Novel compounds possessing anti-inflammatory activity and pharmaceutical compositions comprising thereof

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R1 represents alkyl; R2 represents halogen atom, formyl, substituted or unsubstituted alkyl, hydroxyl, (C1-C6)-alkoxy-group, halogenalkyl; or R and R2 in common with atom to which they are bound form unsubstituted 5-7-membered structure of the formula: -CH2-(CH2)nS- wherein n = 1 or 2; R3 represents hydrogen atom, halogen atom or alkyl; R4 represents alkoxy-group or unsubstituted aryl or aryl substituted with halogen atom, (C1-C6)-alkyl, halogenated (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl; R5 represents hydrogen atom, hydroxyl, alkyl, alkenyl or alkoxy-group; R6 represents hydrogen atom or alkyl; or R5 and R6 represent in common =O; X represents oxygen atom or -NR8 wherein R8 represents aryl substituted with halogen atom; m means a whole number in the range from 0 to 2, and its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on these compounds, method for treatment of diseases mediated by cyclooxygenase and to a method for inhibition of cyclooxygenase activity in cells. Invention provides preparing novel compounds possessing valuable biological effect.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

11 cl, 98 ex

 

The present invention relates to new anti-inflammatory compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutically acceptable compositions. In particular, the present invention relates to new heterocyclic compounds of General formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutically acceptable compositions.

where R1represents amino or substituted or unsubstituted group selected from alkyl, alkylamino, acylamino, cycloalkyl, cycloamino, carbomethoxybiphenyl, hydrazino, hydrazido, amino acid residue, aryl, heteroaryl or-N=CR(NR)2where R represents hydrogen or a lower alkyl group; R2represents halogen, hydroxy, cyano, nitro, azido, formyl, axemaker, thio, or substituted or unsubstituted group selected from amino, alkyl, alkoxy, hydrazino, hydrazinolysis, hydrazido, hydrazinolysis, amino acid balance, alkylaminocarbonyl OST the ka, alkyl, acyl, carbonylcyanide, halogenoalkanes, aminoalkyl, halogenoalkane, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfanyl, aryl, Uralkaliy, aryloxy, Alcoxy, aryloxyalkyl, alcoxialchil, carboxymethylcellulose, carboalumination groups, or, when the group-S(=O)m-R1and R2are neighboring carbon atoms, R1and R2together with the atoms to which they are attached, can also form a substituted or unsubstituted 5-7-membered cyclic structure containing carbon atoms, a sulfur atom and may optionally contain one or two heteroatoms selected from O, S or N; R3represents hydrogen, halogen atom, hydroxy, nitro, cyano, azido or substituted or unsubstituted group selected from hydrazine, hydrazinolysis, hydrazido, hydrazinolysis, amino acid residue, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, acylamino or amino; R4and R5may be the same or different and independently represent hydrogen, halogen, hydroxy, cyano, nitro, thio, hydroxylamino, a substituted or unsubstituted group selected from alkyl, alkoxy, acyl, acyloxy, amino, hydrazino, hydrazinolysis, hydrazido, hydroidolina, amino is slotnik residues, the aminoacyl, carboxyethyl, carboxyethyl, aryl, aryloxy, aralkyl, Alcoxy, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, heteroaryl, heteroaromatic, heteroalkyl, heteroaromatic, heteroarylboronic, heteroarylboronic, heteroarylboronic, heteroarylboronic, geterotsiklicheskikh, aminocarbonyl, aminocarbonylmethyl, carbylamine,cycloalkylation, acylaminoalkyl, acylaminoacyl, carboxylic acid or its derivatives, saturated or partially saturated unfused aromatic or condensed 5-7-membered carbocyclic ring or a saturated or partially saturated or aromatic, unfused or condensed 5-7-membered heterocyclic ring; R6represents hydrogen, halogen, hydroxy, amino, cyano, nitro, thio, hydroxylamino or unsubstituted or substituted group selected from alkyl, alkoxy, carboxyethyl; and furanone ring, if possible, may be condensed with R4, R5and R6together may represent a =C(Ra)(Rb), where Raand Rbmay be the same or different and independently represent hydrogen, substituted or unsubstituted (C1-C6)alkyl or aryl; =O or =NR7where R7the submitted is a hydrogen, aryl or heteroaryl group; X represents oxygen or NR8where R8represents hydrogen or unsubstituted or substituted group selected from (C1-C6)alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, alalcnoolo, alcanol, and m is an integer from 0 to 2.

The present invention also relates to a method for producing the above novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvate containing pharmaceutical compositions.

The present invention also relates to novel intermediate compounds, methods for their preparation and their use for producing compounds (I).

Compounds of General formula (I) are useful as anti-inflammatory, analgesic, antipyretic, anti-arthritis, anti-bacterial, anti-tumor agents or for the treatment of Alzheimer's disease. Compounds of the present invention is also useful for the treatment of human or animal diseases, such as pain, fever or inflammation. The compounds of formula (I) also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may COI is to Lisovets for the treatment of dysmenorrhea premature birth and asthma. Compounds of the present invention are useful for the treatment of pain, fever and inflammation associated with common colds, flu, viral infections. Compounds of the present invention can be used for the treatment of arthritis, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, spondylosis arthritis, systemic lupus erythematosus, inflammatory skin diseases such as eczema, burns, dermatitis, psoriasis; pain in lower back and neck, headache, toothache, sprains, strains, myositis, neuralgia, synovitis, bursitis, tendonitis, injuries from surgical and dental procedures, postoperative inflammation, including ophthalmic surgery such as cataract and refractive surgery.

Compounds of General formula (I) are also useful for the treatment of dysmenorrhea, premature labor, asthma and bronchitis, gastrointestinal diseases such as syndrome of inflamed bowel, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, diverticulitis, regional enteritis, gastric ulcer. These compounds can also be used to treat inflammatory diseases such as vascular diseases, migraleve headaches, periarteritis nodosa, thyroiditis, aplastic anemia syndrome B is hcat, Hodgkin's disease, scleroderma, severe myasthenia gravis, sarcoidosis, nephrotic syndrome, diabetes type I, polymyositis, conjunctivitis, gingivitis, myocardial ischemia, nephritis, post-traumatic edema, allergies and the like. Compounds of the present invention are useful for the treatment of allergic rhinitis, respiratory distress syndrome, syndrome, endotoxic shock, atherosclerosis and damage to the Central nervous system as a result of shock, ischemia and trauma, pulmonary inflammation, such as in the case of viral infections and cystic fibrosis; ophthalmic diseases such as retinitis, retinopathy, uoit, ocular photophobia, and of acute injury to the eye tissue. Compounds of General formula (I) are also useful for the treatment of diseases of the Central nervous system, such as cortical dementia (Alzheimer's), they are also useful for the treatment of pain, not limited to dental pain, muscle pain, pain and cancer pain, postoperative pain, and useful for treatment of diseases where NPLS used to significantly reduce the side effects.

Compounds of General formula (I) are inhibitors of cyclooxygenase and thus useful for treating diseases mediated by cyclooxygenase. The compounds of formula (I) are also useful for treatment of mammals (not limited to), such as horses, dogs, cats, sheep, pigs, etc. and also for the treatment of rats, mice, rabbits, etc. of Compounds of formula (I) can also be used in joint therapy for the treatment of inflammation, Alzheimer's disease or cancer, instead of, or along with conventional medicines.

Compounds of General formula (I) useful as a partial or complete substitute for NPLS in the compositions or preparations in which they are currently employed in combination with other agents or ingredients. The present invention also includes pharmaceutical compositions for treating diseases mediated by cyclooxygenase, as described above, including non-toxic therapeutically effective amount of the compounds of formula (I)as defined above, and pharmaceutically acceptable carrier, optionally containing one or more ingredients such as another analgesic agent, such as acetaminophen, phenacetin, potentiate substance, such as caffeine, an antagonist of N2the aluminum hydroxide or magnesium, simethicone, a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, Oxymetazoline, epinephrine, naphazoline, propylhexedrine or levocetirizine, Xylometazoline, sedative or nesecarily antihistamine agents against cough suppressant such as dextromethorphan, carbetapentane, caramiphen, hydrocodoe and codeine and the like, or diuretic. The present invention also includes a method of treating diseases mediated by cyclooxygenase, including placing a patient in need, a non-toxic therapeutically effective amount of the compounds of formula (I) or pharmaceutical compositions described above.

The level of technology

Nonsteroidal anti-inflammatory drugs (NPLS) are widely used for the treatment of arthritis and pain. These agents act by inhibiting the production of prostaglandin, which plays an important role in the inflammatory process. The prostaglandin synthesis is inhibited by blocking the enzyme cyclooxygenase (SOH) (Vane, J. R. Nature [New Biol.] 1971, 231-232). However, these NPLS how it was discovered, though reduce inflammation and associated symptoms induced by prostaglandin also act on prostaglandin, which regulates other processes, causing adverse effects [Allison M. S., and others, J. Med. 1992, 327, 749]. Side effects, manifested NPLS are hypersecretion and heartburn, blockade of platelet aggregation, inhibition uterine, contractility, inhibition of prostaglandin, which regulates renal function and allergic reactions.

It was recently discovered that there are two isoforms of the cyclooxygenase enzyme, namely MOR-1 and MOR-2. Although MOR-1 is the main what sopornoy, found in blood vessels, stomach and kidneys, SOH-2 is produced in the process of inflammation. Therefore, selective inhibition of the enzyme SOH-2 may be useful for treatment of inflammation without the side effects caused by inhibition of MOR-1.

On the other hand, leukotrienes are mediators of inflammation and related diseases. Leukotrienes (LTB4, LTC4, LTD4, and so on) are produced at 5-lipoxygenase-mediated oxidation of arachidonic acid. Therefore, inhibition of the enzyme 5-lipoxygenase (5-LO) may also be useful for treatment of inflammation and related diseases. Consequently, it is possible the treatment of inflammatory agents that can selectively inhibit SOH-2 or 5-LO or both of them without the occurrence of possible side effects that occur with continuous treatment normal NPLS.

Recently it was shown that in tumors of the colon is an increase in the expression of MOR-2. Therefore, agents that can inhibit SOH-2, can also be used to treat cancer.

Studies have shown that brain tissue of patients with Alzheimer's disease often have high levels of MOR-2. This shows the suitability of using SOH-2 inhibitors for treatment of Alzheimer's disease and to improve memory.

Reported on some heterocyclic connect the developments, their derivatives and their analogs are useful for the treatment of inflammation. Some of these compounds are described in the prior art, is shown below.

(i) WO 97/34882 describes compounds of General formula (IIa)

where R1represents alkyl or the group NR4R5where R4and R5each independently represents hydrogen or alkyl or benzyl group; R2represents naphthyl, tetrahydronaphthyl, unsubstituted phenyl or a phenyl group substituted by 1-3 halogen atoms, alkyl, hydroxy, alkoxy or triptoreline groups, and R3represents a hydrogen or alkyl group. Examples of these compounds are shown in formula (IIb)

(ii) DE 19753463 describes compounds of the formula (IIc)

where R1represents hydrogen, alkoxycarbonyl, carboxy, halogen, alkyl, phenyl or alkanoyl; R2, R3and R4represent hydrogen, alkyl, alkoxy or halogen; X represents an alkyl or NH2.

An example of such compounds is the compound of formula (IId)

(iii) WO 95/00501 describes compounds of the formula (IIe)

where Y-Z is selected from the group consisting of-CH2CH2CH2-, -C(O)CH CH2-, -CH2CH2C(O)-, CR5(R5)-O-C(O)-, -C(O)-O-CR5(R5'), CH2-NR3-CH2-, CR5(R5')-NR3-C(O)-, -CR4=CR4'-S-, -S-CR4=CR4'-, -S,-N=CH-, -CH=N-S-, -N=CR4-O-, -O-CR4=N-, -N=CR4-NH-, -N=CR4-S-, -S-CR4=N-, -C(O)-NR3-CR5(R5')-, -NR3-CH=CH-, provided that R1is not-S(O)2Me, -CH=CH-NR3-, provided that R is not-S(O)2Me; when side b is a double bond, and sides a and C are simply connected and X-Y-Z is selected from the group consisting of =CH-O-CH=, =CH-NR3-CH=, =N-S-CH=, =CH-S-N=, =N-O-CH=, =CH-O-N=, =N-S-N=, =N-O-N=, when sides a and C are double bonds and side b is a simple bond; R' is chosen from the group consisting of S(O)2CH3, S(O)2NH2, S(O)2NHC(O)CF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHC(O)CF3, P(O)(CH3HE and P(O)(CH3)NH2; R2selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl; mono, di or trisemester phenyl, where the Deputy is chosen from the group consisting of hydrogen, halogen, (C1-C6) alkoxy, (C1-C6)alkylthio, CN, CF3, (C1-C6)alkyl, N3, -CO2H, -CO2-(C1-C4)alkyl, -C(R5)(R6)-OH, -C(R5)(R6)-O-(C1-C4)alkyl and -(C1-C6)is lcil-CO 2-R5; mono, di or trisemester of heteroaryl where heteroaryl represents a monocyclic aromatic ring of 5 atoms, with the specified ring has one heteroatom, which represents S, O or N, and optionally 1, 2, 3, or 4 additional N atoms, the said substituents are selected from the group consisting of hydrogen, halogen, including fluorine, chlorine, bromine and iodine, (C1-C6)alkyl, (C1-C6)alkoxy, ( C1-C6)alkylthio, CN, CF3N3-C(R5)(R6)-And-C(R5)(R6)-O-(C1-C4)alkyl; R3selected from the group consisting of hydrogen, CF3CN, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, -C(O)-(C1-C6)alkyl and optionally substituted -(C1-C5)alkyl-Q -(C1-C3)alkyl-O-(C1-C3)alkyl-Q -(C1-C3)alkyl-S-(C1-C3)alkyl-Q -(C1-C5)alkyl-O-Q or -(C1-C5)alkyl-S-Q, where the substituents are alkyl, and the Deputy is a (C1-C3)alkyl; or R3represents-Q; R4and R4each independently selected from the group consisting of hydrogen, CF3CN, (C1-C6)alkyl, -Q-O-Q, -S,-Q, and optionally substituted (C1-C5)alkyl-Q, -O-(C1-C5)alkyl-Q-S-(C1-C5)alkyl-Q -(C1-C3 )alkyl-O-(C1-C3)alkyl-Q -(C1-C3)alkyl-S-(C1-C3)alkyl-Q -(C1-C5)alkyl-O-Q or -(C1-C5)alkyl-S-Q, where the substituents are alkyl, and the Deputy is a (C1-C3)alkyl; and R5, R5′, R6, R7and R8each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, or R5, R5′, R6, R7and R8together with the carbon to which they are attached, form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms. Q is a CO2N, CO2-(C1-C4)alkyl, tetrazolyl-5-yl, C(R7)(R8)(OH) or C(R7)(R8)-O-(C1-C4)alkyl; provided that when X-Y-Z represents S-CR4=CR4'then R4and R4'are non-CF3.

