Derivatives of 5-areolation

 

(57) Abstract:

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -NR9R10, -NR9R10or SO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, garboil-C1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and the method of its production. The compounds I are inhibitory enzymatic activity of prostaglandin G/H synthase I and II (YEAR I and YEAR II) and have anti-inflammatory and analgesic activity. Can be used for the manufacture of a drug with anti-inflammatory action. 3 S. and 17 C.p. f-crystals, 8 PL.

The invention relates to compounds having anti-inflammatory and analgesic properties, primarily to certain derivative 5-areolation, containing these compounds, pharmaceutical compositions, methods of use and methods of producing these soedinenieto anti-inflammatory, antipyretic and analgesic agents.

In the patent US 3755455 (in the name of Sandoz) describes (1-alkoxy-2-naphthyl) substituted or unsubstituted, phenylketone for use as anti-inflammatory agents.

The first object of the present invention are compounds that are selected from the group of compounds of formula (I):

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in which a represents a chemical bond, -CH2-, -CH(OH)-, -C=NOR4-, -C(O)-, -NR5-, -O - or-S(O)n- where

n means an integer of 0-2,

R4means hydrogen or alkyl, and

R5means hydrogen, alkyl or acyl,

Z means a group of formula (B), (C), (D) or (E):

< / BR>
< / BR>
where n1means an integer of 0-3,

X is O or S,

R6and R7independently from each other selected from the group comprising hydrogen, alkyl, halogenated, cycloalkyl, cycloalkenyl, acyl, alkylthio, cycloalkyl, cycloalkylation, alkoxy, cycloalkane, cycloalkylation, halogenations, alkenyl, halogen, cyano, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen, alkyl or acyl, or

R6and R7when they are in adjacent to each other positions in the ring, obrazovalasi, halogenations, alkylthio, cycloalkyl, nitro, cyano, hydroxy or halogen,

R1means hydrogen, alkyl, alkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, alkoxy, alkenylacyl, cycloalkane, cycloalkylation, halogenations, hydroxyalkyloxy, alkoxyalkanols, alkylthio, cycloalkyl, cycloalkylation, hydroxy, halogen, cyano, carboxy, alkoxycarbonyl, acyl, -C= NOR4, -NR9R10, -CONR9R10, -OCONR9R10or-OSO2R11where R4, R9and R10have the meanings indicated above, and R11means alkyl, cycloalkyl or halogenated,

R2means hydrogen, alkyl, alkoxy, halogen, nitro, or-NR9R10and

R3means-SO2R12or-SO2NR13R14where

R12means alkyl, hydroxyalkyl, alkoxyalkyl, carboxyethyl or alkoxycarbonylmethyl,

R13means hydrogen, alkyl or acyl, and

R14means hydrogen, alkyl, halogenated, cycloalkyl, cycloalkenyl, alkenyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, amino, aminoalkyl, aryl, aralkyl, heteroalkyl, heterocyclyl, heteroseksualci, acyl, hydroxy or alkoxy, or

R13 the x pharmaceutically acceptable salt, prodrugs, individual isomers and mixture of isomers.

Another object of the present invention relates to pharmaceutical compositions comprising pharmaceutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable non-toxic excipient.

A third object of the present invention relates to a method for treatment of diseases, especially inflammatory and autoimmune, in mammals, which can be cured by the introduction of an inhibitor of prostaglandin G/H synthase, which consists in the introduction of therapeutically effective amounts of compounds of formula (I) or its pharmaceutically acceptable salt.

The fourth object of the present invention relates to methods of preparing compounds of formula (I).

Definition

Unless otherwise stated, the terms and definitions used in the text of the description and in the claims, shall have the meanings indicated below.

"Alkyl" means a linear saturated monovalent hydrocarbon radical containing from 1 to 6 carbon atoms, or branched saturated monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, for example methyl, the first radical, containing from 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, this radical has at least one double bond, for example ethynyl, 2-propenyl etc.

"Quinil" means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, this radical has at least one triple bond, such as ethinyl, PROPYNYL, butynyl etc.

"Alkylene" means a linear saturated divalent hydrocarbon radical containing from 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical containing from 3 to 6 carbon atoms, for example methylene, ethylene, propylene, 2-methylpropene, pentile etc.

"Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclohexyl, etc.

"Halogen" means fluorine, chlorine, bromine and iodine.

"Halogenated" means alkyl substituted by one or more halogen atoms, preferably 1 to 3 atoms Gal who SUB>Cl-CF2, -CH2CF2, -CF2CF3, -CH2CCl3and other

"Alkoxy", "alkenylacyl", "cycloalkane" or "halogenations" means a radical-OR where R is alkyl, alkenyl, cycloalkyl or halogenated respectively, as defined above, such as methoxy, ethoxy, propoxy, 2-propoxy, adenylate, cyclopropylamine, cyclobutylamine, -OCH2Cl-F3and other

"Alkylthio" or "cycloalkyl" means a radical-SR where R is alkyl or cycloalkyl, as defined above, for example methylthio, butylthio, cyclopropylethyl etc.

"Acyl" means a radical-C(O)R, in which R means hydrogen, alkyl or halogenated, as defined above, for example formyl, acetyl, TRIFLUOROACETYL, butanol etc.

"Monosubstituted amine" means a radical other, in which R is alkyl or acyl, such as methylamino, (1-methylethyl)amino, etc.

"Disubstituted amine" means a radical-NHRR', in which R and R' independently of one another denote alkyl or acyl, for example dimethylamino, methylethylamine, di(1-methylethyl)amino, etc.

"Hydroxyalkyl" means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or razwell is as substituted by one or two hydroxy groups, moreover, if there are two hydroxy-group, they are not bound to the same carbon atom. Typical examples of this group include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1 - (hydroxymethyl) -2-hydroxyethyl.

"Alkoxyalkyl" means a linear monovalent hydrocarbon radical containing from 1 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, and such radical substituted by at least one alkoxygroup as defined above, for example 2-methoxyethyl, 2-methoxypropyl etc.

"Hydroxyalkyloxy" or "alkoxyalkyl" means a radical-OR where R means hydroxyalkyl or alkoxyalkyl, as defined above, for example 2-hydroxyethyloxy, 2-methoxyethoxy etc.

"Aminoalkyl" means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or rasweiler at least one group-NHRR', in which R and R' independently from each other selected from the group comprising hydrogen, alkyl and acyl, for example 2-amino-ethyl, 2-N,N-diethylaminopropyl, 2-N-acetylamino etc.

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical containing from 6 to 12 carbon atoms in the ring and optionally substituted independently from each other by one or more substituents, preferably one or two substituents, selected from the group comprising alkyl, halogenated, cycloalkyl, alkoxy, alkylthio, halogen, nitro, acyl, cyano, amino, mono - and disubstituted amino, hydroxy, carboxy and alkoxycarbonyl. More specifically the term aryl includes (but is not limited to, phenyl, biphenyl, 1-naphthyl, 2-naphthyl and derivatives thereof.

"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical containing from 5 to 10 atoms in the ring, from which one or more atoms, preferably one or two atoms, selected from N, O and S and the remaining atoms are carbon atoms. Heteroaryl ring optionally substituted independently from each other by one or more substituents, preferably one or two substituents, katiana, amino, mono - and disubstituted amino, hydroxy, carboxy and alkoxycarbonyl. More specifically the term aryl includes (but is not limited to, pyridyl, pyrrolyl, thienyl, furanyl, indolyl, chinoline, benzopyranyl and their derivatives.

"Heterocyclimamines" means a saturated monovalent cyclic group containing 5 to 8 atoms in the ring, of which at least one atom is N and optionally containing a second ring heteroatom chosen from N, O and S(O)n(where n denotes an integer from 0 to 2), and the remaining atoms in the ring are carbon atoms (for example, morpholino, thiomorpholine, piperidine, piperazine derivatives, pyrrolidine and others). Heterocyclimamines optionally may be condensed with benzene ring or optionally substituted independently from each other by one or more substituents, preferably one or two, which is selected from the group comprising alkyl, halogenated, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroalkyl, halogen, cyano, acyl, amino, mono - and disubstituted amino, carboxy and alkoxycarbonyl. More specifically the term aryl includes (but not limited to) pyrrolidino, piperidino, morpholino, piperazine derivatives is the SCP, containing from 3 to 8 atoms in the ring, from which one or two are heteroatoms, which are selected from the group N, O and S(O)nwhere n means an integer from 0 to 2, the remaining atoms in the ring atoms are C. Heterocyclic group optionally may be condensed with benzene ring or optionally substituted independently from each other by one or more substituents, preferably one or two substituents which are selected from the group including alkyl, halogenated, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroalkyl, halogen, cyano, acyl, mono - and disubstituted amino, carboxy and alkoxycarbonyl. More specifically, the term heterocycle includes (but not limited to) piperidino, piperazine derivatives, pyrrolidine, morpholine, tetrahydropyranyl, thiomorpholine and their derivatives.

