Orthotamine connection - new inhibitors prostaglandins, pharmaceutical compositions containing them and a method of inhibiting prostaglandin h synthase

 

(57) Abstract:

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase. In the compounds of the formula I, J is CH or N, K and L represent CH; X represents a simple bond, -Z(R5)p; Z represents O; R1represents phenyl or 2-naphthyl, substituted by 0-2 substituents R7WITH5-C7cycloalkyl or5-C7cycloalkenyl, provided that R1directly related to the heteroatom, the heteroatom is not associated with the carbon atom containing the double bond in cycloalkene ring, or a 5-10 membered heterocyclic system selected from pyrrolyl, benzothiazyl, 3-pyridyl, optionally substituted C1-C4the alkyl, chinoline or piperidinyl; R2is below group 1) or 2), Y represents methyl; R3represents H, F, Br, Cl, OH, NO2, NR15R16C(=O)R6; R4represents hydrogen, or alternatively, when R3and R4are substituents at adjacent carbon atoms, R3and R4taken together with the carbon atoms to which they are attached, WITH6alkyl; R7represented by the Deputy at the carbon atom selected from the group consisting of fluorine, bromine, chlorine, iodine,1-C4of alkyl, CH2HE, CH2OCH3WITH1-C4alkoxy, Cho, NR15R16; R8is hydrogen; R15represents hydrogen or C1-C4alkyl; R16represents hydrogen or C1-C4alkyl; p = 0 or 1. The proposed pharmaceutical composition for inhibiting prostaglandin H synthase and a method of inhibiting prostaglandin H synthase. 6 C. and 3 h.p. f-crystals, 5 PL.

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The invention relates to orthotamine phenyl compounds suitable for use as inhibitors prostaglandins, pharmaceutical preparations containing these compounds, and methods of using these compounds as anti-inflammatory and fever-reducing drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) for 2 centuries was used as the main anti-rheumatic and anti-inflammatory drugs (Weissman, G. , Scientific American, pages 84-90, 1991). The mechanism of action of NSAIDs is associated with inhibition of the biosynthesis of prostaglandins (Vane, J. R., Nature-New Biology, vol. 231, with the G/H synthase). The cyclooxygenase is the first enzyme in the cascade of biotransformation of arachidonic acid, leading to the formation of prostaglandins subtype D2E2and F2a. In addition, prostacyclin (PGI2and thromboxanes A2and IN2formed from the intermediate products of biosynthesis S2of cyclo-oxygenase. (Prostaglandins and Related Substances - A Practical Approach (1987). Benedetto, S., McDonald-Gibson, R. G., and Nigam, S., and Slater, T. F., in. ZRL Press, Washington, D. C). These metabolites of arachidonic acid are involved in the implementation processes, expressed pain syndrome, fever, platelet aggregation and inflammation. In addition, prostaglandins responsible for the integrity of the mucosa of the gastrointestinal tract (Cryer Friday, September, B., and Feldman, M., Arch Intern. Med., vol. 152, 1145-1155, 1992) and the functioning of the kidneys, especially in stress conditions (Whelton, A. , and Hamilton. C. W., J. Clin. Pharmacol. vol. 31, pp. 588-598, 994). Thus, the means overwhelming cyclooxygenase activity, anti-inflammatory and analgesic effects due to blockade of the synthesis of the mediator of pain and inflammation, however, due to the mechanism of their action, these same agents may have side effects on the gastrointestinal tract and kidneys. Minimizing or eliminating such the military profile of their distribution in the gastrointestinal tract and kidneys (Vane, J. R., Nature, vol. 367, pages 215-216, 1994).

Up until now it was assumed that only one isoenzyme of the cyclooxygenase responsible for prostaglandin G/H2-sitesnow activity. However, recently, there have been reports of other identified mitogen-inducible form of this enzyme, designated as cyclooxygenase 2 (SOH 2) (Xie, W., Chipman, J. G., Robertson, D. L., Erickson, R. L., and Simmons, D. L. , Proc. Natl. Acad. Sci., vol. 88 p. 2692-2696, 1991; Kujubu, D. A., Fletcher, B. S., varnum poor, B. C., Lim, R. W., and Herschman, H. R., J. Biol Chem., vol. 266(20) pages 12866-12872, 1991; MA, T., Neilson, K., the OEWG. Natl. Acad. Sci. 89 p. 7384-7388, 1991; Xie, W., Robertson, D. L., and Simmons, D. L. , Drug Development Research, vol. 25, pages 249-265, 1992). Mor 2 shows the physical and biological properties different from the classical type of cyclooxygenase 1 SOH. Suppose that the mechanism of distribution Mor 2 between tissues and cells of the body along with its regulated gene expression is associated with its mediator function in inflammatory reactions and pathological conditions, such as rheumatoid arthritis, while the gene expression of Mor 1 is associated with constituitive functions. In accordance with the difference between year 1 and year 2 expressed earlier assumptions about the mechanism of action of NSAIDs, which are based on the effect of only one of Letichevsky effects of NSAIDs are associated exclusively with the inhibition of the activity of the isoenzyme 1 SOH. In fact, perhaps more likely seems the hypothesis that the mechanism of anti-inflammatory and analgesic actions of most NSAIDs in response to chronic irritation may be associated with inhibition of mitogen-induced form Mor 2, while the mechanism of action of currently available NSAIDs on the gastrointestinal tract and kidneys associated with inhibition activity constituitive expressed enzyme Mor 1 (Vane, J. R., Nature, vol. 367, pages 215-216, 1994). Thus, I believe that medicinal substances with selective or specific inhibitory action regarding Mor 2, will reduce its harmful effects on the gastrointestinal tract and kidneys, but at the same time to maintain a high level of their anti-inflammatory as well as analgesic activity.

The possibility of using safer NSAIDs through the mechanism of selective inhibition of accelerated studies to assess the effect of compounds on the preparations of the purified enzyme. Selective inhibition of the isoenzyme, and factors with similar inhibitory activity was evaluated using a set of therapeutically suitable NSAIDs (DeWitt, D. L., Meade, E. A. the selectivity for Mor 2, 6-methoxynaphthalene acid (6MNA), the active metabolite of nabumetone. A known number of other substances that have the same selectivity for the Mor-2, including the factor BF389 (Mitchell, J. A., Akarasereenot, P., Thiemermann, C., Flower, R. J., and Vane, J. R., Proc. Natl. Acad. Sci., vol. 90 p. 11693-11697, 1994) and the factor of NS-398 (Futaki, N.,) Takahashi, S. , Yokayama, M, Arai, I., Higuchi, S., and Otomo, S., Prostaglandins, vol. 47, pages 55-59, 1994; Masferrer, J. L., Zuieifel, B. S., Maiming, P. T., Hauser, S. D., Leaky, K. M., Smith, W. G., Isakson, P. C., Seibert, K., Proc. Natl. Acad. Sci., vol. 91 p. 3228-3232, 1994). In the case of the latter compound selective inhibition of Mor-2 led to the blockade of synthesis in vivo precursor of prostaglandin that causes an allergic reaction in response to carrageenan, however, there was no suppression of the synthesis of prostaglandins that promote the secretion of gastric juice, no pathological changes of the gastric mucosa (Masferrer and others, see above).

These data support the assumption that selective inhibitors of the synthesis of Sokh 2 have powerful anti-inflammatory activity and have improved their safety for the patient. Detailed mechanistic studies have shown that a factor of NS-398 and second selectively-acting inhibitor SOH-2, i.e. a factor of DuP 697, provide their selectivity through unique is lective Inhibition of the Inducible Isoform of Prostaglandin G/H Synthase (Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase). Specified the inhibition is competitive relative to both isoenzymes, however, demonstrates election breathability effect on Mor-2, leading to a more potent suppression of its activity over a longer period. Gramasevaka impact provides inhibition of the specific binding reaction, which may be reversible only after denaturation of the enzyme and its extraction from the organic phase.

Newkome, G. R. and others (J. Org. Chem. 1980, vol. 45 p. 4380) report bis (5-carboxy-2-pyridyl)benzene, but does not give any information regarding the destination of these compounds.

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Bushby and others. (J. Chem. Soc. Perkin Trans., vol. I, page 721, 1986) disclose the synthesis of substituted terphenyls, including the examples given later in the description.

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Hori, M. and others (Chem. Pharm. Bull., vol. 22(9), page 2020, 1974) have reported the synthesis of terphenyls, including 2-phenyl-2'-methylthio-1-diphenyl.

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CEMR and others (J. Org. Chem. , vol. 46 p. 5441, 1981) have reported the synthesis of 4-methoxyphenyl-(4'-alkylphenyl)benzene.

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Floyd and others disclosed in U.S. patent 4613611-hydroxy--oxo-[1,1': 2', 1"-terphenyl] -4-econsultancy acid in the form of a monosodium salt cured for the IDA can be used as antagonists of platelet activating factor (Tilley, and others. J. Med. Chem. vol. 32 p. 1814, 1989).

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In the application Europatent 130045 A1, published 01.02.85 disclosed substituted bis-(methoxyphenyl)benzene, suitable for use as analgesics and anti-inflammatory drugs.

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In U.S. patent 3624142 disclosed 4-methylsulfonylmethane acid, are suitable as anti-inflammatory drugs.

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None of the above links are not disclosed or offered methylsulfonyl of the present invention. Thus, the purpose of the present invention is aimed at creating connections related to the synthesis inhibitors prostaglandins, including compounds which are selective inhibitors of Sokh 2, which can be used as a new anti-inflammatory drugs with improved therapeutic profile for the treatment of rheumatic and inflammatory diseases, as well as in pyrogenic therapy.

The present invention relates to orthotamine phenyl compounds of the formula I, disclosed hereinafter in the description, as inhibitors prostaglandins, to drugs based on them and methods of using these compounds in medical praet any compound of formula I:

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or a pharmaceutical salt or Palekastro form,

where J, K, and L each independently mean CR3, CR4or N;

X means a simple link (i.e., the radical X is absent), -(CHR5)2-, -CH=CR5-, -CR5=CH-, -(CHR5)pZ-, -Z(CHR5)p-, -C(=O)CH2or-CH2C(=O)-;

Z denotes O or S;

R1means phenyl, substituted by 0-2 substituents selected from the radicals R7, 2-naphthyl, substituted by 0-2 substituents selected from the radicals R7WITH5-C7cycloalkyl, substituted 0-1 substituents selected from the radicals R9WITH5-C7cycloalkenyl provided that when R1directly related to the heteroatom, the heteroatom is not associated with the carbon atom containing the double bond in cycloalkene ring, 5-10-membered aromatic heterocyclic system selected from the group of furil, teinila, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrole, isoxazolyl, isothiazoline, pyrazolyl, 3-pyridinyl, pyrazinyl, benzofuranyl, benzothiazyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzothiazolyl, benzisoxazole, chinoline, izochinolina or piperidinyl, and heterocyclics is:

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Y represents-CH3or NH2.

R3means H, F, Br, Cl, I, CN, C1-C4alkyl, substituted 0-1 substituents selected from the radicals R12C1-C4halogenated,1-C4alkenyl, substituted 0-1 substituents selected from the radicals R13, NO2, NR15R16, SOmR11, SO2NR15aR16, -C(=O)R6, -COOR17, -C(=O)NR15aR16or OR18;

R4means H, F, Br, Cl, I, C1-C2alkyl, C1-C2alkoxy, C1-C2halogenated, -CF3, -SR10a;

Alternatively, when R3and R4mean the substituents at adjacent carbon atoms, R3and R4taken together with the carbon atoms to which they are directly connected, form a 5-7-membered carbocyclic or heterocyclic aromatic system, and the specified aromatic heterocyclic system containing from 1 to 3 heteroatoms selected from N, O or S;

R5means C1-C2alkyl, C1-C2alkoxy or C1-C2halogenated;

R6means hydrogen, C1-C6alkyl, substituted 0-1 substituents selected from the radicals R9, 5-10-membered aromatic heterocyclic system selected from the group of furil, teinila, thiazolyl, oxazolyl, N-methylpyrrole, isoxazolyl, isothiazoline, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, and specified aromatic heterocyclic system substituted by 0-2 substituents selected from the radicals R7;

R7does the Deputy have a carbon atom selected from the group consisting of H, F, Br, Cl, I, C1-C4of alkyl, phenyl, CH2HE, CH2OCH3C1-C4alkoxy, C1-C4halogenoalkane, -SR10, NR15R16, -C(=0)Rl0aCH2COOR17or or19; provided that when X is a simple bond, R7cannot be orthopaedie relatively X.