An example of such compounds is the compound of formula (IIf)

(iv) WO 96/384312 describes compounds of the formula (IIg)

where a represents a 5 - or 6-membered ring Deputy selected from partially unsaturated heterocyclic and carbocyclic rings, And may be optionally substituted by a radical selected from acyl, halogen, alkyl, halogenoalkane, cyano, nitro, carboxyl, is laksi, oxo, aminocarbonyl, alkoxycarbonyl, carboxyethyl, cyanoalanine and hydroxyalkyl; Y represents a radical selected from hydroxy, thio, sulfinil, sulfonyl, alkyl, alkenyl, quinil, alkyloxy. alkylthio, alkylsulphonyl, cycloalkyl, aryl, halogenoalkane, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkyloxy, hydroxyalkyl, hydroxyalkyloxy, oxygenology, oksiminoalkil, (alkyl)oxygenology, (alkyl)oksiminoalkil, examinatio, oksiminoalkil, (alkyl)examinatio, (alkyl)oksiminoalkil, carbonyloxy, carbonylchloride, carbonrally, carbonylchloride, heterocycle, cycloalkenyl, aralkyl, geterotsiklicheskie, acyl, alkylthiomethyl, alkyloxyalkyl, alkanity, alkylthio, alkenylacyl, alkyloxy, alkenylacyl, alkenylacyl, alkyloxyalkyl, arylcarbamoyl, aralkylamines, aralkyl, alkylresorcinols, alkylresorcinols, alkylresorcinols, alkylresorcinols, halogenoalkane, alkoxyalkyl, alkylaminocarbonyl, heteroatomcontaining, heteroepitaxial, heteroalicyclic, heteroalicyclic, heteroaromatic, heteroalkyl, heteroaromatic, heteroaromatic, alltoall, aryloxyalkyl, halogenoalkanes, kalkiliya, arakaki is Lila, alkoxylalkyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N-arylenecarborane, N,N-dialkylaminoalkyl, N-alkyl-N-arylenecarborane, cycloalkylcarbonyl, heterocyclization, carboxymethylaminomethyl, alkylcarboxylic, alcoxycarboxylates, halogenoalkane, carboxylphenyl, alkoxycarbonylmethyl, aminocarbonylmethyl, alkylaminocarbonyl, N-alkylamino, N,N-dialkylamino, N-arylamino, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-arylamino, aminoalkyl, N-acylaminoalkyl, N,N-dialkylaminoalkyl, N-alluminare, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-alluminare, aminoethoxy, aminoalkoxide, aminoalkylation, aminoalkylsilyl, cycloalkane, cycloalkylation, cycloalkylation, cycloalkylation, aryloxy, Alcoxy, aaltio, Uralkali, alkylsulfonyl, alkylsulfonyl, aminosulfonyl, N-alkylaminocarbonyl, N-arylaminomethylene, arylsulfonyl, N,N-dialkylaminoalkyl, N-alkyl-N-arylaminomethylene, or Y represents the following groups

Ar is selected from aryl and heteroaryl, Ar may be optionally substituted by one or two substituents selected from halogen, guide is oxyl, mercapto, amino, nitro, cyano, carbamoyl, alkyl, alkenylacyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, alkylamino, dialkylamino, halogenoalkane, alkoxycarbonyl, N-allylcarbamate, N,N-dialkylamino, alkanolamine, cyanoethoxy, carbamoylphenoxy, alkoxycarbonyl and

where R1represents one or more substituents selected from heterocycle, cycloalkyl, cycloalkenyl and aryl, R1may be optionally substituted at substitutable position by one or more radicals selected from alkyl, halogenoalkane, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, halogenoalkane, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfonyl, halogen, alkoxy, alkylthio; R2selected from alkyl and amino; where R3and R4together form a group of formula-X-1that together with the carbon atom to which b and b1attached, form a ring having 6 ring atoms, where In and In1that may be the same or different, each represents alkylene, and X represents hydroxy, and the ring may include one, two or three substituent which may be the same or different, selected from hydroxyl, alkyl, alkoxy, alkenylacyl, alkyloxy; where R5choose and is hydroxyl, alkoxy, alkylcarboxylic, arylcarboxylic, alkoxycarbonyl, acyl and cyano, where R6choose from hydrido, alkyl, aryl and aralkyl; where R7selected from alkyl, alkoxy, alkenyl and quinil; where R8represents oximino, optionally substituted by alkyl; where n is 0 or 1; provided that Ar is substituted

where R3, R4R5, R8and n are as defined above.

An example of these compounds is a compound of formula (IIh)

(v) WO 96/24585 describes compounds of the formula (IIi)

where R1is halogenated; R2represents aryl, optionally substituted at a suitable position by one or more radicals independently selected from alkylsulfonyl, alkyl, cyano, carboxyl, alkoxycarbonyl, halogenoalkane, hydroxyl, hydroxyalkyl, halogenoalkane, amino, alkylamino, arylamino, nitro, halogen, alkoxy, alkylthio; R3represents aryl, substituted in a suitable position with a radical selected from alkylsulfonyl and sulfamyl, and R4selected from halogen, alkoxy, alkyloxy.

An example of these compounds is a compound of formula (IIj)

(vi) DE 19533643 op is saweet the compounds of formula (IIk)

where a represents O, S or NH; R1represents an optionally substituted cycloalkyl, aryl or heteroaryl; R2represents hydrogen, optionally substituted alkyl, aralkyl, aryl, heteroaryl or (CH2)nX; Z represents CH2CH2CH2CH2CH2CH2CH2CH=CH, CH2CO, NHCO, NHCH2, N=CH, NHCH, CH2CH2NH, CH=CH, C=O, S(O)mor optionally substituted NH; m has a value of 0-2; n has a value of 0-8; X is a halogen, NO2not necessarily replaced IT, SLEEP, COOH, onion, CONHOH, CONH2, SH, S(O)H, SO2H, NH2, NHCOH or NHSO2H or CN; R6represents an optionally substituted (C1-C4)alkyl.

An example of these compounds is a compound of formula (III)

(vii) WO 95/15316 describes compounds of formula (IIm)

where R2choose from hydrido, alkyl, halogenoalkane, alkoxycarbonyl, cyano, cyanoalanine, carboxy, aminocarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl, arylenecarborane, carboxymethylaminomethyl, carboxyethyl, alcoxycarboxylates, aminocarbonylmethyl, alkoxycarbonyl, cyanoalanine and hydroxyalkyl; where R3the choice is up from hydrido, of alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen; R4choose from aralkyl, aryl, cycloalkyl, cycloalkenyl and heterocyclyl, R4represents an optionally substituted at a suitable position of the one or more radicals selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, halogenoalkane, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, halogenoalkane, sulfamyl, heterocycle and amino; provided that R2and R3are not both hydrido; provided that R2is not carboxyla or stands, when R3is hydrido, and when R4represents phenyl; provided that R4is not triazolium, when R2represents methyl; provided that R4is not arukenimon, when R2is carboxyl, aminocarbonyl or etoxycarbonyl; provided that R4is not phenyl when R2represents methyl and R3is carboxyl; and provided that R4is not unsubstituted tanila, when R2represents trifluoromethyl.

An example of these compounds is a compound of formula (IIn)

(viii) WO 96/19462 describes compounds of the formula (II ° series)

where one of R, R1is methylsulfinylphenyl, aminosulphonylphenyl or alkylaminocarbonyl, and the other represents a 5 to 7 carbon cycloalkyl, optionally substituted alkyl, tanila or fullam, optionally substituted by alkyl or halogen; R2represents lower alkyl.

An example of these compounds is a compound of formula (IIp)

The objective of the invention

For the development of new compounds for the treatment and/or prevention of diseases or conditions mediated by cyclooxygenase, more specifically SOH-2 and other related diseases, such as pain, fever or inflammation, inhibition of prostanoid-induced contraction of smooth muscles, for the treatment of Alzheimer's disease, colon cancer, for the treatment of pain, fever and inflammation associated with common colds, flu, viral infections, for the treatment of arthritis, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, spondylodesis arthritis, systemic lupus erythematosus, inflammatory skin diseases, such as eczema, burns, dermatitis, psoriasis; low back pain and neck, dysmenorrhea, headache, toothache, standard test bar who I am chords, strains, myositis, neuralgia, synovitis, bursitis, tendonitis, injuries from surgical and dental procedures, postoperative inflammation, including ophthalmic surgery such as cataract surgery, aimed at the correction of refractive error, with the best efficiency, activity and lower toxicity of the new compounds effective for the treatment of the above diseases. Research in this direction led to the development of compounds of General formula (I).

The main task of the present invention is therefore to provide new compounds and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutical compositions or mixtures thereof.

Another objective of the present invention is to provide new compounds and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutical compositions or their mixtures having enhanced activity, without toxic effect or with reduced toxic effect.

Another task is th present invention is to develop a method of obtaining new compounds and their derivatives of the formula (I), as defined above, their analogs, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvate.

The next task of the present invention to provide pharmaceutical compositions containing compounds of General formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their regioisomers, their polymorphs, their salts, solvate, or a mixture thereof in combination with pharmaceutically acceptable carriers, solvents, diluents and other media normally used in the preparation of such compositions, optionally containing one or more ingredients such as another analgesic agent, like acetaminophen, fenatsetinu, potentiate substance, such as caffeine, an antagonist of N2the aluminum hydroxide or magnesium, simethicone, a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, Oxymetazoline, epinephrine, naphazoline, propylhexedrine or levocetirizine, Xylometazoline, sedative or nesecarily antihistamine agents against cough suppressant such as dextromethorphan, carbetapentane, caramiphen, hydrocodeine and codeine and the like, or a diuretic.

The present invention also relates to a method for treating diseases mediated by cyclooxygenase, including introduced the e patient needy, non-toxic therapeutically effective amount of the compounds of formula (I) or pharmaceutical compositions described above.

The present invention also relates to novel intermediate compounds of formulas (I-1), (I-3), (I-5), (I-7), (II-1), (II-2) and (II-4).

The invention

The present invention relates to a new compound having the General formula (I)

where R1represents amino or substituted or unsubstituted group selected from alkyl, alkylamino, acylamino, cycloalkyl, cyclic amino, carbomethoxybiphenyl, hydrazino, hydrazido, amino acid residue, aryl, heteroaryl or-N=CR(NR)2where R represents hydrogen or a lower alkyl group; R2represents halogen, hydroxy, cyano, nitro, azido, formyl, axemaker, thio, or substituted or unsubstituted group selected from amino, alkyl, alkoxy, hydrazino, hydrazinolysis, hydrazido, hydroidolina, amino acid balance, alkylaminocarbonyl residue, acyl, carbonyloxy, halogenoalkane, aminoalkyl, halogenoalkane, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfanyl, aryl, aralkyl, aryloxy, Alcoxy, aryloxyalkyl, alcoxialchil, carboxamidates, carboalumination group or when the group-S(=O) m-R1and R2are neighboring carbon atoms, R1and R2together with the atoms to which they are attached, can also form a substituted or unsubstituted 5-7-membered cyclic structure containing carbon atoms, a sulfur atom and may optionally contain one or two heteroatoms selected from O, S or N; R3represents hydrogen, halogen atom, hydroxy, nitro, cyano, azido or substituted or unsubstituted group selected from hydrazine, hydrazinolysis, hydrazido, hydroidolina, amino acid residue, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, acylamino or amino groups; R4and R5may be the same or different and independently represent hydrogen, halogen, hydroxy, cyano, nitro, thio, hydroxylamino, a substituted or unsubstituted group selected from alkyl, alkoxy, acyl, acyloxy, amino, hydrazino, hydrazinolysis, hydrazido, hydroidolina, amino acid residues, aminoacyl, carboxyethyl, carboxyethyl, aryl, aryloxy, aralkyl, Alcoxy, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, heteroaryl, heteroaromatic. heteroalkyl, heteroaromatic, heteroarylboronic, heteroarylboronic, heteroarylboronic, heteroarylboronic, geterotsiklicheskikh, aminocarbonyl, aminocarbonyl is the alkyl, carbylamine, cycloalkylation, acylaminoalkyl, acylaminoacyl, carboxylic acid or its derivatives, saturated or partially saturated or unfused aromatic or condensed 5-7-membered carbocyclic ring or a saturated or partially saturated or aromatic, unfused or condensed 5-7-membered heterocyclic ring; R6represents hydrogen, halogen, hydroxy, amino, cyano, nitro, thio, hydroxylamine or substituted or unsubstituted group selected from alkyl, alkoxy, carboxyethyl; furanone ring may be condensed with R4if possible; R5and R6together may represent a =C(Ra)(Rb), where Raand Rbmay be the same or different and independently represent hydrogen, (C1-C6)alkyl or aryl; =O or-NR7where R7represents hydrogen, aryl or heteroaryl group; X represents oxygen or NR8where R8represents hydrogen or substituted or unsubstituted group selected from (C1-C6)alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, alalcnoolo, alcanol, and m is an integer in the interval from 0 to 2.

Detailed description of the invention

Suitable groups represented the existing R 1can be selected from amino, substituted or unsubstituted linear or branched (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like; and (C1-C6)alkylamino, such as methylamino, ethylamino, propylamino, butylamino, pentylamine, hexylamine and the like, which may be substituted; acylamino, such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC6H5and the like, which may be substituted; and (C3-C8)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which may be substituted; the cyclic amino group such as aziridine, pyrrolidine, piperidine and the like, a cyclic amino group may be substituted; carbomethoxybiphenyl(C1-C6)alkyl groups, such as carbomethoxybiphenyl, carbomethoxybiphenyl, carbomethoxybiphenyl and the like, carbomethoxybiphenyl(C1-C6)alkyl group may be substituted; hydrazine, which may be substituted; hydrazido, which may be substituted; amino acid residues, where the amino acid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; aryl group such the AK phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyrrole, furan, pyridine, thiophene and the like, the heteroaryl group may be substituted; or-N=C(NR)2.

Suitable groups representing R, are selected from hydrogen or (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.