"Cycloalkenyl" means a radical-RaRbin which Rameans alkylen, a Rbmeans cycloalkyl, as defined above, such as cyclopropylmethyl, cyclohexylmethyl, 3-cyclohexyl-2-methylpropyl etc.

"Cycloalkylation" means a radical-OR where R means cycloalkyl, as defined above, for example, cyclopropylmethoxy, 3 cyclohexa is, Rbmeans aryl, as defined above, for example benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl etc.

"Heteroalkyl" means a radical-RaRbin which Rameans alkylen, a Rbmeans heteroaryl, as defined above, for example 2-, 3 - or 4-pyridylmethyl, furan-2-ylmethyl etc.

"Heteroseksualci" means a radical-RaRbin which Rameans alkylene, and Rbmeans heterocycle, as defined above, for example morpholine-4-retil, tetrahydrofuran-2-ylmethyl etc.

"Prodrug" means any compound that is converted into the active compound of the formula (I) in vivo after administration of the prodrug in the body of a mammal. Prodrugs of compounds of formula (I) is obtained by modifying functional groups present in the compound of formula (I), so that in vivo these groups hatshepsuts with the formation of the active compounds. Prodrugs include compounds of formula (I), in which hydroxy, amino or sulfhydryl group of the compound (I) associated with any group which can be converted in vivo, regenerating the free hydroxy, amino or sulfhydryl group, respectively. Examples of prodrugs include the such as esters (for example, derivatives of acetate, formate, benzoate), carbamates (for example, N,N-dimethylaminobenzoyl), etc.

Compounds with the same molecular formula but with a different nature or a different sequence relationships of their atoms or with different spatial arrangement of atoms is called "isomers". Isomers with different spatial arrangement of the atoms are called "stereoisomers".

Compounds according to the invention can have one or more asymmetric centers; such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. If not stated otherwise, the description or name of any connection in the description and in the claims includes both individual enantiomers and their racemic or other mixture. Methods for the determination of stereochemistry and the methods of separation of stereoisomers are well-known specialists in the art (see , for example, the main 4 in the book "Advanced Organic Chemistry", 4th ed., J. March, John Wiley and Sons, N. Y., 1992).

"Pharmaceutically acceptable excipient" means excipient, which finds application in the manufacture of pharmaceutical compositions and which are harmless, non-toxic and not junk either bi is to and in the pharmaceutical industry. The term "pharmaceutically acceptable excipient" as it is used in the description and in the claims includes both one and more than one of this kind of excipients.

"Pharmaceutically acceptable salt" of a compound means a salt that is acceptable in the pharmaceutical respect and which has the necessary pharmacological activity of the parent compound. Such salts include:

(1) acid additive salts formed with inorganic acids such as chloride-hydrogen acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoy-Naya acid, cinnamic acid, almond acid, methanesulfonate, econsultation, 1,2-ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-tolua is a, 4,4'-Methylenebis(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and others, or

(2) salts formed due to the fact that present in the original connection acidic proton or exchanged for metal ions, such as ion, alkaline metal ion, alkaline earth metal or aluminum ion, or forms a coordination bond with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

"Therapeutically effective amount" refers to an amount of compound that is administered to a mammal for the treatment of diseases and is sufficient to exert a therapeutic effect. therapeutically effective amount can vary depending on the connection type, nature and severity of the disease, age, weight and other parameters of the patient.

"Leaving group" has the value associated with synthetic organic chemistry, and usually means an atom or group that can be replaced nuclei the example chlorine, bromine, iodine, mesilate, tosyloxy, triptoreline, methoxy, N,O-dimethyl-hydroxylamine etc.

Nomenclature

Names and numbering of atoms in the compounds according to the invention are given below. Naphthalene nucleus of the compounds of formula (I) is numbered as follows:

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Side chains in the Deputy Z are numbered as shown below:

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Cycles of pyridine, thiophene and furan can be associated with a group And on any position in the cycle, with the exception of position 1. Accordingly, the cycle of pyridine may be present in the form of 2-, 3 - or 4-pyridyl, the cycle of thiophene can be in the form of a 2 - or 3-tanila, and the cycle of furan can be in the form of a 2 - or 3-furil.

The nomenclature of the compounds in the description of the invention based on the recommendations of IUPAC.

As defined in the first object of the invention, preferred compounds of formula (I) are the following:

(I) first preferred group are compounds in which a represents-C(O)-,

(II) a second preferred group are compounds in which a represents-C=NOR4where R4means hydrogen or alkyl,

(III) a third preferred group are compounds in which a represents-O-, -S - or-NR5where R5C group Z, which means a group of formula (C) or (D), most preferably a represents-C(O)-.

In a preferred embodiment, R3means-SO2R12where R12preferably denotes alkyl, more preferably methyl, or R3means-SO2NR13R14where R13preferably means hydrogen, and R14means hydrogen, methyl, 2-hydroxyethyl or hydroxy, more preferably R14means hydrogen.

In these preferred groups is more preferred group are compounds in which Z has the formula (V), where R6and R7independently from each other selected from the group comprising hydrogen, alkyl, cycloalkyl, alkoxy, ethynyl, halogen, and-NR9R10where R9and R10mean alkyl, preferably methyl, more preferably R6and R7mean hydrogen, alkyl, alkoxy or halogen, most preferred hydrogen, methyl, methoxy, fluorine or chlorine, and R2means hydrogen. Preferably R6occupies the 2nd or 3rd position, and R7takes the 4th position.

Another preferred group are compounds in which Z has the formula (D), where X is S, and R8and R2OSN more preferred groups, particularly preferred are compounds, in which R preferably denotes hydrogen, alkyl, alkoxy, cycloalkane, hydroxyalkyloxy, hydroxy, halogen or cyano, more preferred are hydrogen, methyl, methoxy, cyclopropylamino, 2-hydroxyethyloxy, hydroxy, chlorine or cyano, and most preferred are hydrogen, methyl, methoxy, hydroxy, chlorine or cyano.

Especially preferred group are compounds in which R1means hydrogen, alkyl, alkoxy, cycloalkane, hydroxyalkyloxy (preferred 2-hydroxyethyloxy), hydroxy, halogen or cyano, more preferably hydrogen, methyl, methoxy, cyclopropylamino, 2-hydroxyethyloxy, hydroxy, chlorine or cyano, most preferably hydrogen, methyl, methoxy, hydroxy, chlorine or cyano, and R3means-SO2R12where R12means alkyl, preferably methyl, or R3means-SO2NR13R14where R13means hydrogen, and R14means hydrogen, methyl, 2-hydroxyethyl or hydroxy, more preferably R14means hydrogen. Most preferably, R1means hydrogen, methyl, methoxy, hydroxy, chlorine or cyano, and R3means-SO2Me or-SO2NH2.

Especially preferred link>5-(4-methylbenzoyl)-6-methoxy-2-naphthalenesulfonate,

5-(2-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

5-(3-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

5-(4-perbenzoic)-6-methoxy-2-methylsulfonylmethane,

5-(4-perbenzoic)-6-hydroxy-2-methylsulfonylmethane,

5-benzoyl-6-hydroxy-2-methylsulfonylmethane,

5-benzoyl-6-methoxy-2-methylsulfonylmethane,

5-benzoyl-6-cyano-2-naphthalenesulfonate,

5-(4-perbenzoic)-6-cyano-2-naphthalenesulfonate,

5-(4-perbenzoic)-6-methyl-2-naphthalenesulfonate,

5-(4-perbenzoic)-6-chloro-2-naphthalenesulfonate,

5-(2-perbenzoic)-6-cyano-2-naphthalenesulfonate,

5-(2-perbenzoic)-6-hydroxy-2-naphthalenesulfonate,

5-(2-perbenzoic)-6-chloro-2-naphthalenesulfonate,

5-(2-perbenzoic)-6-methyl-2-naphthalenesulfonate,

5-(4-methylbenzoyl)-6-cyano-2-naphthalenesulfonate,

5-(4-perbenzoic)-6-cyano-2-methylsulfonylmethane,

5-benzoyl-6-cyano-2-methylsulfonylmethane,

5-(4-chlorobenzoyl)-6-cyano-2-methylsulfonylmethane,

5-(2-perbenzoic)-6-cyano-2-methylsulfonylmethane.