R8means H, F, Br, C1, I, C1-C4alkyl, C1-C4alkoxy;

R9means H, F, Br, C1, I, hydroxy, C1-C4alkyl or C1-C4alkoxy;

R10means N or C1-C4alkyl;

R10ameans C1-C4;

R11means C1-C4alkyl, C1-C2foralkyl, phenyl or benzyl;

R12means F, OR18; NR-C(=O)NR15aR16or heterocyclic aromatic system selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, furil, teinila, pyridinyl, piperidinyl, pyrimidinyl, pyrazinyl, or tetrahydropyridine, and specified aromatic heterocyclic system substituted by 0-2 substituents selected from the radicals R9;

R13means-CN, -C(=O)R6, -COOR17, -NO2or NR15R16;

R14means F, HE, C1-C4alkoxy, -NH2, phenyl, substituted by 0-2 substituents selected from the radicals R9alkylsulphonyl, arylcarbamoyl, -COOR17or-C(=O)NH2;

R15means H, C1-C4alkyl, substituted 0-1 substituents selected from the radicals R23C6-C10aryl, C3-C7cycloalkyl,4-C11cycloalkenyl,2-C4alkenyl, C1-C4alkoxy, C1-C6alkylsulphonyl, C1-C6alkoxycarbonyl, C7-C14arylethoxysilanes,6-C10aryloxyalkyl, C1-C6alkylaminocarbonyl, C6-C10arylcarbamoyl, C1-C6alkylsulfonyl, C6-C10arylsulfonyl, C7-C14alkylaryl substituents, selected from the radicals R23WITH6-C10aryl, C3-C7cycloalkyl,4-C11cycloalkenyl,2-C4alkenyl or C1-C4alkoxygroup;

R16means N or C1-C4alkyl; or

alternatively, R15and R16taken together, represent the group -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2- or -(CH2)2NR21(CH2)2-,

R17means C1-C4alkyl or arylalkyl;

R18means C1-C4alkyl, substituted by 0-2 substituents selected from the radicals R24C6-C10aryl, C3-C7cycloalkyl, C1-C6alkylsulphonyl, C1-C6alkylaminocarbonyl, C7-C14arylalkylamine or C6-C10arylcarbamoyl, substituted by 0-2 substituents selected from the radicals R9;

R19means C1-C4alkyl, C1-C4halogenated, C1-C4alkoxyalkyl, C1-C6alkylsulphonyl, C1-C6alkylaminocarbonyl, C7-C14arylalkylamine or6-C10arylcarbamoyl, substituted by 0-2 substituents selected from UB> alkoxyalkyl, C6-C10aryl, C3-C7cycloalkyl, C1-C6alkylsulphonyl, C1-C6alkylaminocarbonyl, C7-C14arylalkylamine or C6-C10arylcarbamoyl, substituted by 0-2 substituents selected from the radicals R9;

R21means C1-C4alkyl or benzyl;

R22means N, R2, R1C1-C4alkyl, C4-C10cycloalkyl, C7-C14arylalkyl, or C6-C10heteroaromatic;

R23means H, F, phenyl, substituted by 0-2 substituents selected from the radicals R9, -C(= O)R6, -COOR17, -C(=O)OTHER16or heterocyclic aromatic system selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, furil, tanila or tetrahydropyridine, and specified aromatic heterocyclic system substituted by 0-2 substituents selected from the radicals R9;

R24means H, F, NR15R16, phenyl, substituted by 0-2 substituents selected from the radicals R9C1-C4alkoxy, C1-C4alkylcarboxylic, -C(=O)R6, -COOR17, -C(=O)OTHER15R16or aromatic heterocyclic system is selected and the I aromatic heterocyclic system substituted by 0-2 substituents, selected from the radicals R9;

m means 0-2; and

R means 0-1,

provided that when J and L both mean a nitrogen atom, and By means of CR4, R4can't take the value SR10.

For the preferred compounds of the formula I or their pharmaceutically acceptable salts or proletarienne forms include compounds where:

J denotes CH or N;

K and L each independently mean CR3or CR4;

X means a simple link, (i.e., the radical X is absent), or -(CHR5)pZ-;

R3means the group consisting of H, F, Br, CN, C1-C4of alkyl, substituted 0-1 substituents selected from the radicals R12C1-C4halogenated, NO2, SOmR11, -C(O=)R6or or18;

R4means H, F, CH3or alternatively, when R3and R4have substituents at adjacent carbon atoms, R3and R4taken together with the carbon atoms to which they are directly connected, form a 5-7-membered carbocyclic aromatic system;

R6means hydrogen, C1-C6alkyl, substituted 0-1 substituents selected from the radicals R14or phenyl, substituted 0-2 deputies the dust, consisting of H, F, VG, WITH1-C4of alkyl, CH2HE, CH2OCH3C1-C4alkoxy, C1-C4halogenoalkane, NR15R16, -C(=O)R10;

wherein all other substituents in the structure of the compounds of formula I have the above values.

Particularly preferred compounds of formula I include the compounds or their pharmaceutically acceptable salts or prodrugs, in which:

R8means N;

R9means N;

R12means F, OR18, -CN, -COOR17;

R13means-CN, -C(=O)R6, -COOR17, -NO2or NR15R16;

R14means N;

R15means N or C1-C4alkyl;

R16means N or C1-C4alkyl;

R18means N or C1-C4alkyl;

R19means C1-C4alkyl.

The most preferred compounds or their pharmaceutically acceptable salts or prodrugs include compounds selected from the group consisting of:

(a) compounds of the formula Ia:

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where: R1X represents phenyl, a R3means hydrogen,

R1X is phenyl, and R3means 4-HE,

R1X means is SUP>X is phenyl, and R3means 4-CH3C(=O),

R1X is 4-forfinal, and R3means N,

R1X is 4-methoxyphenyl and R3means N,

R1X is 4-were, and R3means N,

R1X is 3-methoxyphenyl and R3means N,

R1X is 3,4-acid, and R3means N,

R1X is 4-hydroxymethylene, and R3means N,

R1X is 4-ethoxymethylene, and R3means N,

R1X is 4-dimethylaminophenyl, and R3means N,

R1X is 4-formylphenyl, and R3means N,

R1X is 2-naphthyl, a R3means N,

R1X is 5-methoxy-2-naphthyl, and R3means N,

R1X is 3-chinoline, and R3means N,

R1X is 2-chinoline, and R3means N,

R1X is 5-benzothiazyl, and R3means N,

R1X is 2-benzothiazyl, and R3means N,

R1X represents 3-pyridyl, and R3means N,

R1X is and R3means N,

R1X means phenoxy, and R3means N,

R1X means 1-cyclohexenyl, and R3means N,
achet N,

R1X means cyclohexyloxy, and R3means N,

R1X is benzyloxy and R3means N,

R1X means 1-piperidinyl, and R3means N,

R1X means 1-pyrrolyl, and R3means N,

(b) a compound of formula I, which is a

2-(4-methylsulfinylphenyl)-3-phenylnaphthalene,

(c) a compound of formula I, which is a

3-(4-methylsulfinylphenyl)-2-phenylpyridine and

(d) compound of formula I, which is a

2-(4-aminosulphonylphenyl)-1-diphenyl.

The present invention also provides pharmaceutical preparations containing the compound of formula I and a pharmaceutically acceptable carrier.

Compounds disclosed above can be used as anti-inflammatory and fever-reducing drugs when introducing them in the form of drugs in the body of a mammal, if necessary, treatment with these anti-inflammatory and fever-reducing drugs. In the scope of the present invention includes pharmaceutical preparations containing an effective amount of the above compounds of formula I, having the effect of inhibitor activity S2against arthritis and other inflammatory diseases in a mammal, namely, that in the body of a mammal is administered a therapeutically effective amount of the compounds of formula I disclosed above.

Compounds of the invention can also type in combination with one or more additional drugs. The purpose of the compounds of formula I of the present invention in combination with such additional drug has the advantage of relatively separate them because it helps increase therapeutic efficacy of the drug and when to use each of them in smaller doses. The use of the drug in smaller amounts helps to minimize the possibility of adverse effects, thereby increasing the limit of his endurance.

The term "therapeutically effective amount" refers to the amount of the compounds of formula I, administered in pure form or in combination with an additional drug into the cell or the organism of a mammal, which is effective for inhibiting the activity S2in such a way to prevent or alleviate the patient's condition due to inflammation, or block Binyavanga treatment" refers to the compound of formula I and one or more additional drugs, entered in parallel into the body of a mammal in the course of his treatment. When combined therapy of each component can be taken simultaneously or sequentially in any order at different intervals of time. Thus, each component can be taken separately, but in close enough period of time to obtain the desired therapeutic effect.

The proposed compounds may have asymmetric centers. Unless otherwise noted, all chiral, diastereomeric and racemic forms of the proposed compounds included in the scope of the present invention. Many geometric isomers of olefins, conjugated relation C=N and the like can also be present in the proposed connections, and each of these stable isomeric forms considered in the scope of the present invention. It is clear that the compounds of the invention may contain assymetrically substituted carbon atoms, and they may also be allocated in the form of optically active or racemic compounds. Experts in the art are familiar with methods for obtaining optically active compounds, for example, by separation of racemic mixtures or their synthesis from the source optically active coenye, racemic forms and all geometric isomers can be represented in the structure of the proposed connections.

If any variable appears more than 1 time in any constituent or in any formula, its definition at each occurrence is not dependent on its definition at every other occurrence. For example, if you specify that the group is substituted by 0-3 substituents selected from R6this group may not necessarily be up to three substituents selected from R6while the value of R6whenever a variable is chosen independently from the set list of possible values of R6. One can cite as an example the group-N(R5a)2each of the two substituents of the radical R5awhen the N atom is chosen independently from the set list of possible values of the radical R5a. Similarly, for example in the case of a group-C(R7)2- each of the two substituents of R7when an atom is chosen independently from the set list of possible values of the radical R7.

In the case indicated that the relationship with the Deputy passes through the bond connecting two atoms in a ring, such Deputy may be associated with Liu is stitely associated with the other groups, the carbon chain of the compounds of formula I, the Deputy can be linked via any atom. For example, if the Deputy means piperazinil, piperidinyl or tetrazolyl, any specified piperazinilnom, piperidinyl or tetrataenia group, unless otherwise stated, may be associated with other groups of the carbon chain of the compounds of formula I via any atom.

Allowed combinations of substituents and/or variables only, provided that such combination will result obtaining a stable connection. Under stable connection or stable structure should be understood in this connection that has sufficient stability to withstand the operation of separating it from the reaction mixture with the desired degree of purity and the subsequent technology of preparation of effective medicines.

Under used in this application, the term "substituted" should be understood as any one or more of the hydrogen atoms at the indicated atom, substituted by a group selected from the list of values provided that the principal valence of the designated atom is not excessive and that as a result of such substitution to get a stable connection. In Schenna atom.

Used in this description, the term "alkyl" means a radical of the series of saturated aliphatic hydrocarbons with branched or normal chain containing the specified number of carbon atoms (e.g., "C1-C10" means alkyl with 1-10 carbon atoms; the term "halogenated" means radicals of a series of saturated aliphatic hydrocarbons with branched or normal chain containing the specified number of carbon atoms, substituted by 1 or more halogen atoms (for Example, CvFwwhere v=1-3, and w=1 to(2v+l)); "alkoxy" means an alkyl group with the specified number of carbon atoms in the chain, linked through an oxygen bridge; "alkylthio" means an alkyl group with the specified number of carbon atoms in the chain, linked through a sulfur bridge; "dialkylamino" means the N atom, is substituted by 2 alkyl groups with the specified number of carbon atoms; "cycloalkyl" means radicals of the number of unsaturated cyclic hydrocarbons, including mono-, bi - or polycyclic aromatic system, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and substituted; and bicycloalkyl" means radicals of the number of limit bicyclic hydrocarbon term "alkenyl" should be understood chain of carbon atoms as unbranched, or branched configuration with one or more unsaturated carbon-carbon bonds that may be present in the circuit in any stable point, for example ethynyl, propenyl and the like; and "quinil" means a chain of carbon atoms as unbranched and branched configuration with one or more triple carbon-carbon bonds that may be present in the circuit in any stable point, such as ethinyl, PROPYNYL and the like.