Suitable groups representing R2can be chosen from a halogen atom, such as chlorine, fluorine, bromine or iodine; hydroxy, cyano, nitro, azido, formyl, oxime(C1-C6)alkyl groups, such as oximeter, oximeter, oxypropyl and the like; thio, amino group which may be substituted; substituted or unsubstituted linear or branched (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, ISO-butyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like; and (C1-C6)alkoxy, such as methoxy, ethoxy, propyloxy, bucalossi, out-propyloxy and the like, which may be substituted; hydrazine, which may be substituted; hydrazino(C1-C6)alkyl groups, such as hydrazinolysis, hidradenitis, hydrazinophenyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazido(C1-C6)alkyl, such as hidrosadenitis hydrazides, hydrazinophenyl and the like, which may be substituted; amino acid residue, where the amino acid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; and (C1-C6)alkyl amino acid residue, where the amino acid is the same as defined above, which may be substituted; acyl group such as acetyl, propanol, benzoyl and the like, which may be substituted; carbonyloxy(C1-C6)alkyl groups, such as carbontracker, carbonyloxy, carbonyloxy and the like, which may be substituted; halogen(C1-C6)alkyl such as chloromethyl, bromacil, chloropropyl, chloropropyl and the like, which may be substituted; amino(C1-C6)alkyl, such as aminomethyl, aminoethyl, aminopropyl, linosopril and the like, which may be substituted; halogen(C1-C6)alkoxy, such as chloromethoxy, bromoethoxy, chloropropoxy, bromopropane and the like, which may be substituted; hydroxy(C1-C6)alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like, which may be substituted; alkoxy(C1-C6)alkyl groups, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; the IO(C 1-C6)alkyl, such as thiomethyl, thioethyl, thiopropyl, diisopropyl and the like, which may be substituted; and (C1-C6)alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio and the like, which may be substituted; and (C1-C6)alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, butylsulfonyl and the like, (C1-C6)alkylsulfonyl group may be substituted, (C1-C6)alkylsulphonyl, such as methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, butylsulfonyl and the like, (C1-C6)alkylsulfonyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl, such as benzyl, phenethyl,6H5CH2CH2CH2naphthylmethyl and the like, kalkilya group may be substituted; alloctype, such as phenoxy, naphthyloxy and the like, alloctype may be substituted; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy and the like, which may be substituted; aryloxyalkyl group, such as6H5Och2With6H5OCH2CH2naphthylacetyl and the like, which may be substituted; and alkoxyalkyl group, such as6H5CH2Och2With6H5CH2OCH2CH2and the like, which may be substituted; carboxamido(C1-C6)alkyl, such as carboxymethyl, carboxamidates, carboxypropyl and the like, carboxamido(C1-C6)alkyl group may be substituted; carbylamine(C1-C6)alkyl groups, such as carbonylmethyl, carbonylmethyl, carbonylmethyl and the like, carbylamine(C1-C6)alkyl may be substituted.

When R1and R2together form a cyclic structure, R1and R2together represent substituted or unsubstituted-NH-C(=O)-(CH2)n-, -CH2-(CH2)n-, -(CH2)n-C(=O)-, -CH2-C(=O)-CH2-, -NH-(CH2)n-, -NH-C(=O)-, -NH-(CH2)n-C(=O)-, -(CH2)n-C(=O)-NH-, -NH-(CH2)n-O-, -NH-(CH2)n-S-, -CH2-(CH2)n-O-, -CH2-(CH2)n-S-, where n is an integer in the range of 1-2.

The substituents at R1and R2can be selected from hydroxy, linear or branched (C1-C6)alkyl, (C1-C6)alkoxy, aryl, aralkyl, Alcoxy, acyl, heteroaryl, such as pyridyl, furyl, thiophenyl, oxazolyl and the like; heteroalkyl, such as pyridylmethyl, pyridylethyl, furans the Tyl, purinethol and the like; heterocyclyl, such as morpholinyl, piperidinyl, piperazinil, pyrrolidinyl, dihydro-3-oxo-1,1-dioxo-benzo[b]isothiazole, benzisothiazole, benzothiazolyl and the like; sulfonyl, (C1-C6)alkylsulfonyl, arylsulfonyl, such as phenylsulfonyl, naphthylmethyl and the like; and (C1-C6)alkylsulfonyl, arylsulfonyl, such as phenylsulfinyl, naphthylmethyl and the like; where the alkyl and aryl groups may be substituted by hydroxy, a halogen atom, such as chlorine, fluorine, bromine or iodine; nitro or amino.

Suitable groups representing R3can be selected from hydrogen, halogen atom such as chlorine, fluorine, bromine or iodine; hydroxy, nitro, cyano, azido, hydrazino, which may be substituted; hydrazino(C1-C6)alkyl groups, such as hydrazinolysis, hidradenitis, hydrazinophenyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazido(C1-C6)alkyl, such as hidrosadenitis, hydrazides, hydrazinophenyl and the like, which may be substituted; amino acid residues, where the amino acid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; a linear or branched (C1-C6)alkyl group such as methyl, ethyl, n-ropel, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like, which may be substituted; and (C1-C6)alkoxy, such as methoxy, ethoxy, propyloxy, bucalossi, out-propyloxy and the like, which may be substituted; hydroxy(C1-C6)alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and the like, which may be substituted; and (C1-C6)alkoxy(C1-C6)alkyl groups, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropan and the like, which may be substituted; acylamino, such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC6H5and the like, which may be substituted; amino group which may be substituted.

Suitable groups representing R4and R5can be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, thio, hydroxylamine, substituted or unsubstituted linear or branched (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like; and (C1-C6)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, (C1-C6) alkoxygroup may be substituted; acyl gr is PPI, such as formyl, acetyl, propanol, benzoyl and the like; acyl group may be substituted; alloctype, such as the Osom OCOEt, OCOPh and the like, alloctype may be substituted; amino group Mercator may be substituted; hydrazine, which may be substituted; hydrazino(C1-C6)alkyl groups, such as hydrazinolysis, hidradenitis, hydrazinophenyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazido(C1-C6)alkyl, such as hidrosadenitis, hydrazides, hydrazinophenyl and the like, which may be substituted; amino acid residues, where the amino acid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; aminoacyl, such as aminoacetyl, aminopropanol, aminobutanol and the like, which may be substituted; carboxy(C1-C6)alkyl, such as carboxymethoxy, carboxyethyl, carboxypropyl and the like, which may be substituted; carboxy(C2-C6)alkenyl, such as carboxyethyl, carboxypropyl, carboxybutyl and the like, which may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; alloctype, such as phenoxy, naphthyloxy and the like, alloctype may be substituted; and the of alkyl, such as benzyl, phenethyl, C6H5CH2CH2CH2naphthylmethyl and the like, kalkilya group may be substituted; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy and the like, which may be substituted; and (C1-C6)alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and the like, (C1-C6)alkoxycarbonyl may be substituted; aryloxyalkyl, such as phenoxycarbonyl, naphthalocyanines and the like, which may be substituted; alcoxycarbenium groups, such as benzyloxycarbonyl, ventilatsioonil, naphthylenediamine and the like, which may be substituted; aminocarbonyl, which may be substituted; carbylamine, which may be substituted; aminocarbonyl(C1-C6)alkyl, such as aminocarbonylmethyl, aminocarbonylmethyl, aminocarbonylmethyl and the like, aminocarbonyl(C1-C6)alkyl may be substituted; and (C1-C6)alkylamino(C1-C6)alkoxygroup, such as methylaminomethyl, ethyleneoxy, methylenedioxy, Ethylenedioxy, propylaminoethyl and the like, (C1-C6)alkylamino(C1-C6)alkoxygroup may be substituted; and (C1-C6)acylaminoacyl groups, such as metaluminous is l, ethylaminoethanol, methylaminoethanol, ethylaminoethanol and the like, (C1-C6)acylaminoacyl group may be substituted; and (C3-C8)cycloalkylation, such as cyclopropylamino, cyclobutylamine, cyclobutylamine and the like, (C3-C8)cycloalkylcarbonyl may be substituted; substituted or unsubstituted carbocyclic group, such as phenyl, indenyl, indanyl, dihydronaphtho, tetrahydronaphthyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like; heteroaryl and heterocyclic groups such as pyrrolyl, pyrrolidinyl, furyl, dihydrofuran, tetrahydrofuran, furanones, benzofuran, dihydrobenzofuran, benzofuranyl, thienyl, benzothiazyl, dihydrobenzofuranyl, thiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, pyrazolyl, oxazolyl, isooxazolyl, benzoxazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, indolyl, isoindolyl, indolinyl, dihydroindolone, dihydroindolone, isoindolines, pyranyl, benzopyranyl, dihydrobenzofuranyl, tetrahydropyranyl, diazines, triazines, tetrazines, pyridyl, piperidinyl, piperidinyl, pyridinyl, pyrazinyl, piperazinil, morpholinyl, chinoline, dihydroquinoline, oxazinyl, benzoxazines, dihydroisoxazole, TIA is inil, benzothiazines, dihydrobenzofuranyl, hintline, dihydroquinazolines, phthalazine, dihydrophenazine, honokalani, dihydrobenzofuranyl-1-oxide, dihydrobenzofuranyl-1,1-dioxide, which may be substituted; geterotsiklicheskikh groups, such as pyrrolidinylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, piperazinylcarbonyl and the like, heterocyclic group may be substituted; heteroaryl carbonyl group, such as pyridylcarbonyl, thienylboronic, fullcarbon, pyrrolidinones, oxazolidinones, thiazolidinones, oxadiazolidine, thiadiazolidine, tetrachlorocarbon and the like, the heteroaryl group may be substituted; heteroaromatic, heteroalkyl, such as pyridylmethyl, pyridylethyl, furanosyl, and paranatal similar; heteroaromatic, heteroarylboronic, heteroarylboronic, heteroarylboronic, where heteroaryl and heteroalkyl groups are as defined above, which may be substituted; carboxylic acid or its derivatives such as amides, such CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like.

Suitable substituents for the groups representing R4and R5choose from a halogen atom, such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, optionally halogenated(C 1-C6)alkyl, optionally halogenated (C1-C3)alkoxy, acyl, amino, acylamino, (C3-C8)cycloalkyl, (C3-C8)cycloalkene, aryl, aryloxy, aralkyl, Alcoxy, heteroaryl, heterocyclyl, such as morpholinyl, piperidinyl, piperazinil, pyrrolidinyl and the like; heteroaromatic, heteroalkyl, heteroaromatic, heteroarylboronic, heteroarylboronic, heteroarylboronic, heteroatomcontaining, acyloxy, (C1-C6)alkoxycarbonyl, aryloxyalkyl. arylcarbamoyl, mono(C1-C6)alkylamino, such as methylamino, ethylamino, isopropylamino and the like, (C1-C6)dialkylamino, such as dimethylamino, methylethylamine and the like; arylamino, such as phenylamino, naphthylamine and the like; aralkylamines, such as benzylamine, phenethylamine and the like; amino(C1-C6)alkyl, such as aminomethyl, aminoethyl, linosopril and the like; hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, such as methoxymethyl, methoxyethyl, ethoxypropan and the like; aryloxy(C1-C6)alkyl, such as phenoxymethyl, phenoxyethyl, naphthylacetyl, naphthylacetyl and the like; arakaki(C1-C6)alkyl, such as be siloxanes, benzyloxyethyl, genetoxicity, pentoxide and the like; and (C1-C6)alkoxycarbonyl, such as methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl and the like; aryloxypropanolamine, such as phenoxycarbonylamino, naphthalenemethylamine, alcoxycarbenium, such as benzyloxycarbonylamino, penetrationonline and the like; thio, thio(C1-C6)alkyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, butylsulfonyl and the like; and (C1-C6)alkylsulphonyl, such as methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, butylsulfonyl and the like; sulfonic acid or its derivatives, such as SO2NH2, SO2NHMe, SO2NMe2, SO2NHEt, SO2NEt2and the like; or a carboxylic acid or its derivatives such as amides, such as CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like; the substituents for the groups are the same as defined for R4and R5.

Suitable groups representing R6choose from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, amino, cyano, nitro, thio, hydroxylamino, linear or branched (C1 -C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like, (C1-C6)alkyl group may be substituted; and (C1-C6)alkoxy, such as methoxy, ethoxy, propyloxy, bucalossi, out-propyloxy and the like, (C1-C6)alkoxy group may be substituted; carboxy(C1-C6)alkyl, such as carboxymethyl, carboxyethyl, carboxypropyl and the like, carboxy(C1-C6)alkyl may bipy replaced.

Suitable groups representing Raand Rbchoose from hydrogen or (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like; aryl group such as phenyl, naphthyl and the like.

Suitable groups representing R7choose from hydrogen, aryl groups such as phenyl, naphthyl and the like; heteroaryl group such as pyridyl, furyl, thiophenyl, benzothiazolyl, purinol, benzimidazol, pyrimidinyl, tetrazolyl and the like.

Suitable ring structure formed by the condensation of R4with furanones can be selected from 2,3A,4,5-tetrahydronaphthyl[2,1-b]furan-2-it; 4 thioxo-2,3A,4,5-tetrahydronaphthyl[2,1-b]furan-2-it; 4-imino-2,3A,4,5-tetrahydronaphthyl[2,1-b]furan-2-it, 3A,4,5,6-tetrahydronaphthyl[2,1-b]furan-2-it; 2,3A-dihydro what afto[2,1-b]furanone; 2,3A,4,5-tetrahydronaphthyl[2,1-b]furan-2,4-dione; 2,3A-dihydronaphtho[2,1-b]furan-2,4-dione, 3A,4-dihydro-2H-furo[2,3-C]chromen-2-it, 3A,4-dihydro-2H-furo[2,3-C]chromen-2,4-dione; 2,3A,4,5-tetrahydro-2H-furo[2,3-C]chromen-2-it; 4 thioxo-2,3A,4,5-tetrahydro-2H-furo[2,3-C]chromen-2-it; 4-imino-2,3A,4,5-tetrahydro-2H-furo[2,3-C]chromen-2-it; 2,3A,4,5-tetrahydro-2H-furo[2,3-C]chromen-2,4-dione; 2,3A,4,5-tetrahydrofuro[2,3-C]quinoline-2-it; 2,3A,4,5-tetrahydrofuro[2,3-C]the quinoline-2,4-dione; 8,8A-dihydro-2H-indeno[2,1-b]furan-2-it; 4 dioxo-8,8A-dihydro-2H-indeno[2,1-b]furan-2-it; 4-imino-8,8A-dihydro-2H-indeno[2,1-b]furan-2-it; 2,8A-dihydrobenzo[4,5]thieno[2,3-b]furan-2-it; 2,8A-dihydrobenzo[b]furo[3,2-d]furan-2-it; 8,8A-dihydro-2H-furo[2,3-b]indol-2-it; 8,8A-dihydro-2H-indeno[2,1-b]furan-2-it, 3A,4,5,6-tetrahydro-2H-benzo[3,4]cyclohepta[b]furan-2-it, 3A,4,5,8-tetrahydro-2H-indeno[5,4-b]furan-2-it; 4,5,5A,7-tetrahydro-1H-furo[2,3-g]indole-7-it; 4,5,5A,7-tetrahydrothieno[2',3':3,4]benzo[b]furan-7-it; 4,5,5A,7-tetrahydrofuro[2',3':3,4]benzo[b]furan-7-it.