Below are examples of representative compounds according to the invention.

I. the compounds of formula (I) in which a represents-C(O)-, gruppenchat-SO2NR13R14and the remaining groups have the values listed in the table.1.

Below are the names of some of the compounds listed in table.1:

1. 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

4. 5-(4-methylbenzoyl)-6-methoxy-2-naphthalenesulfonate,

10. N-(2-hydroxyethyl)-5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

14. 5-(2-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

15. 5-(3-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

30. N-12-(morpholine-4-yl)ethyl]-5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

41. 5-(2-fluoro-4-trifloromethyl)-6-methoxy-2-naphthalenesulfonate,

51. 5-(4-methylthiophenyl)-6-methoxy-2-naphthalenesulfonate,

64. 5-(4-perbenzoic)-6-cyano-2-naphthalenesulfonate,

79. 5-(4-methoxybenzoyl)-6-carboxy-2-naphthalenesulfonate.

II. The compounds of formula (I) in which a represents-C(O)-, group Z is represented by formula (V), R2means hydrogen, a R3is in the 2nd position, and R3means-SO2NR13R14and the remaining groups have the values listed in the table.2.

Below are the names of some of the compounds listed in table.2:

84. 5-(4-perbenzoic)-6-methoxy-2-(4-methylpiperazin-1-ylsulphonyl)-naphthalene,

88. the means-C(O)-, the group Z is represented by formula (V), R2means hydrogen, R3means-SO2R12and is in the 2nd position, and the remaining groups have the values listed in the table.3.

Below are the names of some of the compounds listed in table.3:

91. 5-(4-perbenzoic)-6-methoxy-2-methylsulfonylmethane,

92. 5-(4-perbenzoic)-6-hydroxy-2-methylsulfonylmethane,

93. 5-benzoyl-6-hydroxy-2-methylsulfonylmethane,

94. 5-benzoyl-6-methoxy-2-methylsulfonylmethane,

96. 5-(4-perbenzoic)-6-cyano-2-methylsulfonylmethane,

97. 5-benzoyl-6-cyano-2-methylsulfonylmethane,

99. 5-(2-perbenzoic)-6-cyano-2-methylsulfonylmethane,

104. 5-(4-chlorobenzoyl)-6-cyano-2-methylsulfonylmethane,

107. 5-(4-perbenzoic)-6-hydroxyethoxy-2-methylsulfonylmethane.

IV. Other connections (see tab.4).

Below are the names of some of the compounds listed in table.4:

110. 5-(4-terbisil)-6-methoxy-2-naphthalenesulfonate,

113. 5-(4-perpenicular)-6-methoxy-2-methylsulfonylmethane.

The General scheme of the synthesis of

Compounds according to the invention can be obtained using the techniques presented in the diagrams below.

Raw materials and reaer supplied by such firms, as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (TORRANCE, CA, USA) and Sigma (St. Louis, Missouri, USA) or synthesized by methods known to experts in the art guided by these sources, as Fieser and Fieser's, Reagents for Organic Synthesis, T. T. 1-17 (John Wiley and Sons, 1991); Rodd''s Chemistry of Carbon Compounds, so-so 1-5 and applications (Elsevier Science Publishers, 1989); Organic Reactions, so so 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th ed.); Larock''s Comprehensive Organic Transformations (VCH Publishers Inc. , 1989). See diagrams only illustrate some methods, which can be obtained the compounds according to the invention, for specialists in the art from the present description that reveals the essence of the invention should be apparent various modifications that can be made to these schemes.

The source and the intermediate is isolated and purified, if necessary, by conventional methods, which include (but are not limited to, filtration, distillation, crystallization, chromatography, etc., Such compounds are characterized by the usual parameters, including physical constants and spectral characteristics.

If not specified, the following reaction is carried out at atmospheric pressure, at which SUP>o
With up to approximately 125oC, most preferably at room temperature (or ambient temperature), for example at about 20oC.

Obtaining compounds of formula (I)

In the diagram A (see end of description) describes the synthesis of compounds of formula (I) in which a represents-C(O)-, a R3means-SO2R12or-SO2NR13R14from naphthalene of formula 1 in which R1means a group that focuses substitution in the ortho - and paraparesia.

In stage 1 5-areolation formula 2 is obtained by acylation of naphthalene of formula 1 allermuir agent ZC(O)L, where Z is specified at the beginning of the description of the values, a L is a leaving group under the reaction conditions for the acylation according to the Friedel-Crafts (for example, halogen, preferably chlorine). The reaction is carried out in the presence of a Lewis acid such as aluminum chloride, tin chloride and other Acceptable solvents are halogenated hydrocarbons such as dichloromethane, dichloroethane, etc. In General, the compounds of formula 1 and the halides are commercially available or these compounds can be synthesized by known in the art methods.

In stage 2 of 5-areolation-2-sulphonylchloride formula 3 policealna chlorosulfonic acid, or in halogenated hydrocarbons such as dichloromethane, etc.

In stage 3, the compound of formula (I) in which R3means-SO2R12or-SO2NR13R14get from 5-areolation-2-sulphonylchloride formula 3 according to method a or method B, respectively, as indicated below.

Method And compound (I) in which R3means-SO2R12get recovery, alkylation and oxidation of compound 3. Recovery sulphonylchloride groups in the thiol is carried out in the presence of triphenylphosphine according to the method described OAU S., H. Togo, Bull. Chem. Soc. Jpn., 56, 3802 (1983). The alkylate thiol education tiefer by reaction with an alkylating agent R12L, where R12is specified at the beginning of the description of the meaning and L is a leaving group under the reaction conditions of alkylation (for example, halogen, methanesulfonate, paratoluenesulfonyl and others). The reaction alkilirovanija carried out in the presence of dinucleophiles base (e.g. cesium carbonate, sodium hydride or potassium carbonate) in an acceptable polar aprotic organic solvent (e.g. ether, tetrahydrofuran, dioxane, dimethylformamide, and others). Then tiefer oxidized to the corresponding sulfone klaric sodium, etc.

Method B compound (I) in which R3means-SO2NR13R14receive by the reaction of 2-naphthalenesulfonate 3 with an excess of amine of the formula HNR13R14acceptable organic solvent (e.g. dioxane, tetrahydrofuran, and others). Thus, the compound (I) in which R13and/or R14mean hydrogen, can be alkilirovanii/allievate with the formation of the corresponding compounds of formula (I) in which R13and/or R14not mean a hydrogen atom, optionally interaction with an appropriate alkylating or allermuir agent in the presence of a base (e.g. sodium carbonate, sodium hydride, triethylamine and others) in a polar aprotic solvent such as methylene chloride, dioxane, etc.

Getting this method the compounds of formula (I) in which a represents-C(O)-, Z means 4-forfinal, R1means-OMe, and R3means-SO2NH2described in example 1.

In scheme B (see end of description) describes the synthesis of compounds of formula (I) in which a represents-C(O)-, and R3means-SO2R12or-SO2NR13R14from 1-naphthoic acid 4, in which R1means a group that focuses for the given substitution reactions with ORGANOMETALLIC compounds [for example, alkoxy (preferably methoxy or ethoxy), dialkylamino or preferably N, O-dimethylhydroxylamine] , is obtained from 1-naphthoic acid of formula 4 according to the method well known in organic chemistry. For example, compound 5, in which L is N, O-dimethylhydroxylamine, it is possible to synthesize, receiving first the acid chloride 4 interaction with the corresponding gloriouse agent, such as oxalylamino, followed vzaimodeistviem hydrochloride of N, O-dimethylhydroxylamine in the presence of an organic base such as triethylamine. Usually 1-naphthoic acid of formula 4 are available for sale.

In stage 2 1-areolation formula 2 is produced by interaction of compound 5 with ORGANOMETALLIC reagent such as a Grignard reagent or organolithium compound (ZMgX or Zli is), under the reaction conditions described in M. Takei, Chem. Lett., 687 (1974) and S. Nahm, A. M. Weinreb, Tet. Lett., 22, 3815 (1981).

At stage 3 compound 2 is converted into a compound of formula (I) in which R3means-SO2R12or-SO2NR13R14as described for scheme a, steps 2 and 3.