The terms "alkylene", "albaniles", "phenylene" and the like mean an alkyl, alkeline and phenyl groups, respectively, which are connected via a double bond with other groups, cyclic structures of the compounds of formula I. for example, "alkylene", "albaniles", "phenylene", and the like in this description can be as an alternative and equivalent designations-(alkyl)-", "-(alkenyl)-", "-(phenyl) -, and the like.

Used in this description, the terms "halo" or "halogen" means, fluorescent, chloro, bromo and iodide; and "counterion" means a small negatively charged molecular particles, for example, chloride, bromide, hydroxide, acetate, sulfate and the like.

Used in this OPI is l" means aryl group, linked through an alkyl bridge.

Used in this description, the term "carbocycle" or "carbocyclic residue" means any sustainable 3-7-membered monocyclic or bicyclic carbocycle, or 7-14 membered bicyclic or tricyclic carbocycle, or polycyclic carbocycle containing up to 26 carbon atoms, each of which may be saturated, partially unsaturated or aromatic. As an example of such carbocycles may serve as, but not limited to volume, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, diphenyl, naphthyl, indanyl, substituted or tetrahydronaphthyl(tetralin).

Under used in this description the terms "heterocycle" or "heteroaryl" or "heterocyclic" should be understood as any sustainable 5-7-membered monocyclic or bicyclic a heterocycle or a 7-10-membered ring of the bicyclic heterocycle, each of which may be saturated, partially unsaturated or aromatic, and which consists of carbon atoms and 1 to 4 heteroatoms, independently selected from the group N, O and S, and the N and S heteroatoms can be optionally oxidized, and the N atoms quaternity, including any bicyclic group in which any of the above heterocycles rotoma or carbon atom, thereby obtaining a stable structure. Heterocycles disclosed in the present description, may be substituted at the carbon atom or nitrogen, provided that the compound obtained stably. As examples of such heterocycles may serve as, but not limited to their volume, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophene, indolyl, chinoline, ethenolysis, benzimidazolyl, piperidinyl, pyrrolidinyl, 2-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline, octahydronaphthalene, pyranyl, isobenzofuranyl 2N-pyrrolyl, isothiazolin, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 12-indazole, pyrrolidinyl, pyrrolidyl, imidazolidinyl, imidazolyl, pyrazolidine. pyrazolines, piperidinyl, piperazinil, indolinyl, isoindolyl, morpholinyl or oxazolidinyl. In the scope of the present invention also includes compounds with condensed ring and Spiro-compounds containing, for example, the above-mentioned heterocycles.

Under used in this description, the term "pharmaceutically acceptable salt" should understand what taking it in the form of salt accession acid or base. As an example, pharmaceutically suitable salts can be, but not limited to volume, salts with mineral and organic acids with the remnants of bases, such as amines; alkali or organic salts with the remnants of acids, such as carboxylic acids; and the like.

Under used in this description, the term "Prodrug" is to be understood any covalently associated media, which release in vivo of the active compound of formula I from the source of the medicinal product with the introduction of the specified proletarienne form in the body of a mammal. Palekastro form compounds of the formula I are obtained by modification contained functional groups, in which there is a transformation of their disintegration as a result of routine manipulation or in vivo, in the original active compounds. In volume proletarienne forms include compounds of formula I, hydroxyl, amino, sulfhydryl, or carboxyl groups which are associated with any group which when introduced into the body of a mammal cleaved with the formation of free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. As examples of such proletarienne the national amino group in compounds of formula I and the like.

In the amount of pharmaceutically acceptable salts of the compounds of formula I include conventional non-toxic salts or the Quaternary ammonium salts of the compounds of formula I formed by, for example, from non-toxic inorganic or organic acids. As such conventional non-toxic salts may be, for example, salts formed from inorganic acids, for example hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids, for example acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pambou, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic acid, methanesulfonate, ethicality, oxalic, italianboy and the like.

Pharmaceutically acceptable salts of the present invention can be obtained from compounds of the formula I, containing the remainder of the base or acid by standard methods of organic synthesis. Such salts are usually obtained by reacting the free base or acid with stoichiometric amounts or an excess sootvetstvushchih mixtures of solvents.

Pharmaceutically acceptable salt accession acids of the present invention can be obtained by reacting compounds of the formula I with an appropriate amount of inorganic bases, such as hydroxides of alkali and alkaline earth metals, such as hydroxides of sodium, potassium, lithium, calcium or magnesium, or organic bases, for example aminoven base, for example dibenziletilendiaminom, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a Quaternary ammonium hydroxide, such as hydroxide of Tetramethylammonium and the like.

As mentioned previously, pharmaceutically acceptable salts of compounds of formula I of the present invention can be obtained by reacting these compounds in the form of the free acid or base with a stoichiometric amount of the appropriate base or acid, respectively, in water or an organic solvent or a mixture of two solvents; usually, preferably carrying out the reaction in an anhydrous medium, such as a simple diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. The list of usable salts can be found in the directory Remington Pharmaceutical SciencLASS="ptx2">

Synthesis of

Compounds of the invention can be obtained in various ways, which are well-known specialists in the field of organic synthesis. Compounds of the present invention can be obtained in accordance with the methods described below, in combination with methods well-known in the field of organic synthesis, or their modifications, which are obvious to experts. To the preferred methods of synthesis of the proposed compounds include the methods disclosed below, which, however, should not be a limit. All opposed to the sources of literature included in this description as a reference material, and should be considered as a whole.

The new compounds of formula I can be obtained by carrying out various reactions and using the methods described in this section. The above reaction is carried out in solvents that are compatible with the reagents and starting materials and suitable for the ongoing transformations. In addition, the implementation of the synthesis methods disclosed below, it must be borne in mind that all proposed reaction conditions, including solvent reaction medium, the temperature holding reacts is this type of reaction, which should be obvious to any person skilled in the art. Specialist in the field of organic synthesis should be understood that the functional groups present in different parts of the released molecule must be compatible with the proposed reagents and reactions. Not all compounds of formula I, fall under this class may be compatible with some of the reaction conditions that are required in some of the disclosed methods. Such restrictions on deputies, which must be compatible with the reaction conditions will be apparent to the person skilled in the art, and then you must use alternative methods.

The compounds of formula I, where R1means substituted aryl, X is a simple bond (i.e., the radical X is absent), R2means 4-methylsulfinylphenyl, a R3, R4, R7and R8have the above meanings, can be obtained in accordance with the General method of synthesis is illustrated in Scheme 1.

The interaction of substituted properly phenylboronic acid with ortho-dibromobenzene in accordance with the methodology proposed by Suzuki (A. Suzuki and others, J. Am. Chem. Soc., 1989, vol. 11, page 513, and V. N. Kalini, suitable for use in this reaction combination, may serve as, but not limited to volume, toluene, dimethylformamide, dioxane and ethanol. The reaction is carried out in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride. The reaction product combinations can be distinguished using standard chromatography methods known to experts in the field of organic synthesis, to obtain the desired intermediate for the synthesis of biphenyls. Interaction by the method of Suzuki received 2-bromodiphenyl 4-phenylboronic acid using the reaction conditions described above gives 2-(4'-methylthio)phenyl-1-diphenyl. The subsequent oxidation of metalcorp to the appropriate methylsulfonyl group receiving compound of formula I. the above oxidation reaction may be conducted using any of the reagents known to specialists in this field for recovery of mercaptans to sulfones. As examples of such reagents may serve as, but not limited volume axon in a mixture of methanol with water (Trost and others. t. Lett. vol. 22 (14), page 1287, 1981), hydrogen peroxide, m-chlormadinone acid or monoperoxyphthalic acid, with, which means a simple link, a R2means 4-methylsulfinylphenyl, can also be obtained from commercially available 2-bromophenols, as shown in scheme 2. The reaction mix for Suzuki 2-bromophenol with phenylboronic acid can be performed under the above described conditions using both free and protected accordingly by a group of the phenol or the corresponding triflate. The second reaction mix by Suzuki between the intermediate triflate and 4-methyldiphenylamine acid with subsequent oxidation by the previously described method gives compound of formula I.

The compounds of formula I, where R2means 4-methylsulfinylphenyl, X is a simple bond, and R1means cycloalkenyl or cycloalkenyl residue, obtained from 2-bromo-(4'-methylthio)biphenyls by a series of reaction stages, shown in figure 3. Required diphenylene compounds used as starting materials are obtained by reaction mix for Suzuki 1,2-dibromobenzene with 4-methyldiphenylamine acid using the above conditions.

Treatment of 2-bromo-(4'-methylthio)of diphenyl strong base at low temperature followed by addition of an appropriate cycloalkane gives promezhutochnoe in this reaction can serve as n-utility, tert-utility or motility. The reaction is carried out in an aprotic solvent, for example tetrahydrofuran, simple ether, hexane or 1,4-dioxane. The received dehydration of the tertiary alcohol can be easily provided by treatment with a catalytic amount of a strong acid, for example p-toluenesulfonic acid, in a suitable solvent, for example toluene. Subsequent oxidation of metalcorp to methylsulfonyl groups according to the method described above can be formed of compounds of formula I, where R1means cycloalkenyl. Catalytic hydrogenation of these cycloalkenyl derived through a suitable catalyst, such as platinum oxide, in an appropriate polar solvent, for example methanol, leads to the production of the compounds of formula I, where R1means cycloalkyl. Alternatively cycloalkyl connection can be obtained from the intermediate alcohol first oxidation metalcorp to methylsulfone with subsequent direct hydrogenation of tertiary alcohols with

using similar conditions dehydrogenization that described above for the recovery of olefin.

The compounds of formula I where X is oxygen, R1means samewe is about)diphenyl, as illustrated in Scheme 4.

Treatment 2-hydroxy-1-(4'-methylsulphonyl)-diphenyl (obtained through the reaction is illustrated in Scheme 3) with a suitable base, such as sodium hydride, followed by addition of 4-fluoro-1-nitrobenzene leads to the formation of intermediate compounds for the synthesis of 2-(4-nitrophenoxy)-diphenyl. When restoring the nitro group (see "Compendium of Organic Synthetic Methods volume. 1, page 266, 1971) produces compound of formula I, where R7= NH2. Removal of the amino group can be performed according to the method of Cadogan, J. I. G., and others. (J. Chem. Soc. Perkin. Trans. vol. I, p. 541, 1973). Alternatively, the amino group can be converted into other functional groups through the intermediate salt of the page when using methods that are well-known specialists in the field of organic synthesis. Using this methodology, synthesis, you can easily get other substituted appropriately simple aryl ethers of formula I.

The compounds of formula 2 where R2means 4-methylsulfonylmethyl, you can get palladium catalyzed the reaction mix on Suzuki 2-diphenylpropanoic acid substituted with properly 4-methyldiethanolamine or triflate (see Scheme 5). Wt is ilti-5-bromo-pyridine reagents, used in Scheme 5, can be obtained in one stage from commercially available 2,5-dibromopyridine, as illustrated in Scheme 6, by treating the alkali metal salt of a mercaptan, for example mertiolate sodium in any polar aprotic solvent, such as anhydrous dimethylformamide.

Other bromine - or the replacement methylthioadenosine that can be used as starting compounds in the reaction of a combination of 2-diphenylpropanoic acid by the method of Suzuki, can be easily obtained in a similar manner from commercially available reagents.

For example, 2-bromo-5-methylthiopyridine can be obtained by treating 2-methoxy-5-bromopyridine (Shiao. M. J., and others. Syn. Comm. vol. 20 (19), page 2971, 1990) n-butyllithium in anhydrous tetrahydrofuran at a temperature of -78oC and subsequent quenching of the reaction with dimethyl disulfide to yield 2-methoxy-5-methylthiopyridine. As a result of demethylation reaction produces 2-hydroxy-5-methylthiopyridine that when interacting with forsteronia gives the desired source connection of 2-bromo-5-methylthiopyridine (Scheme 7).