Suitable groups representing X is selected from oxygen or NR8where R8represents hydrogen or linear or branched (C1-C6)alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like, (C1-C6)alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like is, the aryl group may be substituted; aralkyl, such as benzyl, phenethyl and the like, kalkilya group may be substituted; heteroaryl group such as pyridyl, furyl, thiophenyl, benzothiazolyl, purinol, benzimidazol, pyrimidinyl, tetrazolyl and the like, the heteroaryl group may be substituted; heteroaryl group, such as pyridylmethyl, pyridylethyl, furanosyl, purinethol and the like, heteroalkyl group may be substituted; arancelario group, such as phenylpropenoyl, phenylmethanol, phenylphenol and the like, arancelaria group may be substituted; arachnology group, such as phenylpropanol, phenylmethanol, phenylmethanol and the like, arachnoidea group may be substituted.

The substituents on the R3, R6and R8can be selected from nitro, halogen atom, such as fluorine, chlorine, bromine or iodine; amino, hydroxy, thio or cyano groups.

Pharmaceutically acceptable salts forming part of the present invention include salts derived from inorganic bases such as Li, Na, K, CA, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, geranamine, Isopropylamine, methylglucamine, morpholine, piperazine, Piperi is in, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine, diethanolamine, meglumine, Ethylenediamine, N,N'-diphenylethylenediamine, N,N'-dibenziletilendiaminom, N-benzylpenicillin, choline, kolingerova, dicyclohexylamine, Metformin, benzylamine, phenylethylamine, dialkylamino, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine and the like; chiral bases such as alkylphenolates, glycinol, phenylglycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, Proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine, where the substituents are selected from nitro, amino, alkyl, alkenyl, quinil, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid additive salts, among which are suitable sulfates, nitrates, phosphates, perchlorates, borates, halide, acetates, tartratami, maleate, citrates, succinate, palmoate, methansulfonate, benzoate, salicylates, hydroxynaphthoate, benzoylformate, ascorbate, glycerophosphate, ketoglutarates and the like. Pharmaceutically acceptable solvate may be hydrates or include other the solvents of crystallization, such as alcohols.

Representatives of the compounds obtained in accordance with the method of the present invention may be chosen from:

4-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene-5-yl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3-phenyl-4-(3-methoxy-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-triptoreline)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-tryptophanyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-ethylsulfanyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-chlorophenyl)-3-phenyl-2,5-dihydro-2-furanone;

3-(4-methylsulfinylphenyl)-4-(3-chloro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-chlorophenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-(4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-chlorophenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-chlorophenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-(4-were)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-forfinal)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-chlorophenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-forfinal)-3-(4-were)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-triptoreline)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-triptoreline)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3 -(4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl is)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-forfinal)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-2-chlorophenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-chlorophenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-2-chlorophenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(2,3-dimethyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-sulfanilyl)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-fluoro-4-were)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-ethylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3,4-dimetilfenil)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-bromo-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)3-(1-naphthyl)-2,5-dihydro-2-furanone;

3-(3-methyl-4-methoxyphenyl)-4-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-methyl bromide-4-methylsulfinylphenyl)-3-(4-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

2-{5-[4-(4-forfinal)-2,2-dimethyl-5-oxo-2,5-dihydro-3-furanyl]-2-methylsulfonylbenzoyl}-2,3-dihydrobenzo[d]isothiazol-3-oxo-1,1-dioxide;

4-(2-fluoro-4-methylsulfinylphenyl)-5,5-dimethyl-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-2,5-dihydro-2-furanone;

3-(4-forfinal)-5,5-dimethyl-4-(4-methylsulphonyl-3-morpholinomethyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

3-(3,4-differenl)-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3-(3,5-differenl)-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-is ihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3 isopropoxy-5,5-dimethyl-4-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-hydroxymethyl-4-methylsulfinylphenyl)-3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-5-hydroxy-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-methoxy-3-were)-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

3-(3,4-differenl)-5-ethyl-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3-(3,4-differenl)-5-ethyl-4-(2-fluoro-4-methylsulfinylphenyl)-5-hydroxy-2,5-dihydro-2-furanone;

4-(3-vermeil-4-methylsulfinylphenyl)-3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

3 isopropoxy-5,5-dimethyl-4-(3-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3 isopropoxy-5,5-dimethyl-4-(3-methylsulfanyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3 isopropoxy-4-(3-methoxymethyl-4-methylsulfinylphenyl)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-formyl-4-methylsulfinylphenyl)-3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-hydroxy-2,5-dihydro-2-furanone;

5-ethylidene-4-(2-ft is R-4-methylsulfinylphenyl)-3-(3-forfinal)-2,5-dihydro-2-furanone;

5-ethylidene-4-(2-fluoro-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

5-ethylidene-4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3,4-differenl)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5-methoxy-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-were)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-methoxy-5-methyl-2,5-dihydro-2-furanone;

1-(4-forfinal)-4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-1H-2-atholon;

3-(2-fluoro-4-methylsulfinylphenyl)-1-(4-forfinal)-4-phenyl-2,5-dihydro-1H-2,5-azadian.

Accordingly, compounds of General formula (I), where R1, R2, R3, R4, R5, R6, X and m are as previously defined, can be obtained by any of the following methods shown in the Diagram I:

The interaction of the compounds of formula (I-1) with compound (I-2), or the interaction of the compounds of formula(I-3) with the compound of the formula (I-4), or the interaction of the compounds of formula (I-5) with the compound of the formula (I-6), or the interaction of the compounds of formula (I-7) with the compound of the formula (I-8), where L1is a B(OR)2where R represents hydrogen or (C1-C6)alkyl group, L2represents a halogen atom such as chlorine, bromine or iodine, or other leaving group, such as ZnCl2or triflate, and all other symbols are as defined above, to obtain compounds of formula (I)where all symbols are as defined above, can be carried out in the presence of solvents such as toluene, dimethylformamide (DMF), dioxane, tetrahydrofuran (THF), isopropanol, ethanol, dimethylsulfoxide (DMSO), dichloromethane (DHM), water and the like or their mixtures. The reaction may be conducted in an inert atmosphere, using inert gases such as No, N2, Ar and the like. The reaction may be conducted in the presence of a catalyst, such as bis(triphenylphosphine)palladium (II) chloride, 1,4-bis(diphenylphosphine)palladium(II)chloride, bis(dibenzylideneacetone)palladium(o), palladium acetate, acetate-three(o-tolyl)tofinally, bis(acetonitrile)palladium(II)chloride, palladium on coal + triphenylphosphine, tetrakis(triphenylphosphine)palladium(o) and the like. The amount of catalyst may be in the range of from 0.1 mole% on the 50% mol, preferably from 1 to 10 mole%. The reaction may be conducted in the presence of a base, such as alkali metal carbonates such as sodium carbonate or potassium carbonate; bicarbonates of an alkali metal such as sodium bicarbonate or potassium bicarbonate; organic bases such as triethylamine, pyridine, dimethylaminopyridine (DMAP) or diisopropylethylamine and the like. The number can be from 1 to 20 equivalents, preferably the amount is in the range from 1 to 5 equivalents. Can be used catalysts phase transfer, such as tetraalkylammonium, benzyltriethylammonium, benzyltrimethylammonium, tetraalkylammonium, benzyltriethylammonium or benzyltrimethylammonium. The amount used of the catalyst phase transfer may be in the range of from 0.01 equivalent to 1 equivalent, preferably from 0.05 to 0.5 equivalent. The reaction temperature can be between 0°C to the boiling point of the solvent, preferably from 30°C to the boiling point of the solvent. The duration of the reaction may be in the range of from 0.5 to 76 hours, preferably from 6 hours to 24 hours.

In another aspect of the present invention compounds of General formula (I), where R1, R2, R3 , R4, R5, R6, X and m are as previously defined, can be obtained by any of the following methods shown in Scheme II below:

The reaction of the compound of the formula (II-1), where all symbols are as defined above, with carbon monoxide and water to obtain the compounds of formula (I), where X represents oxygen, and all other symbols are as defined earlier may be carried out in the presence of a suitable palladium catalyst, such as PdCl2Pd(OAc)2, (PPh3)PdCl2and like them. The amount of catalyst may be in the range of from 0.01 mole% to 5 mole%, preferably 2.0% mol. The reaction may be conducted in the presence of aqueous mineral acids such as HCl or HBr; proton solvents, such as EtOH, I-D or BuOH. The reaction temperature may range from -78°to 300°C, preferably at a temperature in the range from 20°C to the boiling point of the used solvent, and the reaction can be conducted in a range of pressure from 50 to 150 atmospheres of carbon monoxide. The duration of the reaction may be in the range of 2 to 80 hours.

Alternatively, the compound of formula (I), where X represents oxygen, and all symbols are as defined earlier, may be is obtained by the interaction of the compounds of formula (II-1), where all symbols are as defined earlier, with carbonyl complexes of transition metal, such as Rh4(CO)12or Rh6(CO)16. The reaction may be conducted in the presence of solvents such as THF, acetone, acetonitrile, benzene, toluene, EtOH, Meon and the like or mixtures thereof. The reaction may be conducted in the presence of a base, such as trialkylamine, such as triethylamine, diisopropylethylamine and the like. The temperature can be between 30°to 300°C, preferably at a temperature in the range from 50°C - 150°at a pressure of from 20 to 300 atmospheres. The reaction may be conducted in an inert atmosphere using an inert gas, such as N2, Ar or Not. The duration of the reaction may be in the range of 2 to 80 hours.

The reaction of the compound of the formula (II-2), where L3represents a halogen atom such as chlorine, bromine or iodine, and all other symbols are as defined above, with a compound of the formula (II-3), where X represents oxygen or NR8and R4is as previously defined, or the reaction of the compound of the formula (II-4)where X represents oxygen or NR8and all other symbols are as defined earlier with a compound of the formula (II-5), where L4represents hydroxy, halogen atom, such as chlorine is, bromine or iodine, to obtain the compounds of formula (I)where all symbols are as defined earlier may be carried out in the presence of a base such as triethylamine (TEA), Diisopropylamine, diisopropylethylamine, pyridine, piperidine, DMAR, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropylamide lithium (LDA), bis(trimethylsilyl)amide, potassium, Na2CO3To2CO3, NaOH, KOH, NaOMe, NaOEt, NaO-ISO-Pr, tert-BuOK, NaH, KN and the like. The number can be from 1 to 5 equivalents, preferably the amount of base ranges from 2 to 3 equivalents. The reaction may be carried out using solvents such as THF, N-methylpyrrolidone, acetonitrile, propionitrile, acetone, 2-butanone, DMSO, DMF, dimethylamine (DMA), DHM, CHCl3and the like, or mixtures thereof. The reaction may be conducted in an inert atmosphere, which can be achieved by using inert gases such as No, N2, Ar and the like. The reaction temperature can be between 0°to 150°C, preferably at a temperature in the range from 20°C to the boiling point of the used solvent. The duration of the reaction may be in the range of 2 to 50 hours, preferably from 2 to 20 hours. In the case of partial dehydrogenation of the compound obtained next digitalout.

Alternatively, the PE the Ktsia the compounds of formula (II-2), where L3represents a halogen atom such as chlorine, bromine or iodine, and all other symbols are as defined above, with a compound of the formula (II-3), where X represents oxygen or NR8and R4is as previously defined, or the reaction of the compound of the formula (II-4)where X represents oxygen or NR8and all other symbols are as defined earlier with a compound of the formula (II-5), where L4represents hydroxy, halogen atom, such as chlorine, bromine or iodine, to obtain the compounds of formula (I)where all symbols are as defined earlier may be carried out in the presence of 2 equivalents of N,N'-dicyclohexylcarbodiimide (DCC) + 0.5 equivalents DMAR or carboxymethylcellulose (CMC) + DMAR. The reaction may be conducted in the presence of solvents such as DHL, CHCl3benzene , toluene, xylene and the like, or mixtures thereof. The reaction temperature may be from room temperature up to the boiling point of the used solvent. The duration of the reaction may be in the range from 2 to 12 p.m.

In accordance with another aspect of the present invention the compound of formula (I), where R1represents an amino group, m is 2 and all other symbols are as defined above, can be obtained by transformation of a compound of formula (I), RG is R 1represents a lower alkyl group, m is 2 and all other symbols are as previously defined, in the presence of Grignard reagent, such as MeMgCl, MeMgBr, EtMgCl, or base, such as nBuLi, LiNH2or LDA. The reaction may be conducted in the presence of trialkylborane, such as triethylborane or tributylin in the presence of a solvent, such as dioxane, diethyl ether, Diisobutyl ether, diphenyl ether, THF and the like, or mixtures thereof. The reaction may be conducted in an inert atmosphere using Ar, N2or Not. The reaction may be conducted at temperatures ranging from -78°C to the boiling point of the used solvent, preferably at 0°C to the boiling point of the used solvent. The reaction may be more effective in anhydrous conditions. The duration of the reaction may be in the range from 12 to 72 hours, preferably in the range from 15 to 24 hours. The oxidative amination reaction can be carried out in the presence of hydroxylamine-O-sulfonic acid and NaOAc. The temperature is in the range from 0°C to the boiling point of the solvent, preferably from 0°C to 50°C. the Duration of the reaction may be from 2 to 20 hours, preferably from 2 to 10 hours.

In accordance with another aspect of the present invention connect the exclusion of the General formula (I), where all symbols are as previously defined, and m is 0, may be obtained by reduction of compounds of formula (I)where all symbols are as previously defined and m has a value of 1 or 2. Recovery can be carried out using a reagent such as LAH, HI, Bu3SnH, TiCl2, MeSiCl3, Nal, PCl3N2-Pd-C, acetylchloride, PPh3, tert-BuBr and Tris(dimethylamino)phosphine-I2. Recovery may also be carried out using a hydride diisobutylaluminum [(ISO-Bu)2AlH], 'lah in accordance with the method described in J. Org. Chem. 48, (1983) 1617.