In alternative compound (I) in which R3means-SO2R12or-SO2NR13R14polysulfon or 2-naphthalenesulfonate formula 7 in the reaction conditions, described for scheme a, steps 2 and 3. Then from compound 7 receive a corresponding compound of formula (I) as described above for scheme B, step 2.

The diagram In (see the end of the description) describes the synthesis of compounds of formula (I) in which a represents-C(O)-, and R3means-SO2R12or-SO2NR13R14from naphtalenesulfonic acid 8 in which R1means a group that focuses substitution in the ortho - and paraparesia.

In stage 1 2-naphthalenesulfonate formula 9 is obtained by interaction of 2-naphtalenesulfonic acid with an acid chloride such as thionyl chloride or oxalicacid.

In stage 2 of 2-naphthalenesulfonyl or 2-naphthalenesulfonate formula 10 is obtained from the compound (9) as described for scheme a, step 3.

At stage 3 the connection 10 acelerou in position 5 with the formation of the compounds of formula (I) in which R3means-SO2R12or-SO2NR13R14as described for scheme a, step 1.

In the diagram G (see end of description) describes the synthesis of compounds of formula (I) in which a represents-C(O)-, and R3means-SO2R12or-SO2NR13R14from bromonaphtalene 11, in which R1means the group is given by the interaction of bromonaphthalene formula 11 with disulphide R12SSR12or R12SO2SR12(where R12is specified at the beginning of the description of the meaning) in the atmosphere of inert gas. The reaction of nucleophilic substitution is carried out either in two stages: first, does not depend make in ORGANOMETALLIC reagent, and then treated with a strong base, such as n-utility, either directly in the presence of a copper catalyst such as copper powder, copper iodide, etc. as a suitable solvent for the reaction using polar aprotic solvents, such as tetrahydrofuran, dimethylformamide, hexamethylphosphoramide etc.

In stage 2 tiefer 12 oxidize in naphthalenesulfonic 13, as described for scheme a, step 3, method A.

At stage 3 the connection 13 (where R12means methyl) does not necessarily translate into the corresponding sulfonamide, in which R13and R14mean hydrogen, according to the method described by Huang H., and others, Tet.Lett., 7201 (1995). The sulfonamide can be alkylated with the formation of the corresponding mono-or di-N-alkyl derivatives, as described for scheme a, step 3, method b

In stage 4 naphthalenesulfonic 13 or sulfonamide 14 acelerou or sulfonylureas in position 5 (when R1is a group, EO is SUB>2-, and R3means-SO2R12or-SO2NR13R14as described for scheme a, step 1.

Getting this method, compounds of formula (I) in which a represents-C(O)- or-SO2-, Z means 4-forfinal, R1means-OMe, and R3means-SO2Me, in examples 2 and 3.

Getting this method, compounds of formula (I) in which a represents-C(O)-, Z means 4-forfinal, R1means-CN, and R3means-SO2Me described in example 6.

In the diagram D (see end of description) describes the synthesis of compounds of formula (I) in which a represents a chemical bond, -O-, -NR5- or-S(O)n-, where n means an integer from 0 to 2, R5means hydrogen or alkyl, and R3means-SO2R12or SO2NR13R14from 5-amino-2-naphthalenesulfonic 15.

In stage 1 5-iodine-2-naphthalenesulfonate 16 is produced by conversion of 5-amino-2-naphthalenesulfonate 15 in salt page, which is treated Jodorowsky reagent (e.g., I2or KI) with the formation of 5-iodine-substituted compounds. The reaction is carried out in accordance with the method described in H. Heaney , Millar I. T., J. Org. Synth., 40, 105 (1960). 5-Amino-2-naphthalenesulfonate commercially available or can be is about Amina.

In stage 2 of 5-iodine-2-naphthalenesulphonic formula 17 is obtained from 5-iodine-2-naphthalenesulfonate 16, as described for scheme B, step 1.

At stage 3 of 5-iodine-2-naphthalene of the formula 18, in which R3means-SO2R12or-SO2NR13R14receive from the connection 17, as described for scheme a, step 3, methods a or B, respectively.

In stage 4 of the compounds of formula 18 receive the compounds of formula (I) in which a represents a chemical bond, -NR5- (where R5means hydrogen or alkyl), -O - or-S-, described in the literature methods. Regarding compounds 18, where a represents a chemical bond, see J. K. Stille, Angew. Chem. Intl. Ed., 25, 508 (1980); McKean, D. R., Parrinello g, Renaldo A. F. and S. K. Stille , J. Org. Chem., 52, 422 (1987); Suzuki, Syn. Commun., 11, 513 (1981). Regarding compounds 18 And means-NR5- (where R5means hydrogen or alkyl), -O-or-S-, see Yamamoto, T., Can. J. Chem., 61, 86 (1983); Burnell J. F. , Chem. Rev., 49, 392 (1951); J. R. Campbell, J. Org. Chem., 29, 1830 (1964); Tesafaferri L., M. Tiecco, Tingol M., Chianelli D., Menfanucci M., Synthesis., 751 (1983), respectively.

Additional methods

The compounds of formula (I) can be obtained by modification of the groups present in the corresponding compound of formula (I). For example, the compound of formula (I) in which R1means hydroxy, Ala may be obtained by dialkylammonium of alkoxysilanes in the corresponding compound of formula (I) followed by treatment acceptable alkylating, allermuir or sulfonylureas agent. The transformation is performed using a known organic chemistry methods. The compounds of formula (I) in which R1means hydrogen, alkyl, alkenyl, cyano, halogen, alkoxycarbonyl, -CONR9R10receive from the corresponding compounds of formula (I) in which R1means hydroxy, by the methods described G. Ortar, Tet. Lett., 27, 5541 (1986); J. K. Stille , J. Org. Chem. , 52, 422 (1987); Capri W., J. Org. Chem., 55, 350 (1990).

The compounds of formula (I) in which a represents-SNON-, -CH2-, -C=NOR4- can be obtained from corresponding compounds of formula (I) in which a represents-C(O)-. These transformations are carried out by restoring the carbonyl group or by treatment of the corresponding hydroxy - or alkoxyamine using known organic chemistry methods.

The conversion of compounds of formula (I) in which R1means methoxy or hydroxy in the corresponding compounds of formula (I) in which R1means hydroxy, cyano, and hydrogen, respectively, described in examples 4 and 5, respectively.

To a person skilled in the art it is obvious that these transformations are not limited to the position of the group R1and can be carried out in other provisions of containing a pharmacologically effective amount of the compounds according to the invention and a pharmaceutically acceptable excipient.

Compounds according to the invention can find use as therapeutically active substances. They are inhibitors of prostaglandin G/H synthase I and II (YEAR I and YEAR II), primarily MOR II, in vitro, and it is assumed that these compounds possess both anti-inflammatory and analgesic properties in vivo (see, for example, Goodman and Gilmans''s "The Pharamacological Basis of Therapeutics, 9th ed., McGraw Hill, new York, 1996, Chapter 27). Therefore, the compounds and compositions containing them can primeneniia as anti-inflammatory and analgesic agents for diseases of mammals, especially humans. They find application in the treatment of fevers, inflammation, pain syndromes, caused, for example, bouts of rheumatic fever, symptoms associated with influenza or exposure to other viral infections of the pica or neck pain, dysmenorrhea, headache, toothache, sprains, myositis, synovitis, arthritis (rheumatoid arthritis and osteoarthritis), gout, Ankylosaurus spondylitis, bursitis, burns and injuries. They can be used for relieving muscle contraction-induced prostanoids (e.g., dysmenorrhea, premature tx2">

In accordance with this present invention relates to compounds of formula (I) for the treatment of autoimmune diseases, especially systemic lupus erythematosus and diabetes type I or for the treatment of inflammatory or autoimmune diseases.

In addition, it should be expected that the compounds according to the invention as inhibitors of prostaglandin G/H synthase can find application in the prevention and treatment of malignant tumors, especially cancer of the colon. It is established that the expression of MOR-II is activated in colorectal tumors in humans, and that drugs that inhibit prostaglandin G/H synthase, effective in animal experiments [Eberhart C. E., and others, Gastroenterology, 107, 1183-1188 (1994); Ara G., Teicher B. A., Prostaglandins, Leukotrienes and Essential Fatty Acids, 54 3-16 (1996)]. In addition, the known data from epidemiological surveys, showing that there is a correlation between the effect of drugs inhibiting prostaglandin G/H synthase and reduced risk of development of colorectal tumors (C. W. Heath Jr. and others , Cancer, 74, 10, 2885-2888 (1994)).