The compounds of formula I, where X represents a simple bond, a R1means an aromatic heterocycle, you can get the R Schemes. As an example, suitable for use bromemerielal may serve as, but not limited to volume, 2 - or 3-bromofuran, 2 - or 3-bromothiophene, 3-bromopyridine, 2-bromobenzophenone (Baciocchi, E. and others. J. Perk. Trans. , vol. II, 1976, page 266) and 5-bromobenzoate (Board and others. J. Het. Chem. vol. 25, page 1271, 1988).

The compounds of formula I, where R8matter except H can be obtained by using as starting material is replaced properly 4-methylthiophenol. Such phenols can be obtained from commercially available reagents by methods known in the field of organic synthesis. One such method of obtaining illustrated in Scheme 8, where at selective demethylation of 3-methyl-4-methylthiazole receive the appropriate phenol, which after processing Trifonova anhydride in the presence of 2,6-lutidine in methylene chloride (Gerlach. U. and others. Tet. Lett. 33(38), 5499, 1992), gives triplet suitable for use in the above-described palladium-catalyzed reactions combination. Received methylthiazolidine intermediate compound can be converted into a compound of formula I by oxidation of the corresponding sulfone by the method described above.

The compounds of formula I, where R3matter except in the as starting materials for the reactions of the combination according to Suzuki, described above. When performing standard manipulations with the functional groups of the compounds obtained using methods that are well know of any specialist in the field of organic synthesis, you can get more substituents of the radical3for which no suitable commercially available starting materials. The following Diagrams serve to illustrate methods for obtaining compounds of the compounds of formula I with a wide variety of substituents for the radicals R3.

Catalyzed by palladium, the reaction mix for Suzuki 3-nitro-4-bromoacetophenone with phenylboronic acid provides an output of 3-nitro-1-aclditional. During the restoration of the nitro group with a solution of tin chloride in hydrochloric acid is formed amine, which can be turned into perborate, page by treatment with a solution of ISO-amilnitrita and thriftimart apirat in methylene chloride (Doyle, M. P. et. al., J. Org. Chem. vol. 44, page 1572, 1979). Salt the page, you can then turn directly to triplet by processing triperoxonane acid (Yoneda, N. and others. Chem. Lett. 1991, page 459). In the interaction of the resulting triflate with 4-methylthiazolidine phenylboronic acid by the method described above, with subsequent oxidation izbicka the/P> This connection can serve as starting material for preparing compounds of the formula I is illustrated in Scheme 10. The transformation of the hydroxyl group in the simple radio communication can be ensured by alkylation reaction using a solution of sodium hydride and the appropriate alkyl halide in anhydrous tetrahydrofuran. A hydroxyl group can also be made triflat by processing Trifonova anhydride in the presence of 2,6-lutidine when using methylene chloride as solvent. Received triplet can be subjected to palladium catalyzed reaction of a combination according to Suzuki (Cacchi and others. t Lett. vol. 27(33), pp. 3931, 1986; Kalinin, V. p. Synthesis 413, 1992) or in combination Stille (Stille, J. K. J. Am. Chem. Soc., 1988, 110, 1557) with the release of substituted derivatives of alkenyl, ketones and carboxylic acids.

In addition to the transformations shown in Scheme 10, by using the methods known in the field of organic synthesis, esters can be amylene to carboxylic acids, which in turn can be converted into substituted amides, ketones or hydroxamate. Complex alkenone esters can also be restored by catalytic hydrogenation with output saturated esters using PAL is th amino group, can be obtained from the intermediate 2-[4-methylthiophenyl]-4-Aceto-1-diphenyl obtained in Scheme 9, the method illustrated in Scheme 11. Bochmanovskaja rearrangement (Donaruma, L. G., and others, Organic Reactions, volume 11, pages 1-156, 1960) ketone, followed by hydrolysis of the obtained amide leads to the formation of amine, which can then be converted into amides, disubstituted amines or substituted amides of well-known methods in the field of organic synthesis. The oxidation of metalcorp according to the method described previously, obtain the compounds of formula I. alternatively, compounds where R3means functional amino group, can be obtained from carboxylic acids via the rearrangement of kurzius (Banthorpe, D. V. "The Chemistry of The Azido Group, Palai, S. Ed., Interscience, New York, 1971. pages 397-405), as illustrated in Scheme 12.

The compounds of formula I, where R3and R4both have values other than hydrogen, can be obtained through many different reactions by methods well-known in this field. One of these reaction pathways are illustrated in Scheme 13.

The conversion of 3-(4'-methylthio)phenyl-1-hydroxy-4-diphenyl N,N-dimethylcarbamate can be accomplished by reacting sodium hydride with N,N-dimethylcarbamoyl the years of second-utility in anhydrous tetrahydrofuran, followed by quenching of the resulting anion with a suitable electrophilic reagent (for example, iodine stands) gives an intermediate compound that can be converted into different compounds of formula I using the methods described above, or well-known methods in the field of organic synthesis.

The compounds of formula I in which one or more groups of the radicals J, K or L means a hydrogen atom, can be obtained by substitution of the heterocycle with a corresponding functional group on monobromobimane or dibromsalan benzenes obtained in the above Schemes. For example, in the case where J denotes the nitrogen atom, the compound of the formula I get the method illustrated in Scheme 14.

Catalyzed by palladium, the reaction mix on Suzuki 2-bromo-3-hydroxypyridine substituted with properly phenylboronic acid gives 2-phenyl-3-hydroxypyridine. In the transformation of the hydroxyl group in triplet when using the above reaction conditions, followed by conducting the reaction in combination with Suzuki 4-methyldiphenylamine acid in an anhydrous medium in the presence of palladium catalyst to obtain 2,3-diarylpyrimidine. As the solvent for this reaction combinations you can use anhydrous 1,4-dioxane. Election N.

The compounds of formula I, where Z means a simple link, a R1mean 1-piperidinyl or 1-pyrrolyl can be obtained from 2-bromoaniline, as shown in Scheme 15. Interaction on Suzuki 2-bromoaniline 4-dimethylphenylacetic acid by the method described above, followed by condensation of 2-(4-methylthiophenyl)aniline with dibromoethane in the presence of an amine base such as triethylamine gives the corresponding 1-[2-(4-methylthiophenyl)phenyl]piperidine. The oxidation reaction, if required, metalcorp to methylsulfonyl by using the methods described above, gives the compound of formula I, where R1mean 1-piperidinyl. Alternatively, the original 2-bromaniline can be converted into 1-[(2-bromophenyl)phenyl] pyrrole by treatment with a solution of 2,5-dimethoxytetrahydrofuran in glacial acetic acid. The interaction Suzuki obtained intermediate compound 4-methyldiphenylamine acid and subsequent oxidation reaction according to the method. as described above, leads to the formation of 1-[2-(4-methylsulfinylphenyl)phenyl]pyrrole.

For a better understanding of the compounds of the present invention and methods for their preparation the following are specific examples which serve only as Illustra is maintained without correction. Except where otherwise indicated, all reactions were conducted under nitrogen atmosphere. All commercially available chemicals were used immediately after their receipt. Chromatography was performed on silica gel 60 Merck (230-400 mesh mesh). Eluent for chromatography are given in the form of a ratio (by volume). Unless, otherwise noted, the organic phase from the solvent-solvent extracts usually dried by magnesium sulfate. Unless, otherwise stated, the solvent is usually removed by evaporation under reduced pressure on a rotary evaporators. The peak position of the spectra1H NMR are given in parts per million) in the direction of the field from tetramethylsilane as an internal standard. Adopted the following abbreviations for spectra1H NMR: s= singlet, d=doublet, m=multiplet, DD=double doublet. Mass spectra were obtained using chemical ionization with ammonia as a gas for reagents. Microanalysis was carried out using equipment of firm Quantitative Technologies Inc., Bound Brook, N. J.

Example 1

2-[(4-methylthio)phenyl]-1-diphenyl (Method 1)

A. Obtaining 4-methyldiphenylamine acid.

To a suspension of magnesium filings (4.3 g, 180 mmol), cooled to 0oWith, Messi added dropwise a suspension of 4-bromothioanisole (30 g, 148 mmol) in tetrahydrofuran (75 ml). Then add a few iodine crystals and the reaction mixture allowed to warm to room temperature and then stirred for 72 hours. The reaction mixture is carefully poured into 500 g of crushed ice. The solution is acidified (pH 3) 1 N. hydrochloric acid and left overnight. The acidic solution is extracted with diethyl ether. Diethyl ether is extracted with 1 N. a solution of sodium hydroxide. The alkaline layer is acidified and then extracted with diethyl ether. After evaporation of the solvent receive colorless crystals which, after recrystallization from ethyl acetate with a small amount of water to give 12.5 g of 4-methyldiphenylamine acid;1H NMR (DMSO) : 7,73 (d, J=8,42 Hz, 2H), 7,21 (d, J=8,42 Hz, 2H), 2,47 (s, 3H). Mass spectrum (Cl, CH4), m/z 195 (M+N+complex etilenglikolevye ether).

C. Obtain 2-bromo-1-(4'-methylthiophenyl) benzene.

A mixture of 4-methyldiphenylamine acid (31.1 g, 185 mmol), 1,2-dibromobenzene with (35 g, 148 mmol), and tetrabutylammonium bromide (1 g, 3.10 mmol) in ethanol (125 ml) and toluene (250 ml), Tegaserod by ozonation of nitrogen through the mixture for 15 minutes. 2 M solution of sodium carbonate (148 ml, 296 mmol) Tegaserod and add to ipatt under reflux for 24 hours. The reaction mixture is cooled to room temperature and filtered to remove the solid precipitate. The filtrate is evaporated and then diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers are combined, washed with saline and dried on sodium sulfate. The ethyl acetate evaporated and the residue precipitated. Adding diethyl ether (200 ml) produced an additional amount of solid precipitate. The precipitation is filtered off and the filtrate is evaporated to obtain crude oil. After cleaning method column chromatography on silica gel using hexane as eluent get the desired product (25,75 g, 62%), which is kept to solubilize, so pl. 33-35oC; 1H NMR (D13) : 7,66 (d, J=8,05 Hz, 1H), was 7.36-7,28 (m, 6N), 7,21 (m, 1H), 2,52 (s, 3H). Mass spectrum, m/z 279,1, 281,1 (M+H).

Elemental analysis for C13H11BrS.

Calculated: 55,92%, N Of 3.97%, VG 28,62%.

Found: 56,24%, N Of 4.04%, VG Of 28.96%.

C. Obtain 2-Bromo-1-(4'-methylsulfinylphenyl)benzene.

The compound obtained in Example 1 in section b (5,2 g, to 18.7 mmol), dissolved in dichloromethane (100 ml) and cooled to a temperature of 0oC. 3-Chlormadinone acid (8,9 g, 41.2 mmol) of probable izbavlyayut dichloromethane and washed successively with sodium bicarbonate, dilute sodium bisulfite, dried on sodium sulfate, filtered and evaporated. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 7: 1 as eluent get colorless crystals which, after recrystallization (dichloro/methane) to give pure product (as 4.02 g, 69%), so pl. 155-157o;1H NMR (CDC13) : 8,02 (d, J= 8,42 Hz, 2H), 7,71 (d, J=of 6.96 Hz, 1H), 7,63 (d, J=8,42 Hz, 2H), 7,43 (m, 1H), 7,32 (m, 2H), 3,13 (s, 3H); IR (KBR): 1306, 1142 cm-1.

Elemental analysis for C13H11BrO2S.

Calculated: 50,17%, N Of 3.56%, S 10,30%.

Found: 50,09%, N 3,41%, S 10,52%.

D. Obtain 2-[(4-methylsulphonyl)phenyl]-1-diphenyl.

2-Bromo-1-(4'-methylsulfinylphenyl)benzene (4 g, 12.8 mmol), phenylboronic acid (1,72 g, 14 mmol), and tetrabutylammonium bromide (0.21 g, of 0.65 mmol) dissolved in a mixture of toluene (70 ml) and ethanol (35 ml) and the resulting mixture was bubbled with nitrogen for 15 minutes. Then add degassed 2M solution containing sodium bicarbonate (14 ml, 28 mmol) and tetrakis(triphenylphosphine)palladium (0,074 g, 0,064 mmol) and the resulting mixture is refluxed for 4 hours. The reaction mixture was evaporated and diluted with water and ethyl acetate. The formed layers rum, dried, filtered and evaporated. After cleaning method column chromatography on silica gel using mixtures of hexane/ethyl acetate 3:1 as eluent, and recrystallization in a mixture of dichloro/methane obtain 2.55 g (65%) of the titled compound as colorless crystals, so pl. 136-138o;1H NMR (D13) : 7,79 (d, J=8,42 Hz, 2H), 7,47 (m, 3H), 7,42 (m, 1H), 7,34 (d, J=8.7 Hz, 2H), 7.23 percent (m, 3H), 7,11 (m, 2H) 3.04 from (s, 3H). Mass spectrum (S1, CH4), m/z 309 (M+H), 337 (M+C2H5).