In another embodiment of the present invention the compound of formula (I)where all symbols are as defined previously, and m represents 1 (sulfoxide), or m represents 2 (sulfon), can be obtained by oxidation of compounds of formula (I)where all symbols are as defined previously, and m represents 0, a suitable oxidant. Oxidation of compounds of formula (I), where m is 0, can be carried out in the presence of an oxidant, such as 30% N2About2m-SRVA, Oxon (peroxymonosulfate potassium), NalO4, KMnO4perborate sodium, the uranyl monoperoxyphthalate magnesium and the like. The amount of reagent ranges from 2 mol to 20 mol, preferably from 4 to 10 mol. The reaction can be effective is the presence of a solvent, such as CHCl3, tert-butanol, CH2Cl2, acetone, CH3COOH and the like, or mixtures thereof. Water can be used as co-solvent. The reaction may be conducted in an inert atmosphere using Not, Na or Ar. The reaction may be conducted at a temperature in the range of 0°to 150°C, preferably in the range from 30°to 120°C. the Duration of the reaction may be in the range of from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

In another embodiment of the present invention the compound of General formula (II-2), where L3represents a halogen atom, R1and R2together with the atoms to which they are attached, form a ring and the ring is selected from dihydrothiophene, R5, R6represent hydrogen and R3is as previously defined, can be obtained by the method shown in Scheme-III:

Oxidation of compounds of formula (II-2A), where R3is the same as defined above, to obtain compounds of formula (II-2b), where R3is the same as defined above, can be carried out using oxidizing agents such as hydrogen peroxide, potassium permanganate, meta-chloroperbenzoic acid (m-HPBC), NaIO4, t-BuOCl, perborate sodium, hydropersulfides potassium and the like. The number used will oxidize the La may vary in the range from 1 to 20 equivalents, preferably 2-10 equivalents. The reaction may be conducted in the presence of solvents such as glacial acetic acid, propionic acid, water and the like, or mixtures thereof. The reaction may be conducted in an inert atmosphere, which is ensured by using inert gases such as No, N, or Ar. The reaction temperature can be between 20°C to the boiling point of the used solvent, preferably from 50°C to the boiling point of the used solvent. The duration may vary in the interval from 15 minutes to 15 hours, preferably from 15 minutes to 3 hours

The recovery of the compounds of formula (II-2b), as defined above, to the compounds of formula (II-2C), where R3is the same as defined above, can be performed using 5-10% Pd-C catalyst, Raney Ni, Pt/C, boride Nickel and the like. The amount of catalyst can range from 0.01 to 1.0% by weight, preferably in the range from 0.01 to 0.50% by weight. The reaction may be conducted in the presence of solvents such as acetic acid, methanol, ethanol and the like, or mixtures thereof. The reaction may be carried out in an atmosphere of H2the pressure varies from 1 to 20 atmospheres, preferably from 1 to 10 ATM. The reaction may be conducted in an inert atmosphere, which is achieved when using inert gases such it is Not, N2or Ar. The reaction temperature may be in the range of from 15 to 100°C, preferably from 15 to 50°C. the Duration of the reaction may range from 0.5 to 20 h, preferably from 0.5 to 5 hours

The recovery of the compounds of formula (II-2C), as defined above, to the compounds of formula (II-2d), where R3is the same as defined above, can be carried out using reducing agents, such as LAH, HI, Bu3SnH, TiCl2. MeSiCl3, Nal, PCl3H2-Pd/C, PPh3, tert-BuBr, Tris(dimethylamino)phosphine-I2and like them. The amount of reducing agent can vary from 0.5 to 10 equivalents, preferably 1 to 5 equivalents. The reaction may be conducted in the presence of solvents, such as (C1-C8linear or branched) alkilany ether, THF, dioxane and the like. The reaction may be conducted in an inert atmosphere, which is achieved when using inert gases such as No, N2or Ar. The reaction temperature can be between 0°C to the boiling point of the used solvent, and the duration of reaction is in the range from 1 to 80 hours, preferably from 1 to 24 h, the Reaction may be carried out in anhydrous conditions.

The reaction of the compound of the formula (II-2d), as defined above, with acetylchloride getting connection Faure the uly (II-2E), where R3is the same as defined above, can be carried out in the presence of solvents such as dichloromethane, ethylene dichloride, chloroform, nitrobenzene and the like, or mixtures thereof. The number of acetylchloride can vary in the interval from 1 to 10 equivalents, preferably 1 to 5 equivalents. The reaction may be carried out using catalysts, such as AlHal3(where Hal represents F, Cl or Br). The amount of catalyst may be in the range from 1 to 10 equivalents, preferably 1 to 5 equivalents. The reaction may be conducted in an inert atmosphere, which is ensured by using inert gases such as No, Na or Ar. The reaction temperature may be from -20°C to the boiling point of the used solvent, preferably from -20°C to 50°C. the Duration of the reaction may range from 1 to 80 hours, preferably from 4 to 24 hours

Oxidation of compounds of formula (II-2E), above, to obtain compounds of formula (II-2f), where R3is the same as defined above, can be carried out using oxidizing agents such as hydrogen peroxide, potassium permanganate, m-SRVA, NalO4, t-BuOCl, perborate sodium, hydropersulfides potassium and the like. The amount of oxidizing agent can vary in the interval from 1 is about 20 equivalents, preferably 2-10 equivalents. The reaction may be conducted in the presence of solvents such as glacial acetic acid, propionic acid, water and the like, or mixtures thereof. The reaction may be conducted in an inert atmosphere, which is achieved when using inert gases such as No, N2or Ar. The reaction temperature can be between 20°C to the boiling point of the used solvent, preferably from 50°C to the boiling point of the used solvent. The duration may vary from 15 minutes to 15 hours, preferably from 15 minutes to 3 hours

The reaction of the compound of the formula (II-2f), above, to obtain compounds of formula (II-2), where L3represents a halogen atom and all other symbols are as defined above, can be performed when using a halogenation agent, such as NIS, NBS, bromine, Cu-Hal, where Hal represents a halogen atom, in an amount ranging from 0.5 to 5 equivalents, preferably from 0.5 to 1.5 equivalents, in the presence of solvents such as acetic acid, methanol, toluene, dichloromethane. The reaction can be effective in the presence of a catalyst, such as HBr, HCl, in an amount ranging from 0.01 to 1.0% by weight, preferably from 0.01 to 0.5% by weight. The reaction temperature can vary from 15°D. the boiling point of the used solvent, preferably from 15 to 75°C. the Duration of the reaction may range from 1 to 20 h, preferably from 1 to 10 p.m.

It is clear that in any of the above reactions, any reactive group in a suitable molecule can be protected in accordance with conventional chemical practice. Suitable protective groups in any of the above reactions are groups commonly used in the prior art. Methods of formation and removal of such protective groups are a common way that is suitable for the protected molecule.

Upon receipt of the compounds of formula (I) via an intermediate connection can be normal transformations of functional groups, such as hydrolysis, recovery or oxidation.

Some transformations of functional groups illustrated by the following examples.

The compounds of formula (I)having CONH2group, can be converted into CN method, opisannym in WO 99/15505.

Similarly, the compound of formula (I), with CO2Et group, can be converted into CH2OH by the way, is described in WO 95/15316.

Pharmaceutically acceptable salts are obtained by interaction of the compounds of formula (I) with a base, taken in an amount of from 1 to 4 equivalents, such as sodium hydroxide, sodium methoxide, sodium hydride, tert-piperonyl potassium, calcium hydroxide, magnesium hydroxide and the like, will dissolve the order, such as ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, etc. May be used a mixture of solvents. Can also be used organic bases, such as lysine, arginine, diethanolamine, choline, tromethamine, guanidine and derivatives thereof, etc. Alternative, apply an acid additive salt is obtained by treatment with acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluensulfonate acid, methanesulfonate acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, sallenave acid, benzoic acid, benzolsulfonat acid, tartaric acid and the like, in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. May also be used a mixture of solvents. Salts of amino groups and other groups can be obtained by the reaction of compounds of formula (I) with the relevant groups in solvents, such as alcohols, ketones, esters, etc. May be used a mixture of solvents.

The stereoisomers of the compounds of formula (I), forming part of the present invention, can be obtained using the reagents in their individual enantiomeric form in the way that if it is possible what about, or when carrying out the reaction in the presence of reagents or catalysts in their individual enantiomeric form, or the splitting of a mixture of stereoisomers by conventional methods. Some of the preferred methods include the breakdown by microorganisms, splitting diastereoisomeric salts obtained with chiral acids such as mandlikova acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, or chiral bases such as brucine, Tikhonova alkaloids and their derivatives, and the like.

The regioisomers of the compounds of formula (I) can be obtained by modification of the reaction conditions using reagents such as acid instead of the base or the base instead of acid, or by reaction with the free base of hydrazine instead of its salts with a diketone. The molar ratio can also change the formation of regioisomer.

Different polymorphs of the compounds of General formula (I), forming part of the present invention can be obtained by crystallization of the compounds of formula (I) under different conditions. For example, using a variety of commonly used solvents or their mixtures for recrystallization; crystallization at different temperatures; various methods of cooling, ranging from very fast to very slow cooling during crystallization of Polymorphs may also be obtained by heating or melting compounds with subsequent gradual or slow cooling. The presence of polymorphs may be determined by solid breakdown of NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, power data, X-rays or any other means.

Pharmaceutically acceptable solvate of the compounds of formula (I), forming part of this invention, can be obtained by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol, etc., preferably in water, and recrystallization, using different methods of crystallization.

Compounds of General formula (I) useful as a partial or complete substitute NPLS in the compositions or formulations, where they are entered with other agents or ingredients. The present invention also includes pharmaceutical compositions for the treatment mediated by cyclooxygenase diseases, as defined earlier, comprising a non-toxic therapeutically effective amount of the compounds of formula (I)as defined above, and pharmaceutically acceptable carrier, and optionally containing one or more other therapeutic ingredients, such as other analgesic agent, such as acetaminophen, phenacetin, potentiate the tool, such as caffeine, an antagonist of N2the aluminum hydroxide or magnesium, simethicone, a decongestant such as phenylephrine, f is dipropylamine, pseudophedrine, Oxymetazoline, epinephrine, naphazoline, propylhexedrine or levocetirizine, Xylometazoline, sedative or nesecarily antihistamine agent against cough suppressant such as dextromethorphan, carbetapentane, caramiphen, hydrocodeine and codeine and the like, or a diuretic. The present invention also includes a method of treating diseases mediated by cyclooxygenase, including placing a patient in need, a non-toxic therapeutically effective amount of the compounds of formula (I) or pharmaceutical compositions described above.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, for example in the form of tablets, pills, pellets, aqueous or oil suspensions, polymer powders or granules, emulsions, hard or soft capsules, or syrups or Alexiou. Compositions suitable for oral administration can be obtained in accordance with any method known from the prior art for the production of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, fragrances, dyes and preservatives to obtain pharmaceutically excellent and enjoyable products. Tablets contain the active ingredient in a mixture with non-toxic, pharmace is almost acceptable additives, which are suitable for the production of tablets. These additives can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja agents such as corn starch or alginic acid; binding agents, for example starch, gelatin or gum Arabic and lubricants, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known methods to delay disintegration and adsorption in the gastrointestinal tract and, thus, to provide a prolonged action over a longer period. For example, for these purposes may be used such materials as glycerol the monostearate or glyceryl distearate. They can also be coated by methods described in US 4256108; 4166452 and 4265874, to obtain the osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peach oil,liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in a mixture with additives, suitable for aqueous suspensions. Such additives are suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone resin tragakant and gum Arabic; dispersing or wetting agents may be natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides hexitol, for example polietilensorbit monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, n-hydroxybenzoate, one or more dyes, one or more fragrances and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oil suspensions can be obtained by suspendirovanie active ingredient in a vegetable oil, such as peanut the PTO oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as described above, and perfumes can be added to ensure a pleasant oral administration. These compositions may be preserved with the introduction of antioxidants, such as ascorbic acid.

The dispersion powders and granules suitable for receiving water suspension with the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or moisturizing agents and suspendresume agents presents those mentioned above. Can also contain additional additives such as sweetening agents, perfumes and dyes.

The pharmaceutical compositions according to the invention may also be in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil, such as olive oil, or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acid is t and lexicological, for example servicemanuals and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain emollients, preservatives and perfumes and dyes. The pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspension. This slurry may be prepared in accordance with the prior art, using suitable dispersing or moisturizing agents and suspendresume agents mentioned above. Sterile injectable composition may also be a sterile injectable solution or suspension in a nontoxic parentalinvolvement diluent or solvent, for example, in the form of a solution in 1,3-butandione. Among the acceptable binders and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are typically used as a solvent or suspendida environment. For these purposes may be used any soft fixed oils, including synthetic mono - Il is diglycerides. In addition, fatty acids such as oleic acid, can be used for injections.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of medication. These compositions can be obtained by mixing the drug with a suitable non-irritating additive which is solid at ordinary temperature and becomes liquid at rectal temperature and then melted in the rectal cavity to release the drug. Such materials are cocoa butter and polyethylene glycols.

For local use apply creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of formula (I) (the purpose of this application, the local application can include rinsing teeth and gargle for the throat).

The dose levels in the range from about 0.01 mg to about 140 mg/kg of body weight per day are useful for the treatment of the above diseases or alternatively about 0.5 mg to about 7 g of the patient per day. For example, inflammation may be effectively cured by the introduction of from about 0.01 to 50 mg of compound per kilogram of body weight per day or alternatively about 0.5 mg to about 3.5 g of the patient per day, preferably from 2.5 mg to 1 g of the patient per day.

The amount of active ingredient that may be combined with the materials of the media getting dinicol dose forms may vary depending on the object to be processed and the particular route of administration. For example, a composition suitable for oral administration to humans may contain from 0.5 mg to 5 g of active agent that is connected to a suitable standard and quantity of material media, which can vary from about 5 to about 95 percent of the total composition. Unit dose forms generally contain between from about 1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg

It is clear, however, that a particular level of dosage for any particular patient depends on various factors, including the age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination with medications and the severity of the particular disease being treated.

The term parenteral, used, includes subcutaneous injections, intravenous, intramuscular, intraperitoneal injection or drip methods. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the connection according to the invention is effective for the treatment of humans.