In addition, it is also expected that the compounds according to the invention will find application in the prevention and treatment of Alzheimer's disease. Found that indomethacin, which also inhibitora simple the other, Neurology, 43, 1609 (1993)]. In addition, the use of drugs inhibiting prostaglandin G/H synthase, epidemiologically associated with the later manifestation of Alzheimer's disease [Breitner J. C. S., and others, Neurobiology of Aging, 16, 4, 523 (1995) and Neurology, 44, 2073 (1994)].

Anti-inflammatory effect of the compounds according to the invention is determined by measuring in vitro inhibitory activity against YEAR I and YEAR II, first of all MOR II, using radiometric analysis, as described in more detail in example 8. In addition, it can determine its activity in vivo, for example, in experiments on rats using a model karragenana foot" ("the Rat Carrageenan Paw") and the model of the "air pocket" ("Rat Air-Pouch"), as described in more detail in examples 9 and 10. Analgesic activity of the compounds according to the invention can be determined in experiments in vivo, such as the test of Randall-Selitto (Randall-Selitto) and a model of arthritic pain in rats, as described in more detail in example 11.

Mainly compounds according to the invention are introduced in a therapeutically effective amount by any means adopted for drugs with the same destination. The actual number of compounds according to the invention, i.e. active ingredient, will depend on many factors, such as severity of illness, age is>/P>Therapeutically effective amounts of compounds of formula (I) can be approximately 0.005 to 10 mg/kg of body weight patineta per day, preferably about 0.05-1 mg/kg/day. Thus, when a patient weight of 70 kg, the dose is preferably from about 3.5 mg to 70 mg per day.

Mainly compounds according to the invention is administered in the form of pharmaceutical compositions by one of the following ways: oral, systemic (e.g., percutaneous, intranasal or by suppository), or parenteral (e.g., intramuscularly, intravenously or subcutaneously). Preferred oral route of administration proper daily dosages that are prescribed based on the severity of the disease. Compositions can take the form of tablets, pills, capsules, semi-solid compositions, powders, compositions prolonged action, solutions, suspensions, elixirs, aerosols, or other acceptable form.

The choice of compositions will depend on several factors such as route of administration (for example, for oral administration, the preferred tablets, pills or capsules) and bioavailability of pharmaceutical compounds. Recently, pharmaceutical compositions usovershenstvovany, and above all it refers to drugs with a low bio is I contact surface, i.e., decreasing particle size. For example, in patent US 4107288 described pharmaceutical composition with a particle size of from 10 to 1000 nm, in which the active compound applied on the matrix of cross-linked macromolecules. In the patent US 5145684 described preparation method of the pharmaceutical composition, according to which the active substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of the surface modifier, and then dispersed in a liquid medium with the formation of a pharmaceutical product having a significantly higher bioavailability.

The compositions include a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic substances that contribute to the drug and not having a negative impact on therapeutic properties of the compounds of formula (I). Such a filler may be any solid, liquid, semisolid, or in the case of aerosol compositions gaseous filler, well-known specialists in this field of technology.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelaterie skim milk and other Liquid and semi-solid excipients are selected from the group comprising glycerine, propylene glycol, water, ethanol, and various oils, including oil refining products, animal, vegetable or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. are Preferred liquid carriers, particularly injectable solutions, include water, saline, aqueous dextrose, and glycols.

For dispersion of the compounds according to the invention for the purpose of preparation of aerosols can be used with compressed gases. Acceptable inert gases are nitrogen, carbon dioxide, etc.

Other acceptable pharmaceutical excipients, and their compositions are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18-e Izd., 1990).

The content of the active substance in the composition can vary over the entire range, used by experts in the field of technology. Typically, the composition contains, in mass percent (wt.%), about 0.01-99.99 wt.% the compounds of formula I in terms of the total weight in combination with one or more acceptable pharmaceutical excipients. Preferably the active substance is present in the preparation in the number of examples is ptx2">

Examples

Below the invention is illustrated in the examples of the preparation of the proposed compounds and examples of the compositions. These examples do not limit the scope of the invention and are intended as illustrative and are characteristic of the present invention.

In the examples used the following abbreviations: Hcl mean chloride-hydrogen acid, DMF means dimethylformamide, means NaOH sodium hydroxide, DMSO means dimethylsulfoxide.

Example 1

Synthesis of 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate [scheme A, stage 1, 2 and 3 (method B)]

< / BR>
Stage 1

A solution of 2-methoxynaphthalene (20,0 g, 120 mmol) and 4-tormentilla (15 ml, 126 mmol) in methylene chloride (200 ml) cooled in an ice bath under nitrogen atmosphere and portions over 10 min add aluminum chloride (18.5 g, 129 mmol, 1.1 EQ.). The reaction mixture was stirred at room temperature for 3 h, and then poured into 2 N. Hcl (500 ml). The product is extracted with methylene chloride, washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuo, getting 34,6 g (yield 97%) of 1-(4-perbenzoic)-2-methoxynaphthalene in the form of a solid substance, which is used at a later stage the config in stage 1) is dissolved in 10 ml of chlorosulfonic acid. After stirring at room temperature for 15 min, the reaction mixture was carefully poured onto ice and the product extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo, polochic of 5.39 g of 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate used at the subsequent stage without further purification.

Stage 3

A solution of 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate (5,39 g, 14.2 mmole) (obtained in stage 2) in dioxane (100 ml) cooled in an ice bath under nitrogen atmosphere and added dropwise concentrated ammonium hydroxide solution (20 ml). After 1 h the dioxane is removed under reduced pressure, the residue is distributed between water and ethyl acetate. The organic layer is separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified Express chromatography (gradient elution from 20 to 60% ethyl acetate/hexane) and recrystallize (ethyl acetate/hexane). The result is 2.7 g of 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate in the form of white crystals.

According to the method described above in example 1, but replacing in stage 1 4-perbenzoate on:

benzoylchloride and

4-acetoxybenzoic (obtained from 4-acetoxybenzoic acid),

receive respectively:

5-benzoyl-6-methoxy-2-naphthalenesulfonate,

5-(4-chlorobenzoyl)-6-methoxy-2-naphthalenesulfonate,

5-(4-methylbenzoyl)-6-methoxy-2-naphthalenesulfonate,

5-(2-perbenzoic)-6-methoxy-2-naphthalenesulfonate,

5-(3-perbenzoic)-6-methoxy-2-naphthalenesulfonate and

5-(4-hydroxybenzoyl)-6-methoxy-2-naphthalenesulfonate.

Example 2

Synthesis of 5-(4-perbenzoic)-6-methoxy-2-methylsulfonylmethane (G)

< / BR>
Stage 1

A solution of 2-bromo-6-methoxynaphthalene (22,2 g, 93,6 mmole) in tetrahydrofuran (500 ml) cooled to -78oC and for 15 min added dropwise n-utility (75 ml, 1.6 M in THF, 121,7 mmole) in THF. After 0.5 h added dimethyl disulfide (13 ml, 140 mmol) and the reaction mixture is left to warm Yes room temperature. After 16 h was added 1 n sodium hydroxide (100 ml) and the reaction mixture is stirred for 1 hour the Organic layer is separated, washed with 1 N. sodium hydroxide, 5% aqueous solution of sodium sulfite, brine and dried over sodium sulfate. The solvent is removed in vacuo, the crude product is recrystallized from ethyl acetate and hexane. In p the>/BR>To a solution of 2-methoxy-6-methylthiopurine (1.0 g, 4.9 mmole) (obtained in stage 1) in methylene chloride (50 ml) is added to individual portions 3-chloroperoxybenzoic acid (3.5 g, 10.3 mmole, 50-60%). After 0.5 h the reaction mixture was cooled in an ice bath, add sodium sulfite (0,53 g, 4.2 mmole) and continue stirring for 20 minutes Then the reaction mixture was poured into water, the organic layer separated and dried over sodium sulfate. The solvent is removed in vacume, the crude product is purified Express chromatography (gradient elution from 30% to 50% ethyl acetate/hexane). The result is 930 mg (vihol 80%) 2-methoxy-6-methylsulfonylmethane.

Stage 3

To a solution of 2-methoxy-6-methylsulfonylmethane (0,93 g, 3,93 mmole) (obtained in stage 2) in 1,2-dichloroethane (40 ml) is added 4-perbenzoate (0,93 ml, 7,87 mmole) and aluminium chloride (1,05 g, 7,87 mmole) and the reaction mixture is refluxed. After 16 h, the reaction mixture was poured into 2 N. Hcl and extracted with methylene chloride. The organic layer is separated, washed with water and dried over sodium sulfate. The solvent is removed in vacuo, the crude product is purified Express chromatography (gradient elution, 10 to 60% ethyl acetate/hexane). In vogo solid.