Elemental analysis for C19H16O2S.

Calculated: 74,00%, N 5,23%, S The 10.40%.

Found: 74,01%, N 5,13%, S 10,63%.

Example la

2-[(4'-methylthio)phenyl]diphenyl (Method 2)

A. Obtaining 2-Phenyl-1-proxycredentialtype.

A mixture consisting of 2-phenylphenol (5 g, 29.4 mmol), N,N-dimethylaminopyridine (0,61 g, 4,99 mmol) and 2,6-lutidine (4,1 ml of 35.0 mmol) in dichloromethane (180 ml), cooled to a temperature of -30oC. the Anhydride of triftoratsetata (5,90 ml of 35.0 mmol) was added to the reaction mixture and removing the cooling bath. After incubation for 1 hour at room temperature the mixture was then washed sequentially with 0.5 n model HC1 solution, water, saturated sodium bicarbonate and saline. The mixture is dried, f is,35-7,50 (m, N). Mass spectrum: (Cl, CH4), m/z 303 (M+N), 331 (M+C2H4).

C. Obtain 2-[(4'-methylthio)phenyl]-1-diphenyl.

2-Phenyl-1-proxycredentialtype (of 13.75 g of 45.5 mmol), 4-methylthiopropionate acid (8,4 g, 50.0 mmol), and tripotassium phosphate (12,6 g, or 59.0 mmol) suspended in 1,4-dioxane and Tegaserod by passing nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium (1.30 grams, to 1.14 mmol) was added to the reaction mixture and the mixture is refluxed for 24 hours. The mixture is cooled, filtered and evaporated. The residue is dissolved in ethyl acetate, then washed with water and brine and dried. After purification of the mixture by chromatography on silica gel using hexane as eluent and recrystallization (EtOH) to obtain the desired product (4,27 g) as white crystals, so pl. 42-44oC. After evaporation of the mother liquor can be added to 4.98 g of the named compound;1H NMR (CDC13) : 7,41 (s, 4H), of 7.23 (m, 3H), 7,16 (m, 2H), 7,13? 7.04 baby mortality (m, 4H), of 2.45 (s, 3H). Mass spectrum, m/z 277,1 (M+N), 294,1 (M+NH4).

Elemental analysis for C19H16S.

Calculated: 82,56%, N Of 5.84%, S 11,60%.

Found: 82,39%, N 5,77%, S 11,60%.

C. Obtain 2-[(4-methylsulphonyl)phenyl]-1-di temperature 0oC. 3-Chlormadinone acid (3,40 g, 15.9 mmol) was added to the reaction mixture and the mixture is stirred for 3 hours. The mixture is washed with sodium bicarbonate, sodium bisulfite, brine and dried. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 4:1 as the eluent and recrystallization (dichloro/methane) get the named compound (0.64 g, 28.6 per cent) in the form of a crystalline product, so pl. 135-137o;1H NMR (CDC13) : 7,79 (d, J=8,42 Hz, 2H), 7,47 (m, 3H), 7,42 (m, 1H), 7,34 (d, J=8.7 Hz, 2H), 7.23 percent (m, 3H), 7,11 (m, 2H), 3.04 from (s, 3H). Mass spectrum, m/z 309 (M+H), 326 (M+NH4); IR (KBR): 1312, 1154, 760 cm-1.

Elemental analysis for C19H16O2S.

Calculated: 74,00%, N 5,23%, S The 10.40%.

Found: 74,07%, N 5,17%, S 10,37%.

Example 109

1-cyclohexen-2-(4'-methylsulfinylphenyl) benzene

A. Obtaining 2-(4'-methylthiophenyl)-1-(1-hydroxy-1-cyclohexyl)benzene.

2-Bromo-(4'-methylthiophenyl) benzene (3,02 g to 10.8 mmol) dissolved in tetrahydrofuran (35 ml), cooled to a temperature of -78oWith and then slowly added n-utility (4,5 ml, 11.3 mmol). The obtained pale yellow mixture is stirred for 2 hours at a temperature of -78oWith, and then add temperature. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried, filtered and evaporated. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 6: 1 as eluent get the desired product (of 2.51 g, 77%) as a clear oil;1H NMR (CDC13) : 7,58 (d, 1H), was 7.36 (m, 2H), 7,27 (m, 4H),? 7.04 baby mortality (DD, 1H), 2,53 (s, 3H), 2,34 (t, 1H), 1,83-1,10 (m, 10H). Mass spectrum (high resolution EI/DEP): calculated M+298,139137; found M+298,138665.

C. Obtaining 1-cyclohexen-2-(4'-methylthiophenyl)benzene.

The compound obtained in Example 109, part a (2.17 g, 7,27 mmol), dissolved in toluene (30 ml) and added catalytic amount of p-toluenesulfonic acid (0.05 g). The mixture is refluxed. After 4 hours the mixture is cooled and washed with sodium bicarbonate, dried, filtered and evaporated. After purification of the residue by the method of column chromatography on silica gel using mixtures of hexane/ethyl acetate 4:1 as the eluent and recrystallization (methanol) get cycloalken (1.29 g, 65%) as white crystals, so pl. 71-73oC. After evaporation of the mother liquor get another 0.15 g of the desired product;1H NMR (CDC1319H2OS.

Calculated: 81,38%, N 7,19%, S 11,43%.

Found: 81,17%, H 7.16 Percent, S 11,53%.

C. Obtaining 1-cyclohexen-2-(4'-methylsulfinylphenyl)benzene.

The compound obtained in Example 109, part b (1.35 g, 4,80 mmol), suspended in methanol (125 ml), cooled to a temperature of 0oWith, and add OxonTM(8,30 g, 13,0 mmol) in water (50 ml). The resulting thick suspension is warmed to room temperature and then stirred for 18 hours. The reaction mixture was diluted with water (200 ml) and the precipitated white crystalline product is collected. The obtained product is washed with water, dilute sodium bisulfite and water, and dried in vacuum. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 4:1 as the eluent and recrystallization (methanol) get a named connection (0,524 g, 35%) as colourless crystals, so pl. 126-128oC. After evaporation of the mother liquor an additional 0,278 g of the desired product;1H NMR (CDC13) : of 7.95 (d, J=8,42 Hz, 2H), 7,63 (d, J=8,42 Hz, 2H), was 7.36-7,25 (m, 4H), 5,63 (m, 1H), 3,10 (s, 3H), of 2.06 (m, 2H), of 1.84 (m, 2H), 1,51-of 1.45 (m, 4H).

Elemental analysis for C19H20ABOUT2S.

Calculated: 73,04%, N 6,45%, S 10,26%. The. Obtain 3-nitro-4-phenylacetophenone.

A mixture of 4-bromo-3-nitroacetophenone (2.0 g, 8,19 mmol), phenylboronic acid (1.2 g, 9,83 mmol), and tetrabutylammonium bromide (of 0.13 g, 0.41 mmol) in 2M sodium carbonate solution (35 ml) in ethanol (20 ml) and toluene (65 ml), Tegaserod by ozonation with nitrogen for 30 minutes. The reaction mixture is refluxed for 4 hours. The mixture is then cooled and the resulting layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried, filtered and evaporated. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 4:1 as eluent get the desired product (1.98 g, 89%) as a yellow powder; 1H NMR (CDC13) : 8,39 (d, 1H), 8,16 (DD, 1H), EUR 7.57 (d, 1H), 7,43 (m, 3H), 7,32 (DD, 2H), 2,69 (s, 3H). Mass spectrum 242,1 (M+H).

C. Obtain 3-amino-4-phenylacetophenone.

A mixture of the product obtained in Example 130, part a (2.0 g, 8,29 mmol), tin chloride (8,23 g, 36,48 mmol), ethanol (30 ml) and conc. hydrochloric acid (7 ml), refluxed for 2.5 hours. The reaction mixture was cooled to 0oWith, then alkalinized (pH 10) 6M NaOH solution and extras the ez silica gel using chloroform as eluent. After evaporation of the solvent receive amine (1.20 g, 69%) as a yellow powder;1H NMR (CDC13) : 7,47 (d, 1H), 7,46 (s, 3H), 7,38 (DD, 2H), was 7.36 (d, 1H), 7,20 (m, 1H), 3,90 (s, 2H), 2,60 (s, 3H). Mass spectrum, m/z 212,1 (M+H).

C. Receiving 5-Aceto-2-phenylbenzothiazole of tetrafluoroborate.

The compound obtained in Example 130, part b (0.50 g, 2.36 mmol), dissolved in dichloromethane (3 ml) and slowly added to a solution of thriftimart apirat in dichloromethane (10 ml) at -15oC. and Then added to the solution containing soliditet (0.35 g, 2,60 mmol) in dichloromethane (3 ml), the ice bath is removed from the deposition of a brown precipitate. To the reaction solution was added pentane (20 ml) and the resulting mixture is again cooled to a temperature of -15oC for 20 minutes. After filtering are salt, page (0,76 g) as a light brown powder;1H NMR (D13) : of 9.55 (d, 1H), 8,71 (DD, 1H), of 7.90 (d, 1H), 7,69 (s, 5H), and 2.79 (s, 3H).

D. Receiving 5-Aceto-2-phenylbenzene triftoratsetata.

5-Aceto-2-phenylbenzothiazole tetrafluoroborate (1,46 g, 4,79 mmol) is slowly added to triftoratsetata (10 ml) at -15oC. the Mixture is heated to a temperature of 50oC for 20 minutes and then poured into the tub with ice (25 g). In the Sofia on silica gel using mixtures of hexane/ethyl acetate 4:1 as eluent get the required triplet (0,428 mg, 77%) as a brown syrup;lH NMR (CDC13) : of 8.04 (DD, 1H), of 7.96 (d, 1H), 7.62mm (d, 1H), of 7.48 (s, 5H), to 2.67 (s, 3H). Mass spectrum, m/z 345 (M+H).

E. Obtain 3-(4'-Methylthiophenyl)-4-phenylacetophenone.

A mixture consisting of the compound obtained in Example 130, part D (1.22 g, 3.54 mmol), 4-methyldiphenylamine acid (0.71 g, of 4.25 mmol), and trehosnovnoy potassium phosphate (1.13 g, 5,32 mmol) in 1,4-dioxane Tegaserod by ozonation with nitrogen for 15 minutes.

To the reaction solution was added tetrakis(triphenylphosphine)-palladium (0.10 g, 0,089 mmol) and the resulting mixture is refluxed for 18 hours. The mixture is cooled, filtered and evaporated. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 4: 1 as eluent get the desired product (1,02 g, 90%) as a brown syrup;1H NMR (CDC13) : to 7.99 (d, 2H), 7,53 (d, 1H), of 7.48 (s, 2H), 7,27 (d, s, 2H), 7,17 (DD, 2H), 7,14 (kV, 3H). Mass spectrum, m/z 319 (M+H).

F. Obtain 3-(4'-Methylsulfinylphenyl)-4-phenylphenol.

To the compound obtained in Example 130, part E (0,30 g, 0,942 mmol) is added adventurou acid (10 ml) and then concentrated sulfuric acid (0.25 ml). The reaction mixture is stirred at to the memory extracted with ethyl acetate and the organic layers dried, filtered and evaporated. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 2:1 as eluent get a named connection (0,064 g, 21%) as a white powder; 1H NMR (CDC13) : 7,79 (d, 2H), 7,35 (d, 1H), 7,34 (d, 2H), 7,21 (d, 1H), 7,19 (d, 2H), 7,06 (m, 2H), 6,97 (DD, 1H), 6.90 to (d, 1H), 4,96 (s, 1H), 3,05 (s, 3H). The mass spectrum of the high-resolution m/z calculated: 342,1, found: 342,116391 (M+NH4).