Information confirming the possibility of carrying out the invention

The invention is explained in detail by examples below, which provide only an illustration and therefore should not be considered as limiting the present izobreteny is.

Preparation 1:

3-Floransa

To ice the solution (˜0°C) 3-foronline (50 g, 450.45 mmol) in 6N hydrochloric acid (200 ml) very slowly and added dropwise to 150 ml ice water solution (˜5° (C) NaNO2(37.3 g, 540.58 mmol). The temperature of the reaction mixture support strictly within 0-5°by adding from time to time every time ice and salt into the space around the reaction flask. Then very slowly add (not more than 2 ml at a time) diasterous a solution of 3-foranyone to aqueous solution of ethylxanthate potassium (101.5 g, 634.37 mmol in 100 ml of N2O) at 40-45°C. the Addition is carried out during 1.5 hours. Then the reaction mixture is stirred for 1 hour at 40-45°C. the Aqueous layer was decanted from the orange oil, which is extracted with chloroform (3×100 ml). The combined organic layers washed with a solution of 5N NaOH (2×50 ml)and then water (2×100 ml), dried over anhydrous Na2SO4and concentrated under low vacuum. Crude oil, thus obtained, is used in the next stage.

To a solution of product obtained above in ethanol (250 ml) gently add the line in the granules (37.91 g, 675.63 mmol). The mixture is then heated to 85-90°C in nitrogen atmosphere with vigorous premesis the Institute for 27 hours. Then the ethanol is removed under low vacuum and the resulting residue is dissolved in acetone (200 ml). The reaction mixture was cooled to ˜10°slowly and added dropwise methyl iodide (127.87 g 900.87 mmol). After stirring for 12 hours at room temperature the solvent is distilled off in vacuo and to the residue add petroleum ether (200 ml). Filtering the reaction mixture through celite, followed by concentration of the filtrate gives the desired crude product which is purified by distillation at 83-85°s at 40 mm Hg, giving 31 g of the above compound (49% yield) as oil.

1H NMR (CDCl3, 200 MHz): δ 7.29-7.18 (m, 1H), 7.02-6.77 (m, 3H), 2.48 (s, 3H). Mass (Cl, ISO-butane) m/e 142 (M+, 20), 96 (100).

Preparation 2:

2-Tortional

2-Tortional get with 71% yield from 2-foronline (30 g, 270.27 mmol)using NaNO2(22.37 g, 324.49 mmol), ethylxanthate potassium (at 43.51 g 271.4 mmol) and methyl iodide (76.72 g, 540.21 mmol), in accordance with the procedure described in preparation 1.

1H NMR (CDCl3, 200 MHz): δ 7.36-7.00 (m, 4H), 2.47 (s, 3H).

Preparation of 3:

2,3-Dimethylthiazol

2,3 - Dimethylthiazol get with 78% yield from 2,3-dimethylaniline (5 g, 41.32 mmol)using NaNO2(5.13 g, 74.37 mmol), ethylxanthate potassium (7.90 g, 49.28 mmol) and yo the East methyl (6.10 g, 42.95 mmol), in accordance with the procedure described in preparation 1.

1H NMR (CDCl3, 200 MHz): δ 7.2-6.9 (m, 3H), 2.46 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H).

Preparation 4:

2-Chloroanisole

2-Chloroanisole get with 89% yield from commercially available 2-chlorothiophenol (4.0 g, 27.6 mmol), using methyl iodide (4.66 g, at 32.81 mmol), in accordance with the procedure described in preparation 1.

1H NMR (CDCl3, 200 MHz): δ 7.3 1-6 .92 (m, 4H), 2.46 (s, 3H).

Preparation of 5:

2-Fluoro-4-methylsulfonylamino

To a suspension of AlCl3(45 g, 339 mmol) in dichloromethane (150 ml) is added dropwise acetylchloride (24.2 ml, 339 mmol) at 0°C. the Mixture is stirred for 0.5 hours at 25°until then, until it forms a bright solution. To the resulting solution was added slowly a solution of 3-portiuncola (37 g, 260.5 mmol) in dichloromethane (50 ml) at 0°C. the duration of the addition is 30 minutes. The mixture is then stirred for 3 hours at 25°C, poured on ice (500 g), extracted with chloroform (3×100 ml). The combined organic layers washed with water (2×100 ml), dried over anhydrous Na2SO4and concentrated in vacuo, giving crude product. The specified product was then purified by chromatographic column on silica gel, using the 1% EtOAc - petroleum ether as eluent, giving 14 g (29% yield) of the named compound as a light brown solid, TPL: 61-62°C.

1H NMR (CDCl3, 200 MHz): δ 7.85-7.77 (m, 1H), 7.06-7.01 (d, J=8,79 Hz, 1H), 6.90-6.86 (d, J=8.3 Hz, 1H), 2.62-2.60 (d, J=4.88 Hz, 3H), 2.52 (s, 3H). Mass (Cl, ISO-butane) m/e 183 (M+, 47), 169(100), 155(89).

Preparation 6:

3-Fluoro-4-methylsulfonylamino

3-Fluoro-4-methylsulfonylamino receive 22% yield from 2-portiuncola (9 g, 63.38 mmol)using acetylchloride (5.97 g, at 76.05 mmol) and AlCl3(10.11 g, 75.82 mmol), in accordance with the procedure described in preparation 5.

1H NMR (CDCl3, 200 MHz): δ 7.72-7.50 (m, 2H), 7.30-7.15 (t, J=7.8 Hz, 1H), 2.56 (s, 3H), 2.51 (s, 3H).

Preparation 7:

2,3-Dimethyl-4-methylsulfonylamino

2,3-Dimethyl-4-methylsulfonylamino get with 28% yield from 2,3-dimethylthiazole (7.5 g, at 49.01 mmol)using acetylchloride (4.60 g, 58.59 mmol) and AlCl3(7.80 g, 58.49 mmol), in accordance with the procedure described in preparation 5.

1H NMR (CDCl3, 200 MHz): δ 7.54-7.49 (d, J=8.71 Hz, 1H), 6.75-6.65 (d, J=8.72 Hz, 1H), 2.55 (s, 3H). 2.49 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H).

Preparation 8:

3-Chloro-4-methylsulfonylamino

3-Chloro-4-methylsulfonylamino get with 69% yield from 2-Horti is anisole (5.0 g, At 31.54 mmol)using acetylchloride (2.7 ml, 37.83 mmol) and AlCl3(4.56 g, 34.19 mmol), in accordance with the procedure described in preparation 5.

1H NMR (CDCl3, 200 MHz): δ 7.90-7.71 (m, 2H), 7.17 (d, J=8.0. Hz, 1H), 2, 55 (s, 2H), 2.52 (s, 3H).

Preparation 9:

2-Bromo-1-(2-fluoro-4-methylsulfinylphenyl)-1-alanon

To a solution of 2-fluoro-4-methylsulfonylamino (12 g, 65.2 mmol) in acetic acid (100 ml) was added Hydrobromic acid (5 ml) at 10-15°C. the Mixture is stirred for 10-15 minutes. To this mixture very slowly add a solution of bromine (3,18 ml, 61.72 mmol) in acetic acid (4 ml). Stirring is continued for another 3 hours until, until there is no longer the color of bromine. To the resulting mixture are added water (300 ml), the solid is separated, filtered and dried in vacuum. Thus obtained powder is treated with petroleum ether (20 ml)to remove the coloring impurities, and then filtered, giving 13.3 g of the named compound with 78% yield as a pale brown solid. TPL 55-59°C.

1H NMR (CDCl3, 200 MHz): δ 7-91-7 .83 (m, 1H), 7.09-7,05 (d, J=8.7 Hz, 1H), 6.98-6,92 (d, J=12.2 Hz, 1H), 4.48-4.47 (d, J=1.96 Hz, 2H), 2,52 (s, 3H). Mass (Cl, ISO-butane) m/e 262 (M+, 8), 169 (100).

Preparation of 10:

2-Bromo-1-(3-fluoro-4-methylsulfinylphenyl)-1-alanon

2-Brom-(3-fluoro-4-methylsulfinylphenyl)-1-Etalon get with 67% yield from 2-fluoro-4-methylsulfanyl of acetophenone (2 g, 10.86 mmol)using bromine (0.58 ml, 0.58 ml, 11.25 mmol), in accordance with the procedure described in preparation 9.

1H NMR (CDCl3, 200 MHz): δ 7.75-7.63 (m, 2H), 7.30-7.15 (t, J=7.40 Hz, 1H), 4.38 (s, 2H), 2, 53 (s, 3H).

Preparation 11:

2-Bromo-1-(2,3-dimethyl-4 - methylsulfinylphenyl)-1-alanon

2-Bromo-1-(2,3-dimethyl-4-methylsulfinylphenyl)-1-Etalon get with 79% yield from 2,3-dimethyl-4-methylsulfonylamino (1.8 g, 9.2 mmol), using bromide (0.45 ml, 8,73 mmol), in accordance with the procedure described in preparation 9.

1H NMR (CDCl3, 200 MHz): δ 7.78-7.56 (d, J=8.21 Hz, 1H), 6.89-6.76 (d, J=8.22 Hz, 1H), or 4.31(s, 2H). 2.51 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H).

Preparation 12:

2-Bromo-1-(3-chloro-4-methylsulfinylphenyl)-1-alanon

2-Bromo-1-(3-chloro-4-methylsulfinylphenyl)-1-Etalon get with 55% yield from 3-chloro-4-methylsulfonylamino (6.6 g, 33 mmol)using bromine (1.60 ml, 31.01 mmol), in accordance with the procedure described in preparation 9.

1H NMR (CDCl3, 200 MHz): δ 8.02-7.81 (m, 2H), 7,19 (d, J=8.0 Hz, 1H), 4.36 (s, 2H), 2.52 (s, 3H).

Preparation 13:

Benzothiophene-1,1-dioxide

To a solution of benzothiophene (10 g, 74.6 mmol) in glacial acetic acid (18.65 ml) is added 30% aqueous solution of N2About2(37.31 ml, 329.20 mmol) and heated at the boil with a reflux is m for 0.5 hours. The reaction mixture is slowly cooled to 10-15°C, filtered, washed with chilled water (15 ml) and dried to obtain the above compound as a white solid (12 g, 97%). TPL 129-130°C.

1H NMR (CDCl3, 200MHz): δ 7.74 (d, J=7.80 Hz, 1H), 7.68-7.54 (m, 2H), 7.38 (d, J=2.40 Hz, m), 7.24 (d, J=7.00 Hz, 1H), 6.72 (d, J=6.80 Hz, 1H).

Preparation 14:

2,3-Dihydrobenzofuran-1,1-dioxide

In the solution benzothiophene-1,1-dioxide (10 g, 60.24 mmol)obtained in preparation 13, dissolved in glacial acetic acid (400 ml), load 5-10% Pd-C (100 mg, 0.01% weight.) and hydronaut using razobratsya H2within 5 hours. The reaction mixture is filtered, using a pillow from celite, and the filtrate poured into ice water (500 ml), extracted with ethyl acetate, dried (Na2SO4) and evaporated to obtain the substance in the form of a thick mass, which chromatographic on a column of silica gel using ethyl acetate: petroleum ether (10:90) to give the titled compound (10 g, 99%). TPL 91-92°C.

1H NMR (CDCl3, 200 MHz): δ 7.76-7.73 (d, J=7.60 Hz, 1H), 7.62-7.40 (m, 3H), 3.53-3.50 (t, J=6.20 Hz, 2H), 3.39-3.36 (t, J=6.00 Hz, 2H).

Preparation 15:

2,3-Dihydrobenzofuran

To 2,3-dihydrobenzofuran-1,1-dioxide (10 g, at 59.52 mmol)obtained in preparation 14, in argon atmosphere, add lithium is alumoweld (5.65 g, 148.80 mmol) and THF (100 ml) and heated at the boil under reflux for 4-5 hours. The reaction mixture is cooled to 10°and slowly added dropwise water, quenching the excess lydialydia. THF is removed under reduced pressure. Add water (100 ml) and ethyl acetate (100 ml) and stirred. The aqueous layer was extracted with ethyl acetate. United an ethyl acetate layers are dried (Na2SO4) and evaporated to obtain the substance in the form of a crude product, which chromatographic on a column of silica gel using 2% ethyl acetate and petroleum ether as eluent, giving a named connection in the form of a viscous liquid.

1H NMR (CDCl3, 200 MHz): δ 7.26-7.01 (m, 4H), 3.39-3.26 (m, 4H).

Preparation 16:

5-Acetyl-2,3-dihydrobenzofuran

2,3-Dihydrobenzofuran (8 g, 58.8 mmol)obtained in preparation 15, is added slowly to a suspension of anhydrous aluminium chloride (11.77 g, 88.2 mmol) and acetylchloride (6.92 g, 88.2 mmol) in dichloromethane (100 ml) at 5-10°C. the Reaction mixture was stirred at 25-30°C for 24 hours and then poured on crushed ice. Then it is extracted with dichloromethane (2×50 ml), dried (Na2SO4) and evaporated to obtain these compounds in the form of a viscous liquid (10 g, 96%).

1H NMR (CDCl3, 200 MHz): δ 7.77 (s, 1H). 7.74-7.70 (d, J=9.70 Hz, 1H), 7.28-7.24 (d,J=7.98 Hz, 1H), 3.47-3.34 (m, 4H), 2.55 (s, 3H).

Preparation 17:

5-Acetyl-2,3-dihydrobenzofuran-1,1-dioxide

To a solution of 5-acetyl-2,3-dihydrobenzofuran (8 g:44.9 mmol)obtained in preparation 16 in glacial acetic acid (16 ml), add 30% aqueous solution of N2About2(22, 92 ml, 202.2 mmol) and heated at the boil under reflux for 1 hour. After cooling to 20°With separated solid is filtered off and washed with water to obtain the above compound (9 g, 96%). TPL 54-56°C.

1H NMR (CDCl3, 200 MHz): 8.02 (m, 2H), 7.82 (doctor J=8.20 Hz, 1H), 3.57-3.51 (dt, J=5.60 Hz, 4H), 2.64 (s, 3H).

