3 cl, 1 dwg, 3 ex

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EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

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

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

35 cl, 2 tbl, 15 ex

FIELD: chemistry of heterocyclic compounds, antibacterial agents.

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3 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

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EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: organic chemistry, medicine, oncology, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent used in treatment of benign and malignant and proliferative diseases. Agent represents derivative of dysorasol of the general formula (I): and using indicated derivatives for treatment of benign and malignant tumor and proliferative diseases. Proposed agent shows the enhanced activity.

EFFECT: enhanced and valuable medicinal properties of drug.

6 cl, 6 tbl, 1 dwg, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), halogen atom and oxygen atom (O); R2 is chosen from consisting of H, halogen atom and N=N; R3 is chosen from group consisting of H and halogen atom; R4 is chosen from group consisting of H, halogen atom, amino and N=N; R5 is chosen from group consisting of H, halogen atom, methoxy, methyl and O; or R1 and R2, or R and R5 are joined and form unsaturated carbon ring; R6 is chosen from group consisting of H, (C1-C6)-alkyl, (C2-C6)-alkenyl, 3-phenyl-2-propin-1-yl, benzyl, benzyl substituted with halogen atom, phenyl or methoxy, CH2-cycloalkyl, CH2-2-furan, -(CH2)2SCH3 and -(CH2)2NHBOC; R7 is chosen from group consisting of H, (C1-C6)-alkyl and cycloalkyl; R8 is chosen from group consisting of benzyl and benzyl substituted with OCH2-phenyl; T represents group of the formula or wherein R9 and R10 represent H; or R9 represents H, and R10 are chosen from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, methyl-substituted (C2-C6)-alkenyl, (C2-C6)-alkynyl, cycloalkyl, phenyl substituted with (C1-C6)-alkyl, halogen atom, methoxy, -SCH3 or -N(CH3)2, 1-naphthyl and CH2-CH2-1,3-dioxolane; or R9 and R10 are chosen independently from group consisting of (C1-C6)-alkyl, (C2-C6)-alkenyl, phenyl, phenyl substituted at position 4 with halogen atom, methoxy, -SCH3 or -N(CH3)2 and 1-naphthyl, or its pharmaceutically acceptable salt, hydrate, or its prodrug as carbamate or ester. Also, invention relates to compounds of the formula (Ia) and the formula (Ib) given in the invention description, and to a method for decreasing levels of beta-amyloid, and to their using and to a method for prophylaxis or treatment of Alzheimer's disease, Down's syndrome. Invention provides preparing novel biologically active compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 17 tbl, 278 ex

FIELD: medicinal chemistry, pharmacy.

SUBSTANCE: invention relates to compounds and pharmaceutical compositions that act as antagonists of metabotropic glutamate receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

7 cl, 3 tbl, 11 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula II , wherein X, Y represent N; Z O; Ar1 represents 2-piridyl; Ar2 represents phenyl and at least one from Ar1 and Ar2 is substituted by at least one residue selected from group comprising of -F, -Cl, -Br, -I, -SR, -CN, -C(O)R, -CH(OR)R', -CH2(OR), -CF3, C1-C10-alkyl and aryl, wherein R of R' are H, -CF3, C1-C10-alkyl and aryl or together form a ring, except for 3-(2-piridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole or 3-(2-piridyl)-5-[3-(trifluotomethyl)phenyl]-1,2,4-oxadiazole; or to new compounds as defined in specification; as well as pharmaceutical composition having activity in relation to metabothrophic glutamate receptors based on the same and method for modulating of metabothrophic glutamate receptors.

EFFECT: new compounds useful as modulators of metabothrophic glutamate receptors.