Example 151

1-[2-(4-methylsulfinylphenyl)phenyl]piperidine

A. Getting 2[(4-methylthio)phenyl)aniline.

A mixture consisting of 2-bromoaniline (2.0 g, are 11.62 mmol), 4-methyldiphenylamine acid (2.3 g, 13,69 mmol), tetrabutylammonium bromide (0,19 g of 0.58 mmol) and 2M sodium carbonate solution (12 ml) in 85 ml of a mixture of toluene/ethanol 2:1, Tegaserod by ozonation nitrogen through it for 10 minutes. To the reaction mixture was added tetrakis(triphenylphosphine) palladium (54 mg, 0,047 mmol) and the resulting mixture is refluxed for 5 hours. The reaction mixture is cooled, evaporated and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried (MgS4), filtered and evaporated. After purification the unpeeled product method from (m, 4H), 7.18 in-to 7.09 (m, 2H), 6,85 to 6.75 (m, 2H), 3,75 (Shir. m, 2H), 2,53 (s, 3H) h/million Mass spectrum (NH3-C1), m/z 215,9 (M+N+, 100%).

C. Obtain 1-[2-(4-methylthiophenyl)phenyl]piperidine.

To a mixture of the product obtained above, part a (0.3 g, of 1.39 mmol), ethanol (10 ml) and triethylamine (of 0.39 ml, 2.77 mmol), was added 1,5-dibromethane (0,29 ml of 2.08 mmol). The reaction mixture is refluxed for 48 hours, then evaporated and chromatographic (a mixture of hexanol) to give a pink oil (0,147 g, 37%). NMR (CDC13) : 7,73 (d, 2H), 7,39 (d, 2N) of 7.36-7,30 (m, 2H), 7,15-7,10 (m, 2H), 2,87-to 2.85 (m, 4H), 2,62 (s, 3H), 1.55V (C, 6N). Mass spectrum (NH3-Cl), m/z 284,2 (M+H+, 100%).

C. Obtain 1-[2-(4-methylsulfinylphenyl)phenyl]piperidine.

To the solution containing the compound obtained in Example 195, part C (0,145 g, 0,512 mmol), in methanol (15 ml), cooled to a temperature of 0oC, add OxonTM(0,79 g, 1.28 mmol). The reaction mixture was stirred at room temperature overnight. Then the reaction mixture is diluted with methylene chloride and extracted. The combined organic layers washed with sodium bicarbonate, sodium bisulfite, brine and dried (MgS4). The crude product chromatographic (mixture Huck is 140-140,5oS.1H NMR (CDC13) : 7,97-a 7.85 (DD, 4H), of 7.36 (t, 1H), 7.23 percent-7,20 (DD, 1H), 7,10-7,05 (m, 2H), 3,10 (s, 3H), of 2.75 (m, 4H), USD 1.43 (m, 6N). Mass spectrum high resolution: calculated for C18H21NS2: 316,137126; found: 316,136504.

Example 153

1-[2-(4'-methylsulfinylphenyl)phenyl]pyrrole

A. Obtain 1-(2-bromophenyl)pyrrole.

A mixture consisting of 2-bromoaniline (1,72 g, 10 mmol), 2,5-dimethoxytetrahydrofuran (1,32 g, 10 mmol) and glacial acetic acid (4.5 ml), refluxed under stirring for 2 hours in nitrogen atmosphere. The mixture is cooled to room temperature. The solvent is distilled off under reduced pressure and the residue purified flash chromatographia (mixture hexane/ethyl acetate 9:1) to yield the desired pyrrole (1.85 g, with 8.33 mmol, 83.3%) as a clear liquid. 1H NMR (D13) : 7,70 to 6.35 (m, 8H); IR (KBR) 3102, 1588 cm-1; Mass spectrum, m/z 221,9 (M+N)+.

C. Obtain 1-(2-(4-Methylthiophenyl)phenyl)pyrrole.

A mixture of 1-(2-bromophenyl)pyrrole (0,666 g, 3.0 mmol), 4-methyldiphenylamine acid (0,554 g, 1.1 equiv.) 2M aqueous sodium carbonate solution (6 ml) and toluene (30 ml), stirred at room temperature under nitrogen atmosphere. Nitrogen is bubbled through the reaction solution in techtimes boil with stirring under reflux for 4 hours. The resulting mixture was cooled to room temperature and then poured into 100 ml of water. The mixture is extracted with three 100 ml portions of ethyl acetate. The combined organic layers are dried on anhydrous magnesium sulfate, filtered and the solvent is distilled off under reduced pressure. The residue is purified flash chromatography (29:1 mixture of hexanol/ethyl acetate). Get the reaction product in the form of oil (0.74 g, and 2.79 mmol, 92,9%).1H NMR (CDC13) : 7,44-6,16 (m, N) to 2.46 (s, 3H); IR (pure): 2918, 1596 cm-1. Mass spectrum, m/z 266,0 (M+N)+.

C. Obtain 1-[2-(4-methylsulfinylphenyl)phenyl]pyrrole.

A mixture of 1-(2-(4-methylthiophenyl)phenyl)pyrrole (0.74 g, at 2,788 mmol), and methylene chloride (35 ml), stirred and cooled in a water bath with ice and salt in the atmosphere of nitrogen. Then to the reaction mixture was added in one portion 3-chlormadinone acid (50-60% solution, 1,924 g, >2 EQ.). The resulting reaction solution was brought to room temperature and stirred over night. The mixture is then poured into a saturated solution of sodium bisulfite and extracted with three portions of 50 ml each of methylene chloride. The combined organic layers are washed with saturated sodium bicarbonate solution, dried on anhydrous magnesium sulfate, filtered and races the ANOVA/ethyl acetate) get the named compound as off-white powder (16 g, 0,538 mmol, 19.2 percent).1H NMR (CDC13) : 7,88-x 6.15 (m, N) a 3.06 (s, 3H); IR (KBr): 2922, 1602 cm-1. Mass spectrum, m/z 298,0 (M+N)+.

Example 201

1 phenoxy-2-(4'-methylsulfinylphenyl)benzene

A. Obtaining 2-(4'-methylthiophenyl)phenol.

A mixture consisting of 2-bromophenol (3.0 g, 17,0 mmol), 4-methylthiopropionate acid (3.5 g, to 20.8 mmol), and tetrabutylammonium bromide (0.28 g, 0,867 mmol) in toluene (100 ml), ethanol (25 ml), and 2M sodium bicarbonate solution (50 ml), Tegaserod by bubbling with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.06 g, 0,052 mmol) was added to the reaction mixture and the mixture is refluxed for 2.5 hours. The reaction mixture is cooled to room temperature and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried, filtered and evaporated. After purification of the residue by chromatography on silica gel using a mixture of 4: 1 hexane/ethyl acetate as eluent get the reaction product (3.03 g, 81%) as a yellow powder;1H NMR (D13) : 7,42 (m, 4H), 7,25 (m, 2H), 7,01 (t, 4H), 5,13 (s, 1H), 2.57 m (s, 3H). Mass spectrum m/z 217 (M+H).

C. Obtaining 2-(4"-nitrophenoxy)-1-(4'-methylthiophenyl)benzene.

2-(4'-Methylthiophenyl)phenol (0.4 g, 1.9 d sodium (80% dispersion in oil, 0,063 g, 2.1 mmol) was added to the reaction mixture and the mixture is brought to room temperature, and then stirred for 18 hours. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers washed with brine, dried, filtered and evaporated. After purification of the residue by chromatography on silica gel using mixtures of hexane/ethyl acetate 6:1 as the eluent and recrystallization (dichloro/methane) get the named product (0,59, g, 96%) as yellow crystals, so pl. 70-72o;1H NMR (CDC13) : 8,11 (d, J=9.15, with Hz, 2H), 7,51 (DD, 1H), 7,41 and 7.36 (m, 4H), 7,20 (d, J=8,42 Hz, 2H), 7,14 (DD, 1H), to 6.88 (d, J=9.15, with Hz, 2H), 2,46 (s, 3H); IR (KBR): 1514, 1342 cm-1.

Elemental analysis for C19H15NO3S.

Calculated: 67,64%, N 4,48%, N 4,15%.

Found: From 7.60%, N 4,39%, N 4.09 To%.

C. Obtaining 2-phenoxy-1-(4'-methylthiophenyl)benzene.

A mixture consisting of the compound of Example 201, part b (0.18 g, of 0.53 mmol), iron powder (0.1 g, 1.8 mmol), glacial acetic acid (0.3 ml, 5 mmol) and ethanol (10 ml), refluxed for 4 hours. The reaction mixture is cooled, filtered and evaporated in vacuum. To the crude amine priba the reaction mixture is refluxed for 4 hours. After evaporation of the reaction mixture and chromatography on silica gel using a mixture of hexane/dichloromethane as eluent get the desired product (0,096 g, 61%) as a yellow oil;1H NMR (D13) : 7,49 (m, J=8,42 Hz, 2H), 7,45 (DD, 1H), 7,30-7,19 (m, 6N), 7,05 (m, 2H) 6,94 (d, J=8,42 Hz, 2H), 2,48 (s, 3H). Mass spectrum m/z 293 (M+H).

D. Obtaining 1 phenoxy-2-(4'-methylsulphonyl)phenylbenzene.

The product obtained in Example 201, part C (0,096 g, 0.35 mmol), dissolved in dichloromethane (5 ml) and cooled to a temperature of 0oC. To the resulting solution was added 3-chlormadinone acid (0.15 g, 0.73 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, washed successively with sodium bicarbonate, sodium bisulfite, brine and then dried, filtered and evaporated. The resulting residue is purified by chromatography on silica gel using mixtures of hexane/ethyl acetate 4:1 as the eluent and recrystallization (dichloromethane/hexane) get a named connection (0,063 g, 56%), so pl. 130-131oC. After evaporation of the mother liquor an additional 0.02 g of the desired product; 1H NMR (CDC13) : 7,94 (d, J= 8,79 Hz, 2H), to 7.77 (d,entry analysis for C19H16O3S.

Calculated: 70,35%, N Equal To 4.97%, S 9,88%.

Found: 70,28%, N 4,89%, S Of 9.99%.

When using the above methods or their modifications which are obvious to experts in the field of chemical synthesis, it is also possible to obtain the compounds shown below in Tables 1-3.

Industrial applicability

The compounds of formula I are inhibitors prostaglandins, and therefore, can find application in the treatment of inflammatory diseases, as well as antipyretics. Inhibitory activity of compounds of the invention relative to the prostaglandin G/H synthase demonstrated in the tests described below were conducted to determine the activity of inhibitors of prostaglandin G/H synthase. Preferred compounds of the present invention provide selective inhibition activity S2and production of PGE2in human monocytes, as demonstrated by the results of the test cell described below.

The compounds of formula I have the ability to suppress pyrexia in vivo, for example, as demonstrated in experimental animal described below. Compounds of this image is x animal models with induced acute and chronic inflammation, described below. Compounds of the present invention also have the ability to suppress or inhibit pain syndrome in vivo, as demonstrated by the results obtained on the model of analgesia in an animal, the method described below.

Used in this description, the terms "μg" means microgram, "mg" (milligrams, "g" is gram; "μl" means microliter, "ml" means milliliter, "l" means liter, "nm" refers to nanomoles, "μmol" means micromoles, "mmol" means millimoles, "m" represents the moles, and "nm" means nanometer. Sigma mean Sigma-Aldrich Corp. of St. Louis, MO.

Any connection is active in the test for inhibition of prostaglandin G/H synthase, as described below, if it inhibits prostaglandin G/H synthase under IC50<300 Microm. Selective inhibitors S2demonstrate the attitude IR50: S-1/IR50:S-2, which is >1.

Test for Inhibition of Prostaglandin G/H Synthase

The activity of prostaglandin G/H synthase (cyclooxygenase, S, Mor) was determined by spectrophotometry according to the method described Kulmacz and others (used in this description as a reference material). In this test, use TMPD (4,4,4', the band, observed at 610 nm. The sample was calibrated by format 96-well tiralongo microplate according to the method? described below. Compound is incubated with the enzyme source, S-1 or S-2, 125 μl of buffer (40 μmol of Tris-maleate, 0.8% tween-20, 1.2 µm heme, 0.4 mg/ml gelatin, pH 6.5) for two minutes at room temperature with initiation during this period of time the enzymatic reaction by adding 125 ál of arachidonic acid buffer (0.1 M Tris/HCl, 0.2% tween-20, pH 8.5) to obtain a final concentration arachidonate 100 μm. Agglutinins tablet immediately placed in microtitration recorder and the data read at 610 nm for 1.5 minutes every 3 seconds. Values of the reaction rate was calculated by the curvature of the curve of the linear plot of the absorption bands depending on time. The speed of response of the control samples, which were not added enzyme inhibitors are used to calculate % inhibition of the enzymatic activity of each of the tested compounds. The results are presented as an indicator IR50that is the concentration of the introduced compound that causes 50% inhibition of the reaction rate Control.