Preparation 18:

5-Bromoacetyl-2,3-dihydrobenzofuran-1,1-dioxide

To a solution of 5-acetyl-2,3-dihydrobenzofuran-1,1-dioxide (8 g, 38.1 mmol) (obtained in preparation 17), dissolved in acetic acid (45 ml) in an argon atmosphere, is added slowly an aqueous solution of HBr (0.5 ml, 47%), bromine (of 5.84 g, 36, 54 mmol) at 15-20CC and the reaction mixture is stirred for about 0.5 hours. Then slowly add more bromine (4.84 g) and stirring is continued for 10 hours at 25-30°C. the Supply of argon is stopped and the reaction mixture is kept open in the current of air in a boiling Cup to dispel the free bromine. Vitalises solids is filtered off and washed with acetic acid (2× 10 ml), then with petroleum ether, giving a named connection (10 g, 91%). TPL 68-70°C.

1H NMR (CDCl3, 200 MHz): 8.06 (d, J=8.20 Hz, m), 8.00 (s, 1H), 7.86 (doctor J=8.40 Hz, 1H), 4.44 (s, 2H), 3.62-3.40 (dt, J = 5.40 Hz, 4H).

Preparation 19:

2-(4-Ftoranila)-1-(3-methyl-4-methylsulfinylphenyl)-1-alanon

To a mixture of p-foronline (1.14 g; 10.3 mmol) and NaHCO3(0.865 g, 10.3 mmol) in ethanol (25 ml) is added 2-bromo-1-(3-methyl-4-methylsulphonyl) acetophenone (3 g, 10.3 mmol) in a nitrogen atmosphere at 25°C. the Mixture is vigorously stirred for 3.5 hours at the same temperature and then diluted with water (100 ml). Separated solid is filtered off, washed with water (2×25 ml), then with petroleum ether (2×10 ml) and dried in vacuum, giving 2.9 g of the above compound with 88% yield.

1H NMR (CDCl3, 200 MHz): δ 8.19-8.15 (d, J=8.7 Hz, 1H), 7.96-7.93 (m, 2H), 6, 97-6 .88 (m, 2H), 6.68-6.62 (m, 2H), 4.59 (s, 2H), 3.10 (s, 3H), 2.79 (s, 3H).

Preparation of 20:

2-(4-Ftoranila)-1-(2-fluoro-4-methylsulfinylphenyl)-1-alanon

2-(4-Ftoranila)-1-(3-methyl-4-methylsulfinylphenyl)-1-Etalon get with 95% yield using n-ftoranila (0.22 g, 1.96 mmol) and 2-bromo-1-(2-fluoro-4-methylsulfinylphenyl)-1-Etalon (0.6 g, 1.96 mmol), in accordance with the procedure described in preparation 19.

1H NMR (CDCl3, 200 MHz): δ 8.22-8.14 (m, 1H), 7.85-7.78 (m, 2H) 6.95 - 6.87 (m, 2H), 6.65-6.59 (m, 2H), 4.55 (s, 2H), 3.09 (s, 3H).

Preparation 21:

N1-(4-Forfinal)-N1-(3-methyl-4-methylsulfinylphenyl)-2-oxoethyl]-2-phenylacetamide

To a solution of 2-(4-ftoranila)-1-(3-methyl-4-methylsulfinylphenyl)-1-ethanone (1.5 g, 4.67 mmol) (obtained in preparation 19) in anhydrous THF (15 ml) is added very slowly penicillanic (0.722 g, 0.62 mmol) under nitrogen atmosphere at 25°C. the Mixture is stirred for 2 hours and diluted with water (25 ml). The solid separated was filtered, washed with water (2×15 ml), then with petroleum ether (2×5 ml) and dried in vacuum, giving 1.6 g of the above compound with 78% yield.

1H NMR (CDCl3, 200 MHz): δ 8.14-8.10 (d, J=8.8 Hz, 1H), 7.89-7.86 (m, 3H), 7.39-7.00 (m, N), 5.04 (s, 2H), 6.57 (s, 2H), 3.08 (s, 3H), 2.75 (s, 3H).

Preparation 22:

N1-(4-Forfinal)-N1-[2-(2-fluoro-4-methylsulfinylphenyl)-2-oxoethyl]-2-phenylacetamide

N1-(4-Forfinal)-N1-[2(3-methyl-4-methylsulfinylphenyl)-2-oxoethyl]-2-phenylacetamide get with 93% yield from 2-(4-ftoranila)-1-(2-fluoro-4-methylsulfinylphenyl)-1-ethanone (0.55 g, 1.84 mmol) and penicillamine (0.285 g, 1.84 mmol), in accordance with the procedure described in preparation 21.

1H NMR (CDCl3, 200 MHz): δ 8.18-8.11 (m, 1H), 7.84-7.73 (m, 2H), 7.35-7.04 (m, N), 4.95 (s, 2H), 3.56 (s, 2H), 3.08 (s, 3H).

Example 1:

3-(4-Forfinal)--(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone

Stage 1:

Obtaining 2-(2-fluoro-4-methylsulfinylphenyl)-2-oxyethyl-2-(4-forfinal) acetate

To a solution of 4-florfenicol acid (7.6 g, 49.3 mmol) in DMF (30 ml) is added an aqueous solution of KOH (2.7 g, 48.11 mmol in 5 ml water) and the mixture was stirred at 25°C for 30 minutes. To the resulting mixture add a solution of 2-bromo-1-(2-fluoro-4-methylsulfinylphenyl)-1-ethanone (13 g, 49.3 mmol) in DMF (100 ml) and stirring is continued for 1 hour at 25°C. Then the solution was added water (500 ml), the separated solid is filtered off and dried in vacuum. The crude solid is treated with isopropanol and filtered, giving 15 g of the above compound with 90% yield as a pale brown solid. TPL 78-81°C.

1H NMR (CDCl3, 200 MHz): δ 7.91-7.83 (t, J=7.8 Hz, 1H). 7.35-7.28 (m, 2H), 7.08-6.90(m, 4H), 5.21-5.20 (d, J=3.42 Hz, 1H), 3.78 (s, 2H), 2.51 (s, 3H). Mass (Cl, ISO-butane) m/e 336 (M+, 8), 169 (100).

Getting

3-(4-forfinal)-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone.

To a solution of 2-(2-fluoro-4-methylsulfinylphenyl)-2-oxyethyl-2-(4-forfinal) acetate (12 g, 35.7 mmol) (obtained in stage 1) in acetonitrile (100 ml) is added dropwise 1, 8-diazabicyclo[5.4.0] undec-7-ene (DBU) (11 ml, 71.5 mmol) at 25°C in nitrogen atmosphere. A mixture of AC who're asked for 30 minutes at the same temperature. To the resulting mixture are added water (200 ml), then added 2N HCl (200 ml). The mixture is then extracted with EtOAc (2×250 ml), the organic layers collected are pooled, dried over anhydrous Na2SO4and concentrate. The resulting crude product was then purified using a chromatographic column with silica gel using 10% EtOAc-petroleum ether, giving 5 g of the above compound with 44% yield as a white solid. TPL 118-122°C.

1H NMR (CDCl3, 200 MHz): δ 7.45-7.38 (m, 2H), 7.25-6.87 (m, 5H), 5.17 (s, 2H), 2.48 (s, 3H). Mass (Cl, ISO-butane) m/e 318 (M+, 100), 261 (85).

Stage 3:

Obtaining 3-(4-forfinal)-4-(2-fluoro-4-methylsulfinylphenyl)-2.5-dihydro-2-furanone.

To a solution of 3-(4-forfinal)-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone (6 g, 18.8 mmol) (obtained in stage 2) in acetone (150 ml) add a solution oxone (34.8 g, 56.6 mmol) in water (75 ml). The reaction mixture was vigorously stirred for 2 hours at 25°C. After completion of the reaction, the solvent is removed under low vacuum and then the residue is added water (200 ml). The mixture is then extracted with EtOAc (2×100 ml), the organic layers collected are pooled, dried over anhydrous Na2SO4and concentrated in vacuo. Then the crude product is treated with Meon (2×20 ml) and filtered, giving 5.6 g of the named compound with 85% yield in the form of powder off-white color. TPL 160-162° C.

1H NMR (CDCl3, 200 MHz): δ 7.77-7.66 (m, 2H), 7.45-7.35 (m, 3H), 7.25-7, 01 (m, 2H), 5.19 (s, 2H), 3.09 (s, 3H). Mass (Cl, ISO-butane) m/e 350 (M+, 50), 322 (10), 293 (100).

Connection examples 2-93 obtained using the methods described in example 1

Example 97:

1-(4-Forfinal)-4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-1H-2-atholon

To a solution of N1-(4-Forfinal)-N1-[2-(3-methyl-4-methylsulfinylphenyl)-2-oxoethyl]-2-phenylacetamide (1 g, 2.27 mmol) in acetonitrile (15 ml) is added DBU (0.346 g, 2.27 mmol) in nitrogen atmosphere at 0-5°C. the Mixture is stirred for 4 hours, poured into water (50 ml) and extracted with EtOAc (3×15 ml). The organic layers separated, unite together, sushi is t over anhydrous Na 2SO4and concentrated in vacuo. Selected residue purified by chromatographic column using EtOAc - petroleum ether (1:3) as eluent, giving 0.2 g of the above compound with a 21% yield. TPL 207-209°C.

1H NMR (CDCl3, 200 MHz): δ 7.9-7.7 (m, 3H), 7.4-7.0 (m, N), 4.7 (s, 2H), 3.0 (s, 3H), 2.6 (s, 3H). Mass (Cl, ISO-butane) m/e 421 (M+, 100).

Example 98:

3'-(2-Fluoro-4-methylsulfinylphenyl)-1-(4-forfinal)-4-phenyl-2,5-dihydro-1H-2,5-azadian

Specified in the title compound are obtained from 7% yield of N1-(4-forfinal)-N1-[2-(2-fluoro-4-methylsulfinylphenyl)-2-oxoethyl]-2-phenylacetamide (0.79 g, 1.58 mmol)using DBU (0.481 g, 1.58 mmol), in accordance with the procedure described in Example 2. TPL 198-200°C.

1H NMR (200 MHz, CDCl3,): δ 7.8-7.1 (m, N), 3.1 (s,3H). Mass (Cl, isobutane) m/e 439 (M+, 100).

Compounds of the present invention are tested in vitro for their MOR-1 and MOR-2 inhibitory activity using described in the prior art testing methods. The effectiveness of compounds in vivo test in male Sprague-Dawley rats using test edema in the paws of rats caused by carrageenan (Proc. Soc. Exp. Biol. Med., 111, 544 (1962), Laboratory models for testing NPLS on non-steroidal anti-inflammatory drugs (J. Lombardino, ed., 1985).

Biochemical tests In Vitro

1. Range of the photometric testing of MOR-1 and MOR-2:

Microsomal fraction lamb testicles used as a source of MOR-1 enzyme (Hemler and others, 1976) and microsome assay of sf-9 cells infected with baculovirus containing the human MOR-2 to a-DNA, used as a MOR-2 enzyme (Wanda and others, 1994). The enzyme activity is measured chromogenic tests, based on the oxidation of N,N,N1N1-tetramethyl-p-phenylenediamine (TMPD) in the recovery process PGG2 to PGH2as for the method described Copeland and others, 1994 with the following modifications. The test mixture (1000 ml) contains 100 mm TRIS, pH 8.0, 3 μm EDTA, mm of gelatine, 150 units of enzyme and 8% DMSO. The mixture is incubated at 25°C for 15 minutes prior to initiation of the enzymatic reaction in the presence of compound/binder. The reaction is initiated by addition of 100 μm arachidonic acid and 120 µm TMPD. The enzyme activity is measured by determining the initial rate of oxidation of TMPD within the first 25 seconds of the reaction with a subsequent increase of the absorption at 603 nm. IC50values calculated from nonlinear regression analysis of percentage inhibition.

ExampleConcentrationThe percentage of inhibition
MOR-1SOH-2
1Mm 33100
6100 mm082
52100 mm12100
53100 mm44100
55100 mm30100
58100 mm1993
68100 mm0100
69100 mm1093
70100 mm4992
71100 mm399
8910 µm095

2) Tests on whole human blood:

MOR-1 inhibitor test

Fresh heparinized whole human blood incubated with lipopolysaccharide (LPS) from E. coli at 100 µg/ml and 2.5 ál of binding agent (DMSO) or test compound for 24 hours at 37°C. PGE2plasma levels measured EIA equipment (Cayman chemicals, USA) after deproteinization.

SOH-2 inhibitor trials

An aliquot of fresh blood mixed with either DMSO or test compounds and leave clotting for 1 hour at 37°C. TXB2the levels measured in serum EIA equipment (Cayman chemials, USA) after deproteinization.

ExampleIC50(nm)
COX-ICOX-II
1194.5±27.52.72+0.425
6>5005.7
521220±200.578±0.011
53247±240.368
55>1001
58357±7.450.524±0.062
68296.51.248
69>5000.318±0.013
701150.913
89>10006.13

In vivo screening methods

1. Carrageen-induced swelling of the paws of rats

Male Wistar rats (120-140 g) no food for 16 h before the experiment. Compounds suspended in 0.25% CMC (CMC) and administered orally in a volume of 10 ml/kg for 2 h before injection of Cartagena. Swelling of the hind paws induce in rats, subcutaneous injection of 50 μl of 1% lambda Cartagena in the salt solution to the surface of the right foot. The volume of paw was measured before and 3 h after injection of Cartagena using plethysmometer (Ugo-Basile, Italy). Swelling of the legs compared with the control group binders epicist percentage inhibition, choose values for the control group at 0%.

ExampleDoseThe percentage of inhibition
63023
523062
533039
551048
583044
683044
693051
703051
713017
893031

1. The compound of formula (I)

where R1represents alkyl;

R2represents halogen, formyl, substituted or unsubstituted alkyl, hydroxyl, (C1-C6)alkoxy, halogenated,

or R1and R2together with the atom to which they are attached, form an unsubstituted 5-7-membered ring structure of the formula-CH2-(CH2)nS-, where n=1 or 2;

R3represents hydrogen, halogen atom or alkyl;

R4represents alkoxy or aryl, unsubstituted or substituted with halogen, (C1-C6)alkyl, halogenated (C1 -C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl;

R5represents hydrogen, hydroxyl, alkyl of alkenyl or alkoxy;

R6represents hydrogen or alkyl, or

R5and R6together represent =O;

X represents oxygen or NR8where R8represents aryl substituted by halogen;

m is an integer from 0 to 2,

its pharmaceutically acceptable salt.