Stage 4

A mixture of 5-(4-perbenzoic)-6-hydroxy-2-methylsulfonylmethane (1.0 g, 2.9 mmole) (obtained in stage 3), methyliodide (0,65 ml, 10,45 mmole) and potassium carbonate (0.64 g, the 4.65 mmole) in N,N-dimethylformamide (10 ml) was stirred at room temperature. After 16 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer is separated, washed with brine and dried over sodium sulfate. The solvent is removed in vacuo, the crude product is purified Express chromatography (gradient elution from 40 to 100% ethyl acetate/hexane). The result is 1.0 g (yield 96%) of 5-(4-perbenzoic)-6-methoxy-2-methylsulphonyl-naphthalene in the form of a solid substance.

Replacing in stage 3 4-perbenzoate on it, get a mixture of 5-benzoyl-6-methoxy-2-methylsulfonylmethane and 5-benzoyl-6-hydroxy-2-methylsulfonylmethane, which is shared by rapid chromatography (gradient elution from 20 to 50% ethyl acetate/hexane).

According to the method described above in example 2, but replacing in stage 3 4-perbenzoate 4-chlorobenzylchloride receive a mixture of 5-(4-chlorobenzoyl)-6-methoxy-2-methylsulfonylmethane and 5-(4-chlorobenzoyl)-6-hydroxy-2-methylsulfonylmethane which Express the d 2-perbenzoate, get a mixture of 5-(2-perbenzoic)-6-methoxy-2-methylsulfonylmethane and 5-(2-perbenzoic)-6-hydroxy-2-methylsulfonylmethane, which is shared by rapid chromatography.

Example 3

Synthesis of 5-(4-perpenicular)-6-methoxy-2-methylsulfonylmethane (G)

< / BR>
Aluminium chloride (1.13 g, 8,46 mmole) are added to a solution of 2-methoxy-6-methylsulfonylmethane (1.0 g, 4.2 mmole) (obtained according to example 2) and 4-fluoro-benzosulfimide (1.65 g, 8,46 mmole) in 1,2-dichloroethane (40 ml). The reaction mixture was refluxed for 16 h, then poured into 2 N. Hcl and extracted with methylene chloride. The organic layer was separated, washed with water, brine and dried over sodium sulfate. After rapid chromatography receive 0.1 g (yield 16%) of 5-(4-perpenicular)-6-methoxy-2-methylsulfonylmethane in the form of a solid substance.

Example 4

Synthesis of 5-(4-perbenzoic)-6-cyano-2-naphthalenesulfonate

< / BR>
Stage 1

Tribromide boron (55.7 ml, 1 M solution in methylene chloride) are added to a suspension of 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate (5 g, 14 mmol) (obtained according to example 1) in methylene chloride (100 ml) at 0oC. After 30 min the reaction mixture valiym solution dried over sodium sulfate and concentrated to complete dryness in a vacuum, after which the crude product is purified Express chromatography (gradient elution, 20-80% ethyl acetate/hexane). The result is 4.0 g (83% yield) of 5-(4-perbenzoic)-6-hydroxy-2-naphthalenesulfonate in the form of a solid substance.

Stage 2

Pyridine (4,25 ml, 52.1 mmole) and triftormetilfullerenov (4,4 ml of 26.1 mmole) are added to a solution of 5-(4-perbenzoic)-6-hydroxy-2-naphthalenesulfonate (3.0 g, 8.7 mmole) (obtained in stage 1) in methylene chloride (50 ml) at 0oC. After 0.5 h, to the reaction mixture was added 1 n sodium bisulfate and continue stirring for 30 minutes the Organic layer is separated, washed with brine and dried over sodium sulfate. After removal of solvent in vacuo obtain 3.1 g (yield 75%) of 5-(4-perbenzoic)-6-tripterocalyx-2-naphthalenesulfonate in the form of butter.

Stage 3

A mixture of 5-(4-perbenzoic)-6-tripterocalyx-2-naphthalenesulfonate (1.0 g, 2.1 mmole) (obtained in stage 2), potassium cyanide (0.15 mg, 2.3 mmole) and tetrakis(triphenylphosphine)palladium (0) in dioxane (15 ml) is refluxed in an argon atmosphere. After 2 h the reaction mixture was cooled to Cola dried over sodium sulfate and concentrated in vacuo. The crude product is purified Express chromatography (gradient elution, 20-50% ethyl acetate/hexane) and then recrystallized (ethyl acetate/hexane). The result of 0.44 g (yield 54%) of 5-(4-perbenzoic)-6-cyano-2-naphthalenesulfonate in the form of a white solid.

According to the method described above in example 4, but replacing 5-(4-perbenzoic)-6-methoxy-2-naphthalenesulfonate 5-(2-perbenzoic)-6-methoxy-2-naphthalenesulfonate receive 5-(2-perbenzoic)-6-cyano-2-naphthalenesulfonate.

Example 5

Synthesis of 5- (4-perbenzoic) -2-methylsulfonylmethane

< / BR>
Stage 1

Pyridine (0,74 ml, 9.2 mmole) and triftormetilfullerenov (0,78 ml, 4.6 mmole) is added at 0oTo a solution of 5-(4-perbenzoic)-6-hydroxy-2-methylsulfonylmethane (0.4 g, 1.2 mmole) (obtained according to example 2) in methylene chloride. After 0.5 h, to the reaction mixture was added 1 n sodium bisulfate and continue stirring for 30 minutes the Organic layer is separated, washed with brine and dried over sodium sulfate. The solvent is removed in vacuum, obtaining of 0.62 g of 5-(4-perbenzoic)-6-tripterocalyx-2-methylsulfonylmethane in the form of butter.

Stage 2

A mixture of 5-(4-perbenzoic)-6-triftormetilfosfinov (0,36 ml, 2.5 mmole), palladium acetate (14 mg, 0.06 to mmole) and 1,3-bis(diphenylphosphino)propane (0.10 g, 0.03 mmole) in DMF (10 ml) was stirred at room temperature. After 16 h, the reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo. The crude product is purified Express chromatography (gradient elution, 10 to 30% ethyl acetate/hexane) and then recrystallized (ethyl acetate/hexane). The result is 0.1 g (yield 48%) of 5-(4-perbenzoic)-2-methylsulfonylmethane in the form of a solid substance.

Example 6

Synthesis of 5- (4-perbenzoic) -6-cyano-2-methylsulfonylmethane

< / BR>
Stage 1

Pyridine (0,38 ml and 4.65 mmole) and triftormetilfullerenov (of 0.39 ml, 2,32 mmole) is added at 0oTo a solution of 5-(4-perbenzoic)-6-hydroxy-2-methylsulfonylmethane (0.4 g, 1.16 mmole) (obtained according to example 2, stage 3) in methylene chloride (10 ml). After 0.5 h, to the reaction mixture an additional amount of pyridine (0,38 ml and 4.65 mmole) and triftormetilfullerenov (of 0.39 ml, 2,32 mmole) and continue mixing. After 0.5 h, to the reaction mixture was added 1 n sodium bisulfate and continue stirring for 30 minutes the Organic layer which are square-0.6 g (yield 90%) of 5-(4-perbenzoic)-6-tripterocalyx-2-methylsulfonylmethane in the form of butter.

Stage 2

A mixture of 5-(4-perbenzoic)-6-tripterocalyx-2-methylsulfonylmethane (2.5 g, 5.2 mmole) (obtained in stage 1), potassium cyanide (0,41 mg, 6.3 mmole) and tetrakis(triphenylphosphine)palladium (0) (0,30 g of 0.26 mmole) in dioxane (50 ml) is refluxed in an argon atmosphere. After 16 h, the reaction mixture was cooled to room temperature, poured into brine and the reaction product is extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified rapid chromatography on silica gel (gradient elution, 10-60% ethyl acetate/hexane) and paracrystalline-live from ethyl acetate/hexane. The result of 1.16 g (yield 63%) of 5-(4-perbenzoic)-6-cyano-2 - methylsulfonylmethane in the form of a solid substance.