Comparative analysis SUB> received two isoforms of the enzyme. The ratio IR50S-1/IR50S-2 is expressed as the degree of affinity to a specific enzyme. Connection with a higher specific affinity characterize compounds with a stronger effect of inhibiting isoforms S-2 enzyme.

In table a, below, presents data on the activity of the tested compounds of the present invention obtained in the above test on the inhibition of prostaglandin G/H synthase. In the specified Table indicators IR50marked as +++=IR50<10 μm, ++=IR5010-50 μm, and +=IR5050-300 μm (μm=micromolar concentration).

Cellular Test

Monocytes in human peripheral blood was obtained from blood samples taken from healthy donors by the method of leukocytapheresis and selection by otmuchivanie. Monocytes suspended in RPMI medium at a concentration of 2106cells/ml and the cell suspension was made in 96-well titration the microplate at a concentration of 200 μl/well. For cell culture were added to solutions containing the subjects of compounds in dimethyl sulfoxide DMSO at the appropriate concentration so as to obtain a final concentration of them in ccasa at a temperature of 37oAnd with the stimulation of the cells by adding 1 µg/ml LPS-environment (liposaccharide, Salmonella typehrium, 5 mg/ml in 0.1% aqueous solution of tetraethylammonium (TEA) for induction of enzyme activity S-2 and prostaglandin synthesis. Cells were incubated for 17.5 hours at a temperature of 37oC in an atmosphere of 95% O2and 5% CO2. Cultural adosados was separated and used to determine the level of production of prostaglandin E2(PGE2) by ELISA analysis (PerSeptive Diagnostics). The ability of the tested compounds causing 50% inhibition of the synthesis of PGE2comparable to cultures treated with DMSO only, is expressed as IR50, and is a criterion for evaluating the capacity effect with respect to inhibitory S-2.

In the Table, below, presents data on the activity of the tested compounds of the present invention obtained in the above described test cell. In the specified Table indicators IR50marked as +++=IR50<10 nmol, ++= IR5010-50 nmol and +=IR5051-100 nmol (nmol=nanomolar concentration).

Antipirena test in rats

Antipyretic activity of the tested compounds was evaluated by met ittelson compartment for 7 hours, during which rats clean food and injected them subcutaneously) 20% solution of yeast by Schiff (physiological solution), causing a feverish state. A control group receiving only saline solution contained also in a similar situation. On day 2 through 19 hours after provocation in rats measured temperature, and then administered orally, subcutaneously, intraperitoneally or intravenously appropriate doses of the tested compounds or media. After the introduction temperature is removed within six hours after every hour. The degree of pyrexia determined by the change in average values of rectal temperature in the control group and animals with yeast provocation. Antipirena activity is expressed as the degree of reduction in the average rectal temperature under the action of the tested compounds in those animals that were administered the compound relative to animals receiving only the media. ED50calculated as the dose of compound required to reduce pyrexia 50%.

Compounds of the present invention were tested in the above enterogenous test on rats and had ED5030 mg/kg

Karragenana sample, inducing swelling of the paws in rats

Protivovospalitel)), which can be briefly summarized as follows. Rats-males Lewis injected 0.1 ml of 1% solution of carrageenan (in saline) into the plantar surface of the hind paws. Rats of the control group injected only with saline. After three hours, the degree of swelling of the legs assess the inflammatory response. An hour before the injection of provocative tests in the ball of the feet of animals administered orally, subcutaneously, intraperitoneally or intravenously compound or the media. The reduction in rear paw swelling under the influence of the tested compounds compared to the control group with the media is a criterion for assessing anti-inflammatory activity. ED30calculated as the dose of active compound required to reduce swelling of the feet by 30%.

Adjuvant test, inducing arthritis in rats

Anti-inflammatory activity of the tested compounds was determined by the method of Pearson, C. M. (Proc. Soc. Exp. Biol. Med., vol. 91, pages 95-101 (1956)), which can be briefly summarized as follows. Rats-males Lewis was injected into the ball of the rear foot injection complete adjuvant's adjuvant (0.1 ml 5 mg/ml of light mineral oil) or only one mineral oil (0.1 ml). On the 18th day the animals sing, which was introduced only injection of mineral oil, appreciate the inflammatory response. From day 0 to day 18 animals administered orally, subcutaneously, intraperitoneally or intravenously compound or the media. The reduction in joint swelling under the influence of the tested compounds compared to the control group with the media is a criterion for assessing anti-inflammatory activity. ED50calculated as the dose of compound required to reduce the degree of joint swelling by 50%.

Provocative test in rats by Randall Selitto

Analgesic activity of the tested compounds was assessed in test with yeast provocation in the rat paw, modified in accordance with the method of Randall, L. O. And Selitto, J. J. (Arch. Int. Pharmacodyn. Ther. vol. 3, pp. 409-419 (1957) when using analgesiometer Ugo Basile (Stoelting). Fixed rats-males on both hind paws were selected for their response to induced yeast pain (squeak or signs of resistance), which are crawled less than 15 cm on the surface of analgesiometer. In the right back paw then induced inflammatory response by injection into the plantar surface (0.1 ml) of 20% aqueous suspension of active dry yeast Fleischmann.Les injection of yeast suspension. The threshold of pain sensitivity determined after 0.5, 1, 2 and 4 hours. ED30calculated as the dose of compound required to increase the pain threshold by 30% compared to Control.

Composition and dosage forms

Compounds of the present invention can be given orally when using any pharmaceutically acceptable dosage form known in the art. The active ingredient can be introduced into the body in a solid dosage form, for example in the form of powders, granules, tablets or capsules, or in liquid form, for example in the form of syrups or aqueous suspensions. The active ingredient can be administered in pure form, but it is usually injected in a mixture with a pharmaceutically acceptable carrier. Valuable information regarding release forms of drugs can be found in the Handbook Remington's, Pharmaceutical Sciences, Mack Publishing.

Compounds of the present invention can be administered in dosage forms for internal use, such as tablets, capsules (each of which contains a composition with a slow or fast release of the active ingredient), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Similarly, we offer drybrushing, subcutaneous or intramuscular injection, and each of these dosage forms is well known in the field of pharmacy. An effective but non-toxic amount of compound can be used as anti-inflammatory drugs, or ingesting.

Compounds of the invention can be introduced into the body of a mammal by any method that provides the interface of the active substance from the site of its impact, i.e. S-2. The proposed compounds can enter the body by any traditional bioavailable ways in combination with the pharmaceutical compositions in the form of individual drugs, and in combination with other drugs. They can be taken in its pure form, but usually in a mixture with a pharmaceutically acceptable carrier selected on the basis of selected regimens and standard pharmaceutical technology.

Regimen compounds of the present invention, of course, varies depending on known factors such as the pharmacodynamic characteristics of the particular medicinal substance, and the method and route of administration; type, age, gender, and severity of the disease, and weight bgrav treatment; regimens, renal function and liver of the patient and the desired effect. Usually a qualified physician or veterinarian can readily determine and prescribe the effective dose of the drug required to prevent warnings, normalization or block the development of the disease.

As General guidance, the daily dose for oral administration of each active substance, if it is used to achieve the above effects, varies from about 0.001 to 1000 mg/kg body weight, preferably approximately from 0.01 to 100 mg/kg of body weight per day, and most preferably from about 1.0 to 20 mg/kg/day. For a normal adult male weighing about 70 kg, this corresponds to a dose of from 70 to 1400 mg/day. When administered intravenously, the most preferred dose of approximately 1 to approximately 10 mg/kg/min constant rate infusion.

In a preferred embodiment, compounds of the present invention can be administered in a single daily dose or the total daily dose can be divided into two, three, or four servings per day.

Compounds of the invention can be administered in intranasal dosage form using appropriate entrana the skin in the form of a patch, which well-known experts in this field. When the transdermal delivery system for the receipt of medical substances, of course, occurs according to the scheme of continuous and not fractional introduction.

In the methods of the present invention, compounds disclosed in detail herein, can form the active principle, and are typically administered in a mixture with pharmaceutically acceptable diluents, excipients, or carriers (denoted herein by the generic term substance-media), selected appropriately depending on the dosage form, intended for reception, i.e. tablets, capsules, elixirs, syrups and the like for oral administration and are compatible with traditional pharmaceutical activities.

For example, for oral administration in the form of tablets or capsules, the active ingredient of medicines can be used in a mixture with non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form ingredients of medicinal drugs is LEM, for example, ethanol, glycerol, water and the like. In addition, if desired or if necessary, suitable binders, sizing, disintegrator and dyes can also enter into the mix. As a binder can be used, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums such as acacia gum, tragacanth gum or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. As oiling agents that are suitable for use in these dosage forms can be, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. As disintegrators can be used, for example, but without limiting their scope, starch, methylcellulose, agar, bentonite, xantanovu resin and the like.

Compounds of the present invention can also be introduced in the form of delivery systems using synthetic liposomes, for example small liposomal, large single-layer liposomal vesicles and multi-liposomal vesicles. Liposomes can be obtained from a wide diversity is part II of the invention can also be used in the form of a conjugate with soluble polymers as carriers of drug to the targeted object. As such polymers can be used, for example, polyvinylpyrrolidone, a copolymer on the basis of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted palmitoleate groups. In addition, the compounds of the present invention can be used in related biomassebaserede polymers form for controlled release of medicinal substance, such as polixena acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polishlanguage, polyhydroxyalkane acid, complex poliorcetes, Polyacetals, policyidreference, polycyanoacrylate, and sewn or amphoteric block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 to 100 mg of the active ingredient on the standard unit. In these pharmaceutical compositions the active ingredient is usually about 0.5 to 95 wt.% from all pharmaceutical composition.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets and powders, and siderale in the form of sterile solutions. Gelatin capsules can contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar fillers can be used to obtain CT. As tablets and capsules can be obtained in the form of a product with a prolonged release of the active substance to provide a continuous therapeutic effect of the drug over an extended period of time. Molded tablets can be made in the form of sugary coating, or they may contain film coated to mask any unpleasant taste and protect the tablet from exposure to the environment or to contain intersolubility floor for election raspadaemosti of the drug in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring additives to improve the perception of the patient to the drug. As carriers for the preparation of solutions for parenteral administration can usually use water, suitable oil, saline, aqueous dextrose (glucose) and solutions related compounds class ora preferably contain the active substance in the form of soluble salts, suitable stabilizers and, if necessary, buffer substances. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, are suitable for use as stabilizers, individually, and in combination with each other. You can also use citric acid and sodium salt of EDTA. In addition, solutions for parenteral administration may contain preservatives, such as benzalkonium chloride, methyl - or propyl-paraben, and chlorobutanol. Information pharmaceutically suitable carriers can be found in Remington's Pharmaceutical Sciences, firms Mack Publishing Company, a standard bibliographic reference in this field.

Suitable for use dosage forms for administration of the compounds of the present invention can be illustrated by the following examples,

Capsules

Capsules get traditional methods so that the standard tablet contains 500 mg of active ingredient, 100 mg of cellulose and 10 mg of magnesium stearate.

A large number of standardized capsules can also be obtained by completing divided into two parts capsules of hard gelatin with a standard dose, each of which contains 100 mg of powdered and Content, wt.%:

Active ingredient - 10

Sugar syrup - 50

Sorbitol - 20

Glycerin - 5

The fragrance, dye and preservative - If necessary

Water - If necessary

The final volume is brought to 100% by adding distilled water.

Water suspension

Components - Content, wt.%:

Active ingredient - 10

Saccharin sodium - 0,01

Keltron(food grade xanthan gum) - 0,2

Sugar syrup - 5

The fragrance, dye and preservative - If necessary

Water - If necessary

Xanthan gum is slowly added to the distilled water before the introduction of the active ingredient and other ingredients of the composition. The resulting suspension is passed through a homogenizer to give the aesthetics of the final product.