2. The compound according to claim 1, which is selected from such compounds as:

4-(1,1-dioxo-2,3-dihydrobenzo[b]thiophene-5-yl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-f is ranon;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3-phenyl-4-(3-methoxy-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-triptoreline)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-tryptophanyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-chlorophenyl)-3-phenyl-2,5-dihydro-2-furanone;

3-(4-methylsulfinylphenyl)-4-(3-chloro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-chlorophenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-(4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-chlorophenyl)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-chlorophenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-(4-were)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-forfinal)-3-phenyl-2,5-dihydro-2-furanone;

4-(4-metals Lionel-3-chlorophenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-forfinal)-3-(4-were)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-triptoreline)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-triptoreline)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-were)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-isobutylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-3-forfinal)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-forfinal)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-2-chlorophenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(4-methylsulphonyl-3-chlorophenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

4-(4-methylsulfanyl-2-chlorophenyl)-3-(4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(2,3-dimethyl-4-methylsulfinylphenyl is)-3-phenyl-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-sulfanilyl)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-fluoro-4-were)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(4-ethylphenyl)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3,4-dimetilfenil)-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-bromo-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(1-naphthyl)-2,5-dihydro-2-furanone;

3-(3-methyl-4-methoxyphenyl)-4-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-5,5-DIMET the l-2,5-dihydro-2-furanone;

4-(3-methyl-4-methylsulfinylphenyl)-3-(3-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-methyl bromide-4-methylsulfinylphenyl)-3-(4-forfinal)-5,5-dimethyl-2,5-dihydro-2-furanone;

2-{5-[4-(4-forfinal)-2,2-dimethyl-5-oxo-2,5-dihydro-3-furanyl]-2-methylsulfonylbenzoyl}-2,3-dihydrobenzo[d]isothiazol-3-oxo-1,1-dioxide;

4-(2-fluoro-4-methylsulfinylphenyl)-5,5-dimethyl-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-2,5-dihydro-2-furanone;

3-(4-forfinal)-5,5-dimethyl-4-(4-methylsulphonyl-3-morpholinomethyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-2,5-dihydro-2-furanone;

3-(3,4-differenl)-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3-(3,5-differenl)-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3 isopropoxy-5,5-dimethyl-4-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

4-(3-hydroxymethyl-4-methylsulfinylphenyl)-3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-5-hydroxy-2,5-dihydro-2-furanone;

5-ethyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-methoxy-3-were)-2,5-dihydro-2-furanone;

5-the Tyl-4-(3-fluoro-4-methylsulfinylphenyl)-3-(3,4-differenl)-2,5-dihydro-2-furanone;

3-(3,4-differenl)-5-ethyl-4-(2-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3-(3,4-differenl)-5-ethyl-4-(2-fluoro-4-methylsulfinylphenyl)-5-hydroxy-2,5-dihydro-2-furanone;

4-(3-vermeil-4-methylsulfinylphenyl)-3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

3 isopropoxy-5,5-dimethyl-4-(3-fluoro-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3 isopropoxy-5,5-dimethyl-4-(3-methylsulfanyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

3 isopropoxy-4-(3-methoxymethyl-4-methylsulfinylphenyl)-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-formyl-4-methylsulfinylphenyl)-3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methylsulfinylphenyl)-2,5-dihydro-2-furanone;

5-ethyl-4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-hydroxy-2,5-dihydro-2-furanone;

5-ethylidene-4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-2,5-dihydro-2-furanone;

5-ethylidene-4-(2-fluoro-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-2-furanone;

5-ethylidene-4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-methyl-4-methoxyphenyl)-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(3-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-methyl-2,5-dihydro-2-furan is n;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3,4-differenl)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(3-forfinal)-5-methoxy-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-were)-5-methyl-2,5-dihydro-2-furanone;

4-(2-fluoro-4-methylsulfinylphenyl)-3-(4-forfinal)-5-methoxy-5-methyl-2,5-dihydro-2-furanone;

1-(4-forfinal)-4-(3-methyl-4-methylsulfinylphenyl)-3-phenyl-2,5-dihydro-1H-2-atholon and

3-(2-fluoro-4-methylsulfinylphenyl)-1-(4-forfinal)-4-phenyl-2,5-dihydro-1H-2,5-azadian.

3. The compound according to claim 1, for which the pharmaceutically acceptable salt is chosen from Li, Na, K, CA, Mg, Fe, Cu, Zn, Mn salts; salts of organic bases, such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, geranamine, Isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine, diethanolamine, meglumine, Ethylenediamine, N,N'-diphenylethylenediamine, N,N'-dibenziletilendiaminom, N-benzylpenicillin, choline, kolingerova, dicyclohexylamine, Metformin, benzylamine, phenylethylamine, dialkylamino, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, SP is ridin; chiral bases such as alkylphenolates, glycinol, phenylglycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, Proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine, where the substituents are selected from nitro, amino, alkyl, alkenyl, quinil, ammonium or substituted ammonium salts and aluminum salts; salts can include acid additive salts, among which are suitable sulfates, nitrates, phosphates, perchlorates, borates, halide, acetate, tartratami, maleate, citrates, succinate, palmoate, methansulfonate, benzoate, salicylates, hydroxynaphthoate, benzoylformate, ascorbate, glycerophosphate or Ketoglutarate.

4. Pharmaceutical composition for the treatment of diseases mediated by cyclooxygenase, which includes an effective amount of the compounds of formula (I)

as defined in claim 1, or a compound according to claim 2 and a pharmaceutically acceptable carrier, diluent, filler or MES.

5. The pharmaceutical composition according to claim 4, which is in the form of tablets, capsules, powder, syrup, solution or suspension.

6. Method of treatment the disease, mediated by cyclooxygenase, including the introduction to a mammal in need, a therapeutically effective amount of compounds of General formula I according to claim 1, or a compound according to claim 2, or a pharmaceutical composition according to claim 4.

7. The method according to claim 6, in which the disease is an inflammation, arthritis or pain.

8. A method of inhibiting cyclooxygenase in cells comprising treating the cells with an effective amount of compounds of General formula (I) according to claim 1, or a compound according to claim 2, or a pharmaceutical composition according to claim 4.

9. The method according to claim 8, in which the processing cells perform in vitro.

10. The method according to claim 8, in which the processing of the cells is performed in vivo.

11. The method according to item 8, in which the cyclooxygenase-2 (CAH-2) inhibited stronger than cyclooxygenase-1 (CAH-1).



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel retinoid compounds of the structural formula (I) or their pharmaceutically acceptable salts and pharmaceutical compositions possessing agonistic activity with respect to retinoid receptors and comprising indicated compounds wherein n = 1; d = 0 or 1; B means -CR7=CR8-, -CH2O- wherein R7 and R8 each means independently hydrogen atom; X means phenyl optionally substituted with halogen atom, or 5-membered heteroaryl comprising sulfur atom (S) as a heteroatom; R1 means -C(=O)-R9 wherein R9 means alkyl, hydroxyl, amino-, heteroaryloxy-group comprising oxygen atom (O) or 6-membered heterocyclyl comprising nitrogen atom (N) as a heteroatom; R2 means: (a) -(CR10R11)m-Yp-R12; m means a whole number from 1 to 10; p means 0 or 1; R10 and R11 mean hydrogen atom; Y means -O-, -S- or -NR13-; R13 means hydrogen atom; R12 means hydrogen atom, alkyl, cycloalkyl, phenyl, 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heteroarylalkyl comprising atoms N, S, O as a heteroatom, heteroalkyl comprising atoms N, S, O as a heteroatom, 5- or 6-membered heterocyclyl comprising atoms N, S, O as a heteroatom, or 5- or 6-membered heterocyclylalkyl comprising atoms N, S, O as a heteroatom under condition that when p means 0 then R12 doesn't mean hydrogen atom or alkyl; (b) 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (c) -Z-L wherein Z means -CR14=CR15-, -C≡C-, -C(=O) or -S-; R14 and R15 mean hydrogen atom; L means 5- or 6-membered heteroaryl comprising atoms N, S, O as a heteroatom; (d) -CR14=CR15-L1 wherein L1 means -S(O)2R17 or -SO2NR18R19 wherein R17 means alkyl; R18 and R19 mean hydrogen atom; each R3 means independently hydrogen atom, hydroxyl or oxo-group; t means 1 or 2.

EFFECT: valuable medicinal properties of compounds and compositions.

59 cl, 10 tbl, 54 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

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

7 cl, 2 sch, 2 tbl, 1 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

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

4 cl, 2 tbl, 568 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

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, -СОNR9R10, -ОСОNR9R10or ОSO2R11where 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, hydroxy SS1-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 method thereof

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

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

9 cl, 2 tbl, 50 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

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

9 cl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present innovation deals with developing preparations based upon essential oils to treat inflammatory diseases of respiratory organs and motor system. The composition suggested contains chitosan and essential oils of different plants upon emulsion foundation. The method suggested could be applied as an additional remedy for external application at treating inflammatory diseases of respiratory organs, degenerative and inflammatory diseases of motor system. The composition is of high spectrum of action and prolonged analgesic effect.

EFFECT: higher efficiency of application.

11 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation refers to medicinal preparations applied for treating puerperal purulent-catarrhal endometritis and mastitis in cows and to the method of applying the present medicinal preparations. The suggested preparation for treating puerperal purulent-catarrhal endometritis, serous, seroso-catarrhal and subclinical mastitis in cows includes 1.4-di-N-oxide 2.3-bis-(oxymethyl) quinoxaline, trecresan (cresacin), dimethyl sulfoxide, propandiol 1.2 at the following ratio, (g/%): 1.4-di-N-oxide 2.3-bis-(oxymethyl) quinoxaline 1.0-1.2; trecresan (cresacin) 3.0-3.18; dimethyl sulfoxide 10.0-10.5; propandiol 1.2 20-25; distilled water - the rest. The innovation deals with intra-uterine introduction of the preparation suggested at the dosage of about 70-100 ml once daily for about 4-5 d. Moreover, this preparation should be introduced into affected part of the udder at the dosage of 10 ml once daily for 3-5 d. The innovation enables to shorten the multiplicity of introduction and accelerate the terms of recovery.

EFFECT: higher efficiency of therapy.

4 cl, 2 ex, 6 tbl

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel O-substituted derivatives of 6-methyltramadol of the general formula (I) being optionally as their racemates, their pure stereoisomers but primarily as enantiomers or diastereomers, or as mixtures of stereomers being primarily as enantiomers or disatereomers in any their ratio in the mixture as a presented formulation or as their physiologically compatible salts. In the general formula (I) the value R means hydrogen atom (H), (C1-C3)-alkyl that can be saturated or unsaturated, branched or a direct, unsubstituted or substituted with -O-(C1-C3)-alkyl-group or OH-group, -CH2-(C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl or thienyl group. Also, the invention relates to a method for synthesis of compounds of the general formula (I) by interaction of 2-dimethylaminomethyl-6-methylcyclohexanone of the formula (I) with metal-organic compound of the formula (III) wherein Z means Li; R has values given in the formula (I). The synthesized compounds of the formula (I) if necessary are converted to their physiologically compatible salts and/or racemates that are subjected for cleaving. Also, invention relates to a pharmaceutical composition.

EFFECT: improve method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 sch, 2 tbl, 30 ex

FIELD: chemical-pharmaceutical industry, medicine, peptides.

SUBSTANCE: invention relates to preparing and using peptides of the formula (I) possessing analgesic activity: A-B-Tyr-Pro(D-Pro, dHPro, D-dHPro, DL-dHPro, Hyp)-C-X wherein A means -O, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; B means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; C means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; X means -OH, -OCH3, -NH2. Proposed peptides can be used for design of new medicinal preparations. Peptides possess the enhanced activity as compared with pentalgin, analgin and morphine and have no toxic properties.

EFFECT: improved and valuable medicinal properties of peptides.

5 tbl, 4 ex

FIELD: pharmaceutical industry, in particular analgesic, vasodilatation, anti-inflammation ointment for topical application.

SUBSTANCE: claimed ointment is prepared in form of fine dispersed formulation containing bee venom extract melittin, lavender oil, camphor, arnica tincture, rosemary oil, eucalyptus oil, revitalin, carbopol, 30 % solution of sodium hydroxide, hydrophilic anionic ointment, soy lecithin, glycerol, conserving solution, ethanol, distilled water.

EFFECT: reduced toxicity of bee venom, decreased side effects and improved therapeutic effect.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, veterinary science, pharmacy.

SUBSTANCE: invention relates to derivatives of tetrahydropyranyl-cyclopentyl-tetrahydropyridopyridine of the formula (1): , wherein R3 means oxygen atom or absent; R8 is chosen from: (a) hydrogen atom; (b) (C1-C3)-alkyl that can be unsubstituted or substituted with 1-6 fluorine atoms; (c) -O-(C1-C3)-alkyl; (d) fluorine atom, and (e) hydroxy-group, and their pharmaceutically acceptable salts and separate diastereomers. These compounds are modulators of activity of chemokine receptors. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), method for modulation of activity of chemokine receptors in humans and animals and a method for preparing a medicinal agent. Invention provides preparing novel modulators of chemokine receptors activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexane of the formula (I): wherein U means a free electron pair; V means a simple bond, -CH2-, -CH=CH-, -CH=CH-CH2-O-, -C≡C-; W means -COO, -CSO or -SO2; m and n mean independently of one another numbers from 0 to 4; m + n = 0-7; A1 means hydrogen atom (H), lower alkyl, hydroxy-(lower)-alkyl or lower alkenyl; A2 means pyrrolyl, pyrimidinyl, optionally substituted (lower)-alkyl or lower alkyl optionally substituted with R2; or A1 and A2 are bound to form ring; -A1-A2- means lower alkylene optionally substituted with R2 wherein one group -CH2- in -A1-A2- can be optionally replaced for -NR3 or oxygen atom (O); A3, A4, A5, A6, A7 and A8 mean H; R9 means H, lower alkyl; R10 means (lower)-alkyl, phenyl wherein phenyl can be substituted with 1-3 substitutes chosen independently from the group comprising halogen atom, -CF3, (lower)-alkyl; p means 0, 1; R2 means H; R3 means H, lower alkyl, and their pharmaceutically acceptable salts. Compounds of the formula (I) possess the inhibitory effect on activity of enzyme oxidosqualene lanosterol cyclase and can be used in pharmaceutical composition. Also, method relates to a method for treatment and/or prophylaxis of hyperlipemia, artheriosclerosis, hypercholesterolemia and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 9 sch, 10 tbl, 43 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: one should introduce 10 ml 0.1%-serotonin adipinate twice daily for 10 d parenterally. The innovation enables to achieve rapid resorption of blood in ocular cavity after the hemorrhage occurred due to deblocking serotonin receptors against hemoglobin that provides normalization of microcirculation in choroidea and retina along with reconstructing inflow-outflow of intraocular liquid in ocular cavity.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

Up!