According to the method described above in example 6, but replacing 5-(4-perbenzoic)-6-hydroxy-2-methylsulfonylmethane on:

5-benzoyl-6-hydroxy-2-methylsulfonylmethane,

5-(4-chlorobenzoyl)-6-hydroxy-2-methylsulfonylmethane and

5-(2-perbenzoic)-6-hydroxy-2-methylsulfonylmethane,

receive respectively:

5-benzoyl-6-cyano-2-methylsulfonylmethane,

5-(4-chlorobenzoyl)-6-cyano-2-methylsulfonylmethane and

5-(2-f the stage 2 cyanide potassium trimethylaluminum, get 5-(4-perbenzoic)-6-methyl-2-methylsulfonylmethane.

Example 7

The following are examples of pharmaceutical compositions containing the compounds of formula (I).

Tablets

The following components are thoroughly mixed and pressed into tablets with a notch.

Component - Quantity per tablet, mg

The connection according to the invention - 400

Corn starch - 50

Nitrocresols - 25

Lactose - 120

Magnesium stearate - 5

Capsules

The following components are thoroughly mixed and filled capsules hard gelatin shell.

Component - the Amount in one capsule, mg

The connection according to the invention - 200

Lactose, spray dried - 148

Magnesium stearate - 2

Suspension

The following components are mixed, obtaining a suspension for oral administration.

Component - Number

The connection according to the invention - 1.0 g

Fumaric acid 0.5 g

Sodium chloride, 2.0 grams

Methylparaben 0.15 g

Propyl paraben 0.05 g

Granulated sugar - 25,5 g

Sorbitol (70% solution) - is 12.85 g

Gum, Veegum K (Vanderbilt company Co.) - 1.0 g

Flavor - a 0.035 ml

Dyes - 0.5 mg

Dis what I suspension for oral administration.

Component - Number

The connection according to the invention - 0.4 mg

0.4 M Buffer solution of sodium acetate - 2.0 ml

HCl (1 BC) or NaOH (1 ad) - q.s. to the required pH

Water (distilled, sterile) - q.s. to 20 ml

Example 8

Inhibition of YEAR I and YEAR II in vitro

Inhibitory activity of the compounds according to the invention in relation to the COVER I and COVER II in vitro determined on partially purified preparations of the enzyme COVER I and COVER II, obtained in accordance with the method described by J. Barnett and others, Biochim. Biophys. Acta, 1209, 130-139 (1994).

The samples COVER I and COVER II is diluted with Tris-HCl - buffer (50 mm Tris-Hcl, pH 7,9) containing 2 mm etc and 10% glycerol, and restore incubare during the first 5 min with 2 mm phenol, and then for 5 min with 1 µm gelatina. 125 μl of the recovered enzyme SOKH I or YEAR II pre-incubated with shaking in a water bath at room temperature for 10 min with the connection according to the invention, dissolved in 2-15 μl DMSO, or with solvent (control samples). The enzymatic reaction is initiated by adding samples of 25 μl solution of 1-[14C]arachidonic acid (80000-100000 pulse/min/tube; final concentration 20 μm), and then continue incubation for 45 C. Reacts the ku C18Sep-Pak (J. T. Baker, Philipsburg, NJ) in a volume of 1 ml, which is pre-washed with 2-3 ml of methanol and balance 5-6 ml of distilled water. The oxidized reaction products quantitatively elute 3 ml of a mixture acetonitrile/water/acetic acid (50:50:0.1 and about./about.) and radioactivity in the eluates is determined in a scintillation counter.

When testing the specified connection method according to the invention have activity.

Inhibiting activity (expressed as IC50i.e. as the concentration causing 50% inhibition of enzyme activity SOH) of a number of compounds according to the invention in comparison with indomethacin are shown in table.5.

Example 9

Determination of anti-inflammatory activity

Anti-inflammatory activity of the compounds according to the invention is determined by measuring the degree of inhibition of edema in hind paws of rats induced karaganna. Use a modication of the method described in Winter C. A., and others, Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs, Proc. Soc. Exp. Biol. Med., 111, 544-547 (1962). This method is used for primary screening for anti-inflammatory activity most NSAID and is considered to be sufficiently informative to evaluate the effectiveness of Govorov or suspensions in aqueous media, containing 0.9% sodium chloride, 0.5% of sodium salt of carboxymethyl cellulose, 0.4% Polysorbate 80, 0.9% of benzyl alcohol and 97.3% of distilled water. A control group of rats receives water media. After 1 h the animals inject (subplantar region of the right hind paws) 0.05 ml of 0.5% solution of carrageenan (Type IV Lambda, the company Sigma Chemical Co.) in 0.9% saline. After three hours, the rats killed in the atmosphere of carbon dioxide, hind legs cut off at the hip joint, right and left paws weighed. In this case, each animal to determine the increase in weight of the right foot against the weight of the left foot and calculating the mean value for each group. Anti-inflammatory activity of the tested materials expressed as percent inhibition of weight gain hind legs in the experimental group compared with the control group.

When testing the specified connection method according to the invention have activity.

Anti-inflammatory activity (% inhibition) of a number of compounds according to the invention are given in table.6.

Example 10

Inhibition of the synthesis of eicosanoids in vivo

The active compounds according to the invention in relation to inhibition of the synthesis of Eik is nanom ("model air pocket"), using a modification of the method described by Futaki, M., and others, Selective inhibition of NS-398 on prostanoid production in inflamed tissue in the rat Carrageenan Air pouch inflammation, J. Pharm. Pharmacol., 45, 753-755 (1993); Masferrer, J. L., and others, Selective inhibition of inducible cyclooxygenase 2 in vivo is antiflammatory and nonulcerogenic, Proc. Natl. Acad. Soc. USA, 91, 3228-3232 (1994). The test is that in the animal body create air pocket and determine the level of prostaglandin E2in exudate using immunofermentnogo analysis. In General this technique is that male rats anaesthetize a mixture of CO2:O2in the ratio of 60:40, and then aseptically injected subcutaneously (in the middle region of the backrest 20 ml of sterile air. Injection of sterile air causes the formation of subcutaneous "air pocket". The next day the same way in the formed pocket impose additional 10 ml of sterile air. Test materials administered orally in a volume of 1 ml/100 g body weight in the form of solutions or suspensions in aqueous media containing 0.9% sodium chloride, 0.5% of sodium salt of carboxymethyl cellulose, 0.4% Polysorbate 80, 0.9% of benzyl alcohol and 97.3% of distilled water. A control group of rats receives water media. After 30 min in air pocket inject 5 ml of 0.5% solution karatancheva 10 mg/l of indomethacin and 5.4 mm add in 0.9% sterile saline solution, and air pocket cut, collecting exudate for further analysis. Measure the total volume of exudate and in the obtained samples determine the content of prostaglandin2(G2) and 6-ketoprostaglandin F1(PGF1method ELISA with a set of reagents Titerzyme (firm PerSeptive Diagnostics, Boston, MA), and DV2determined by radioimmunoassay (firm New England Nuclear Research, Boston, MA, catalogue number NEK-037) according to the recommendations of the manufacturer.

Calculate the average concentrations of G2for each group of animals. Anti-inflammatory activity of test compounds is expressed as the percentage inhibition of the formation of PGE2in the experimental group compared with the control group.

When testing the specified connection method according to the invention have activity.

Anti-inflammatory activity (% inhibition of the formation of PGE2in an air pocket) of a number of compounds according to the invention in comparison with indomethacin are shown in table.7.

Example 11

Determination of analgesic activity

Analgesic activity of the compounds according to the invention is determined using a modication of the method described by Randall L. O., J. J. Selitto, A method for measynthesis inhibitor, J. Pharmacol. Exp. Ther., 254, 1, 180 (1990). In this test, male rats Sprague Dawley inject (subplantar region of the left hind foot) of 0.1 ml of 20% related to Baker's yeast in Leonidovna water (firm Sigma, St. Louis). After 2 h the animals orally administered test materials in a volume of 1 ml/100 g body weight in the form of a suspension or solution containing 0.9% sodium chloride, 0.5% of sodium salt of carboxymethyl cellulose, 0.4% Polysorbate 80, 0.9% of benzyl alcohol and 97.3% of distilled water. A control group of rats receives water media. After 1 h the rear legs of the animal are placed on the platform of the device for measuring analyzing effect Basile Analgesy-Meter (firm Ugo Biological Research Apparatus, Model 7200, Italy) and at the rear region of the rear legs have a mechanical effect. Compounds according to the invention have activity when tested in this way.