Resuspending powder

Components - Content, wt.%:

Active ingredient - 50,0

Lactose - 35,0

Sugar - 10,0

Acacia - 4,7

Sodium carboxymethyl cellulose - 0,3

Each ingredient is finely pulverized, and then mixed to obtain a homogeneous mixture. Alternatively, the powder can be obtained in the form of a suspension, which is then dried by the method
Saccharin sodium - 0.02

Gelatin - 2

The fragrance, dye and preservative - If necessary

Water - If necessary

Gelatin is dissolved in hot water. Finely ground active ingredient is suspended in a gelatin solution, and then add the remaining ingredients of the composition. The obtained suspension fill in suitable packaging container with the preparation of a gel after cooling.

Semi-solid paste

Components - Content, wt. %:

Active ingredient - 10

Gelcarin(karragenana gum) - 1

Saccharin sodium - 0,01

Gelatin - 2

The fragrance, dye and preservative - If necessary

Water - If necessary

Gelcarinthrow in hot water (temperature about 80oC) and then finely ground active ingredient is suspended in the resulting solution. To a suspension add saccharin sodium and other ingredients of the composition while it is still warm. The suspension is homogenized and the homogenate obtained by fill in appropriate containers.

Emulsifiable paste

Components - Content, wt.%:

Active ingredient - 30

Tween 80 and Span 80 - 6

Keltron(food santanoni pasta.

Soft gelatin capsules

The active ingredient is mixed with vegetable oil, such as soybean, cottonseed or olive and pumps volumetric pump into gelatin to obtain soft gelatin capsules containing 100 mg of active ingredient. The capsules are washed and dried.

Tablets

Tablets can be obtained by traditional methods so that the standard tablet contains 500 mg of the active ingredient, 150 mg of lactose, 50 mg of cellulose and 10 mg of magnesium stearate.

A large number of tablets can also be obtained in accordance with conventional techniques, so that a unified tablet contains 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98,8 mg of lactose. To improve the bioavailability and slow absorbability you can use the appropriate coverage.

The composition for parenteral administration

A parenteral composition suitable for administration in the form of injections, is produced by stirring 1.5% by weight the active ingredient in 10% vol. propilenglikola with water. Adding sodium chloride receive isotonic solution, which is then sterilized.

Suspenzionnogo active ingredient, 200 mg of sodium salt of carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (USP) U. S. P. and 0.025 ml of vanillin.

Compounds of the present invention can be administered in combination with a second drug. The compound of formula I and the additional therapeutic agent can be taken separately and in mixtures containing a single dose, in any dosage form and different routes of administration as described above.

The compound of the formula I can be used in the formulation together with the second drug standard odnokratnoe dose (i.e. in the form of a mixture in one capsule, tablet, powder, or liquid media, and the like). If the compound of formula I and the second drug used separately, the compound of formula I and the specified second tool can be taken simultaneously or in parallel in any order; for example, you can take a first compound of the formula I, and then the second drug. Non-simultaneous reception it is preferable that the interval between the reception of the compounds of formula I and the second drug was less than about 1 hour, more preferably less than about from the flax introduction the compounds of formula I and a second drug in the same way (i.e., for example, orally), if desired, each of them can be taken in different ways and in different dosage forms (i.e. one component can be given orally, and another component to be administered intravenously). The dose of a compound of formula I as a separate reception and in combination with a second drug may vary depending on various factors such as the pharmacodynamic characteristics of the particular drug substance and method, and regimens, age, condition and weight of the patient, the nature and symptoms of the disease, treatment of concomitant disease; the frequency of repeated courses of treatment and the desired effect, as mentioned earlier. In particular with the introduction of a single dosage form there is the possibility of chemical interaction between the combination of the current basis. For this reason, while the introduction of the compounds of formula I and II medications, they are formulated such that although these existing start combined for receiving a uniform dose, physical contact between the active substances should be minimal. For example, one active substance may contain eneration allows not only to minimize the contact between the combination of active substances, but also provides modified release of one of such components in the gastrointestinal tract, which results in the release of one active substance in the stomach and another in the small intestine. One of the active components may also be coated with a material which provides a slow release of the beginning of the current, thus leading to a uniform distribution throughout the gastrointestinal tract, as well as to minimize physical contact between the combination of active substances. Additionally, the delayed release may further comprise intersolubility coating that ensures its release only in the small intestine. In yet another variant, the composition of the combined drug, in which one component is coated with a polymer material, providing a prolonged release and/or release into the small intestine, and another component may also contain a polymer coating, for example, from low viscosity of hydroxypropylmethylcellulose (receiver array) or other suitable materials known in the art for separation of active ingredients. Polymer coating enables the SS is s to provide minimum contact between the components of the combined drug of the present invention, regardless of entered whether they are in the same dosage form or forms that are entered separately, but in parallel the same way, it will become obvious to experts in the art upon familiarization with the present description of the invention.

In the scope of the present invention also includes pharmaceutical kits, for example, used in the treatment or prevention of inflammatory diseases, which include one or more containers with pharmaceutical composition containing a therapeutically effective amount of compounds of formula I. In such a kit may also include, if desired, one or more components of various conventional pharmaceutical kits, for example the container with one or more pharmaceutically acceptable carriers, additional containers, and the like, which are easily understandable for specialists in this field of technology. The kit can also include instructions, such as liners, or as marking labels, where are the quantitative characteristics of the input components, as well as guidance on the scheme is the introduction and combination of components.

You must understand that in the present description of the disclosed materials and conditions play an important znany be excluded from the scope as long while they do not prevent the receipt of a positive effect in the implementation of the present invention.

The term "comprising", when used in the present description, has its traditional meaning; that is, all specified materials and conditions are very important in the practical implementation of the present invention, however, the materials and conditions that are not described, should not be excluded from the scope until they do not prevent the receipt of a positive effect in the implementation of the present invention.

In the proposed description of the invention provide all the necessary information to the specialist in the art could implement in practice the claimed invention. As opposed to materials can provide additional useful information, it should be understood that these materials are included in the description by reference.

Although the present invention is described above with specific examples of its implementation, it is necessary to understand that the invention is not limited to the described variants of its implementation or some of their parts and that various modifications, not beyond being and the quantity supplied is controlled salt,

where J is CH or N;

K and L represent CH;

X represents a direct link, -Z(CHR5)p;

Z represents O;

R1represents phenyl or 2-naphthyl, substituted by 0-2 substituents R7WITH5-C7cycloalkyl or5-C7cycloalkenyl, provided that when R1directly related to the heteroatom, the heteroatom is not associated with the carbon atom containing the double bond in cycloalkene ring, or a 5-10 membered heterocyclic system selected from pyrrolyl, benzothiazyl, 3-pyridyl, optionally substituted C1-C4the alkyl, chinoline or piperidinyl;

R2is

< / BR>
< / BR>
Y represents methyl;

R3represents H, F, Br, CL, HE, NR2, NR15R16C(= O)R6;

R4represents hydrogen, or alternatively, when R3and R4are substituents at adjacent carbon atoms, R3and R4taken together with the carbon atoms to which they are attached, form a 5-7 membered carbocyclic system;

R5represents hydrogen;

R6represents C1-C6alkyl;

R7is Vice carbon atoms, UB> C1-C4alkoxy, Cho, NR15R16;

R8represents hydrogen;

R15represents hydrogen or C1-C4alkyl;

R16represents hydrogen or C1-C4alkyl;

p = 0 or 1.

2. Connection on p. 1 of formula Ia

< / BR>
in which R1X represents phenyl, 4-forfinal, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-acid, 4-hydroxymethylene, 4-methoxymethyl, 4-dimethylaminophenyl, 4-formylphenyl, 2-naphthyl, 5-methoxy-2-naphthyl, 2-chinoline, 3-chinoline, 2-benzothiazyl, 5-benzothiazyl, 3-pyridyl, optionally substituted C1-C4the alkyl, phenylacetylene, phenoxy, cyclohexenyl, cyclohexyl, 4-fervency, cyclohexyloxy, benzyloxy, 1-pyrrolyl or 1-piperidinyl;

R3represents H, 5-chloro, 4-hydroxy-, 4-nitro-, 5-nitro - or 4-Aceto-;

or their pharmaceutically acceptable salts.

3. Connection on p. 2 or their pharmaceutically acceptable salts, in which R1X is phenyl, and R3represents H, 4-hydroxy-, 4-nitro-, 5-nitroso 4 Aceto-; or R1X represents 4-forfinal, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-acid, 4-hydroxymethylene, 4-methoxymethyl, 4-dimethylaminophenyl, 4-formylphenyl, 2-NAFI the stands, phenylacetylene, phenoxy, cyclohexenyl, cyclohexyl, 4-fervency, cyclohexyloxy, benzyloxy, 1-pyrrolyl or 1-piperidinyl, and R3represents H or 5-chloro.

4. Connection on p. 1, which are 2-(4-methylsulfinylphenyl)-3-vinylnaphthalene, 3-(4-methylsulfinylphenyl)-2-vinylpyridine, and 2-(4-aminosulphonylphenyl)-1-diphenyl.

5. Pharmaceutical composition for inhibiting prostaglandin H synthase, including anti-inflammatory amount of a compound under item 1 and a pharmaceutically acceptable carrier.

6. Pharmaceutical composition for inhibiting prostaglandin H synthase, including anti-inflammatory amount of a compound according to p. 2 and a pharmaceutically acceptable carrier.

7. Pharmaceutical composition for inhibiting prostaglandin H synthase, including anti-inflammatory amount of a compound according to p. 3 and a pharmaceutically acceptable carrier.

8. Pharmaceutical composition for inhibiting prostaglandin H synthase, including anti-inflammatory amount of a compound according to p. 4, and a pharmaceutically acceptable carrier.

9. Method of inhibiting prostaglandin H synthase in a mammal, characterized in that it includes a

 

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The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= -H3or their salts, which can be used as anticancer agents

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

The invention relates to previously unknown compounds, useful in medical and veterinary practice, to their pharmaceutically acceptable salts and biopremier derivatives, to methods for obtaining data of new compounds, to pharmaceutical compositions containing these new compounds, to a single dosage forms of these compositions and to methods of treating patients using these compositions and dosage forms

The invention relates to unknown compounds useful in the treatment of humans and animals, their pharmaceutically acceptable salts, to their bioapatite derivatives, methods of producing these new compounds, pharmaceutical compositions containing the new compounds, to dosage units of the compositions and to methods of treating patients using these compositions and unit dosages

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

The invention relates to 4-mercapto-benzoylpyridine formula (I), where R1denotes A; R2means And, unsubstituted or substituted by F, Cl, Br, phenyl, pyridyl; And - alkyl with 1-6 C-atoms, and their physiologically acceptable salts, methods for their production and pharmaceutical compositions based on them

The invention relates to some 2,6-disubstituted pyridinium and 2,4-disubstituted the pyrimidines, the way they are received, to herbicide compositions on their basis and to a method of combating the growth of unwanted vegetation

The invention relates to derivatives of pyridine-2-or pyridine-2-thione F.-ly (I), where Y Is O, S or NH; R1-C20-alkyl, oxygen or sulfur, provided that R is different from chlorbenzyl, which has an antimicrobial activity

The invention relates to new derivatives of 4-hydroxypiperidine General formula (I), where X denotes-O-, -NH-, -CH2-, -CH= , -CO2-, -SOP(lower alkyl) -, or-CONH-, R1- R4independently from each other, is hydrogen, hydroxy, nitro-group, a lower alkylsulfonyl, 1 - or 2-imidazolyl, 1-(1,2,4-triazolyl), R5and R6independently from each other, is hydrogen, lower alkyl, hydroxy - or oxoprop, R7- R10independently from each other, is hydrogen, lower alkyl, halogen, trifluoromethyl or lower alkoxygroup, n = 0 or 1, or their pharmaceutically acceptable acid additive salts

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 3-intellipedia formula I, where R1, R2, R3and R4denote H, A, OH, OA, F, Cl, Br, J, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA, or R1and R2and R3and R4together denote methylenedioxy, R5Is H or OH, R6- H or R5and R6together denote a bond, And represents C1- C6-alkyl, n denotes a number from 2 to 6, and their physiologically acceptable salts
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