14 cl, 10 ex, 1 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (1): wherein R1 means (C1-C6)-alkyl that can be substituted with phenyl; R2, R3, R4 and R5 represent independently each of other hydrogen halogen atom, nitro-group, (C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-, (C6-C10)-aryloxy-group, (C6-C10)-aryl that can be mono-, di- or tri-substituted with halogen atom; 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 under condition that R2, R3, R4 and R5 can't mean simultaneously hydrogen atom and at least one residue among R2, R3, R4 and R5 represents 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 at value R6 - hydrogen atom, (C1-C4)-alkyl or (C6-C10)-aryl-(C1-C4)-alkyl wherein aryl can be substituted with halogen atom; A means a simple bond, -COn, -SOn or -CONH; n = 1 or 2; R7 means hydrogen atom; (C1-C18)-alkyl or (C2-C18)-alkenyl that can be substituted from one to three times with (C1-C4)-alkyl, (C1-C4)-alkyloxy-group, -N-((C1-C4)-alkyl)2-group, -COOH, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl, (C6-C12)-aryloxy-group, (C6-C12)-arylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxy-group, halogen atom, -CF3 or oxo-group wherein aryl, in turn, can be substituted with halogen atom, (C1-C)-alkyl, aminosulfonyl- or methylmercapto-group; (C6-C10)-aryl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl, (C6-C10)-aryl-(C2-C6)-alkenyl, (C6-C10)-aryl, diphenyl, diphenyl-(C1-C4)-alkyl, indanyl that can be mono- or di-substituted with (C1-C18)-alkyl, (C1-C18)-alkyloxy-group, (C3-C8)-cycloalkyl, hydroxy-group, (C1-C4)-alkylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-group, (C6-C10)-aryloxy-group, nitro-, cyano-group, (C6-C10)-aryl, fluorosulfonyl, (C1-C6)-alkyloxycarbonyl, (C6-C10)-arylsulfonyloxy-group, pyridyl, -NHSO2-(C6-C10)-aryl, halogen atom, -CF3 or -OCF3 wherein alkyl can be substituted once again with halogen atom, -CF3 or (C1-C4)-alkyloxy-group; or group Het-(CH2)r wherein r = 0, 1, 2 or 3 wherein Het means saturated or unsaturated 5-7-membered heterocycle comprising atoms nitrogen (N), oxygen (O) or sulfur (S) and can be condensed with benzene and substituted with (C1-C4)-alkyl, (C6-C10)-aryl, halogen atom, (C1-C4)-alkyloxy-group, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C)-alkylmercapto- or nitro-group and wherein aryl condensed with benzene can be, in turn, substituted with halogen atom, (C1-C4)-alkyloxy-group; and to their pharmacologically acceptable salts and additive salts of acids, and to a method for their preparing. Proposed compounds show inhibitory effect on activity of hormone-sensitive lipase.

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

14 cl, 199 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new amide derivatives of carboxylic acid that are antagonists of NMDA receptors of the formula (I): , wherein one radical among R1, R2, R3 and R4 represents -OH or NH2-group and others are hydrogen atoms; or two adjacent groups R1, R2, R3 and R4 in this case in common with one or more similar or different additional heteroatoms and -CH= and/or -CH2-groups form 5-6-membvered homo- or heterocyclic ring but preferably pyrrole, pyrazole, imidazole, oxazole, oxooxazolidine or 3-oxo-1,4-oxazine ring; two other groups among R1, R2, R3 and R4 radicals represent hydrogen atoms; R5 and R6 in common with nitrogen atom between them form saturated or unsaturated 4-6-membered heterocyclic ring that is substituted with phenoxy-, phenyl-[(C1-C4)-alkoxy]-, phenoxy-[(C1-C4)-alkyl]-, benzoyl-group optionally substituted in aromatic ring with one or more halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; X and Y mean independently oxygen, nitrogen atom or group -CH=, and to their salts formed with acids and bases. Also, invention relates to a method for preparing compounds of the formula (I) and pharmaceutical compositions showing activity as selective antagonists of NR2B receptor based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of the following diseases: chronic neurodegenerative diseases, chronic painful states, bacterial and viral infections.

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

11 cl, 2 tbl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

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

10 cl, 4 tbl, 26 ex

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