In addition, the analgesic activity of the compounds according to the invention can be defined on the model of adjuvant-induced arthritic pain in rats, when pain is assessed according to the individual response of an animal to compression or bending inflamed ankle joint, as described in Winter C. A., G. W. Nuss, Treatment of adjuvant arthritis in rats with antiinflammatory drugs, Arthritis Rheum., 9, 394-403 (1966); Winter, C. A., P. J. Kling, D. J. Tocco, Tanabe K., P> Although the present invention is described above with specific examples of its implementation, for specialists in the art it is obvious that it can be made various changes and modifications within the scope of the attached claims. Therefore, it should be noted that the above description is only illustrative purposes, explaining the essence of the present invention and does not limit its scope. Thus, the scope of the invention is defined not by the above description and attached claims, including all possible equivalents. Test data are presented in table.8.

1. Derivatives of 5-areolation formula I:

< / BR>
in which a represents-CH2-, -C(O)- or-S(O)2-;

Z means a group of formula b or D:

< / BR>
where X is O or S;

R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl;

R1means hydrogen, C1-C6alkyl, C1- <)2, -NR9R10, -NR9R10or SO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3;

R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy2-C6alkyl, C1-C6alkoxy-C1-C6alkyl,

WITH1-C6alkoxycarbonyl-C1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino;

and their pharmaceutically acceptable salts, or esters or carbamates, individual isomers and mixture of isomers.

-SO2- C1-C6alkyl or-SO2OTHER14where R14means hydrogen, C1-C6alkyl or 2-hydroxyethyl.

4. The compound according to any one of paragraphs. 1-3, in which R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen or cyano; R6and R7independently of one another denote hydrogen, C1-C6alkyl, C1-C6alkoxy or halogen.

5. Connection on p. 4, in which R1means hydrogen, methyl, hydroxy, methoxy, chlorine or cyano, and R3means SO2IU or SO2NH2.

6. The compound according to any one of paragraphs.1-5, in which R6and R7independently from each other selected from hydrogen, methyl, methoxy, fluorine and chlorine.

7. The compound according to any one of paragraphs.1-6, in which R6is in position 2, and R7is in position 4, or, when R6is in position 3, and R7is in position 4.

8. Connection on p. 1, which is a 5-benzoyl-6-cyano-2-methylsulfonylmethane.

9. Connection on p. 1, which is 5-(4-perbenzoic)-6-cyano-2-methylsulfonylmethane.

10. Connection on p. 1 is AutoRAE represents 5-(4-perbenzoic)-6-cyano-2-naphthalenesulfonate.

12. Connection on p. 1, which is 5-(3-perbenzoic)-6-methoxy-2-naphthalenesulfonate.

13. Connection on p. 2, in which Z denotes a group of formula D, where X is S, associated with And in position 2 of the ring D.

14. Connection on p. 13, in which R12stands WITH1-C6alkyl; R13denotes hydrogen, and R14denotes hydrogen, C1-C6alkyl or 2-hydroxyethyl.

15. Connection on p. 13 or 14, where R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, 2-hydroxyethoxy, hydroxy, chlorine or cyano.

16. Connection on p. 15, in which R3means-SO2IU or-SO2NH2and R1means hydrogen, methyl, hydroxy, methoxy, chlorine or cyano.

17. The pharmaceutical composition inhibiting enzymatic activity of the prostaglandin G/H synthases I and II (YEAR I and YEAR II) and have anti-inflammatory and analgesic action, containing a pharmaceutically effective amount of a compound according to any one of paragraphs.1-16 and a pharmaceutically acceptable non-toxic excipient.

18. The method of obtaining the compounds of formula I under item 1, in which a represents-C(O)-;

Z means a group of the formula; where R6and R7UP>12stands WITH1-C6alkyl;

R1denotes hydroxy, cyano, C1-C6alkoxy;

R2denotes hydrogen;

namely, that the connection formulas

< / BR>
where R1, R2and R12have the meanings specified above,

subjected to interaction with allermuir agent of the formula ZC(O)L, where L is a leaving group under the reaction conditions of acylation, and Z have the above meaning, with subsequent optional conversion of the group R1in one of its other values.

19. The compound according to any one of paragraphs.1-16, inhibiting enzymatic activity of the prostaglandin G/H synthases I and II (YEAR I and YEAR II) and have anti-inflammatory and analgesic activity.

20. The compound according to any one of paragraphs.1-16, intended for the manufacture of a drug with anti-inflammatory action.

 

Same patents:

The invention relates to the use of compounds of the type of retinoids as active agents in cosmetic compositions or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors PPK and/or hypervitaminosis A

,-unsaturated ketones aromatic or heteroaromatic number" target="_blank">

The invention relates to synthetic organic chemistry, and in particular to methods of obtaining,unsaturated carbonyl compounds, aromatic and heterocyclic series, many of which are biologically active, and are widely used as intermediates for the synthesis of diverse heterocyclic and other hard-to-reach connections

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of railbirding formula I, where X and Y independently of one another denote N or CH; ring a is an unsubstituted or substituted benzene ring, or their salts

The invention relates to 4-amino-1-piperidinecarbonitrile formula (I):

< / BR>
where R1and R2each independently of one another denote H, A, Ph, Ph-ALK, CO-A, CO-Het, or known of the chemistry of protective peptides for amino group;

R1and R2together also denote alkylene with 4-5 C atoms, and one or two CH2- groups may be replaced by-O-, -S-, -CO-, -NH-, -NA - and/or N-CH2-Ph and, if necessary, the benzene ring may be precondensation so that the formed dihydroindole, tetrahydropyrimidines, tetrahydroisoquinolinium or dehydrobenzperidol the rest;

R3and R4each independently of one another denote H, A, Gal, -X-R5, CN, NO2, CF3CH2-CF3, SOn-R7or SO2-NR5R6;

R5denotes H, A, CF3CH2-CF3Ph, Ph-alk, C5-C7- cycloalkyl or C5-C7-cycloalkyl-alk;

R6denotes H or A, or

R5and R6together also denote alkylene with 4-5 C atoms, and one CH2group can be replaced by-O-, -S-, -NH-or-N-CH2-Ph;

R7denotes A or Romani;

Gal denotes F, Cl, Br or I;

Ph denotes unsubstituted or one-or two-, or three times substituted by A, OA, Gal, CF3, NH2, NHA or NA2phenyl;

Het denotes a saturated or unsaturated five - or six-membered heterocyclic residue with 1 to 4 atoms of nitrogen, oxygen and/or sulfur; and

"n" represents 1 or 2;

and their physiologically acceptable salts

The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts

The invention relates to ortho-substituted derivatives alkylbenzoates formula I

< / BR>
R1means A or Hal,

Alk means C1-C8-alkyl branched or unbranched chain C3-C8-cycloalkyl,

A represents C1-C6-alkyl,

Hal is F, Cl, Br or I,

and their pharmaceutically acceptable salts

The invention relates to derived hydroxyethylaminophenol formulas I, II, III, where R is phenyl-C1-C8alkoxycarbonyl, where phenyl may be substituted C1-C8alkoxy; chinainternational, mono - or di-C1-C8alkylamino-C1-C8alkanoyl; R' is H, C1-C8alkyl; R1- H, C1-C8alkyl, C2-C8alkenyl, -C(O)NH2CH2C(O)NH2, -CH2C(O)NHCH3C(CH3)2(SCH3), amino acid side chain, such as glycine; R1'and R1"both - H; R2- phenyl-C1-C8alkyl; R3- H, C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C2-C8alkenyl; R4- C1-C8alkyl, phenyl, methoxyphenyl; R6Is H; Y Is O; x = 1, 2; t = 0 or 1

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl, X represents nitrogen or CH, m is 0, 1 or 2, n is 0, 1 or 2, and

The invention relates to benzoylpyridine General formula (I)

(I)

where R(1) means hydrogen or R(5) - SOm,

m means 0, 1 or 2,

R(5) means (C1-C8)-alkyl,

R(2) means-CF2R(14), -CF[R(15)][R(16)],

R(14) means (C1-C4)-alkyl,

R(3) is defined as R(1),

R(4) means hydrogen, -(CH2)s-(CF2)t-CF3,

s denotes 0 or 1, t is 0, 1 or 2,

and their pharmaceutically compatible salts

The invention relates to ortho-substituted derivatives alkylbenzoates formula I

< / BR>
R1means A or Hal,

Alk means C1-C8-alkyl branched or unbranched chain C3-C8-cycloalkyl,

A represents C1-C6-alkyl,

Hal is F, Cl, Br or I,

and their pharmaceutically acceptable salts
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