RU2288225C2 - Novel compounds possessing anti-inflammatory activity and pharmaceutical compositions comprising thereof - Google Patents

Abstract

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

Description

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

where R ¹ represents an amino or substituted or unsubstituted group selected from alkyl, alkylamino, acylamino, cycloalkyl, cycloamino, carbethoxycarbonylalkyl, hydrazino, hydrazido, amino acid residue, aryl, heteroaryl, or —N = CR (NR) ₂ , where R represents hydrogen or a lower alkyl group; R ² represents a halogen, hydroxy, cyano, nitro, azido, formyl, oxyalkyl, thio or a substituted or unsubstituted group selected from amino, alkyl, alkoxy, hydrazino, hydrazinoalkyl, hydrazido, hydrazidoalkyl, amino acid residue, alkylamino acid residue, alkyl, acyl , carbonyloxyalkyl, haloalkyl, aminoalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl , Aralkoksialkilnoy, karboksamidoalkilnoy, karbonilaminoalkilnoy groups, or, when the groups -S (= O) _m -R ¹ and R ² are on adjacent carbon atoms, R ¹ and R ² together with the atoms to which they are attached may also form a substituted or an 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; R ³ represents hydrogen, a halogen atom, hydroxy, nitro, cyano, azido or a substituted or unsubstituted group selected from hydrazino, hydrazinoalkyl, hydrazido, hydrazidoalkyl, amino acid residues, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, acylamino or amino groups; R ⁴ and R ⁵ may 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, hydrazinoalkyl, hydrazido , hydrazidoalkyl, amino acid residues, aminoacyl, carboxyalkyl, carboxyalkenyl, aryl, aryloxy, aralkyl, aralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryl, heteroaryloxy, heteroaryl, heteroaryloxy, heteroaryloxy aryloxycarbonyl, heteroaralkylcarbonyl, heteroaralkoxycarbonyl, heterocyclylcarbonyl, aminocarbonyl, aminocarbonylalkyl, carbonylamino, cycloalkylacylamino, alkylaminoalkoxy, alkylaminoacyl, carboxylic acid or derivatives thereof, saturated or partially saturated aromatic non-condensed or non-saturated aromatic non-condensed or condensed or a fused 5-7 membered heterocyclic ring; R ⁶ represents hydrogen, halogen, hydroxy, amino, cyano, nitro, thio, hydroxylamino or an unsubstituted or substituted group selected from alkyl, alkoxy, carboxyalkyl; moreover, the furanone ring, if possible, can be condensed with R ⁴ , R ⁵ and R ⁶ together can be = C (R ^a ) (R ^b ), where R ^a and R ^b can be the same or different and independently represent hydrogen, substituted or unsubstituted (C ₁ -C ₆ ) alkyl or aryl; = O or = NR ⁷ , where R ⁷ represents hydrogen, an aryl or heteroaryl group; X represents oxygen or NR ⁸ , where R ⁸ represents hydrogen or an unsubstituted or substituted group selected from (C ₁ -C ₆ ) alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, aralkenoyl, aralkanoyl, and m is an integer from 0 up to 2.

The present invention also relates to a method for producing the above new compounds, their analogues, their derivatives, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.

The present invention also relates to new intermediates, methods for their preparation and their use for the preparation of compounds (I).

The compounds of general formula (I) are useful as anti-inflammatory, analgesic, antipyretic, anti-arthritic, antibacterial, anti-tumor agents or for the treatment of Alzheimer's disease. The compounds of the present invention are also useful in 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, therefore, can be used to treat dysmenorrhea, premature birth and asthma. The compounds of the present invention are useful for treating pain, fever and inflammation associated with general hypothermia, influenza, and viral infections. The compounds of the present invention can be used to treat arthritis, such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, spondylosis arthritis; systemic lupus erythematosus, skin inflammatory diseases such as eczema, burns, dermatitis, psoriasis; pains in the lower back and neck, headache, toothache, sprain, sprains, myositis, neuralgia, synovitis, bursitis, tendovaginitis, injuries from surgical and dental procedures, postoperative inflammation, including ophthalmic surgery such as cataract and refractive surgery.

The compounds of general formula (I) are also useful for treating dysmenorrhea, preterm labor, asthma and bronchitis, gastrointestinal diseases such as inflammatory bowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, diverticulitis, local enteritis, and gastric ulcer. These compounds can also be used to treat inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Behkat’s syndrome, Hodgkin’s disease, scleroderma, severe myasthenia gravis, sarcoidosis, nephrotic syndrome, type I diabetes, polymyositis, conjunctivitis, gingivitis, myocardial ischemia, nephritis, post-traumatic edema, allergies and the like. The compounds of the present invention are useful for the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, 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, juveitis, ocular photophobia and acute damage to eye tissues. The compounds of general formula (I) are also useful for treating diseases of the central nervous system, such as cortical dementia (Alzheimer's disease), they are also useful for treating pain, not limited to toothache, muscle pain, cancer pain, postoperative pain and are useful for treating diseases where NSAIDs are used to significantly reduce side effects.

The compounds of general formula (I) are cyclooxygenase inhibitors and, therefore, are useful for the treatment of diseases mediated with cyclooxygenase. The compounds of formula (I) are also useful for the treatment of mammals (not limited to humans) such as horses, dogs, cats, sheep, pigs, etc., as well as for the treatment of rats, mice, rabbits, etc. The compounds of formula (I) can also be used in joint therapy for the treatment of inflammation, Alzheimer's disease or cancer, instead of or together with conventional drugs.

The compounds of general formula (I) are useful as partial or complete substituents for NSAIDs in the compositions or preparations in which they are currently used in combination with other agents or ingredients. The present invention also includes pharmaceutical compositions for treating cyclooxygenase-mediated diseases as described above, comprising a non-toxic therapeutically effective amount of a compound of formula (I) as defined above, and a pharmaceutically acceptable carrier, optionally containing one or more ingredients, such as another analgesic agent, such as acetaminophen, phenacetin, a potentiating substance such as caffeine, an H ₂ antagonist, aluminum or magnesium hydroxide, simethicone, decongestant thyroid, such as phenylephrine, phenylpropanolamine, pseudo-ephedrine, oxymetazoline, epinephrine, nefazolin, propylhexadrine or lilodeoxyephedrine, xylomatazoline, a sedative or non-sedative antihistamine, anti-cough agents such as dextromethorphan, carbetapentane, and iurene di-carafine, and karamine and kaifen; The present invention also includes a method of treating cyclooxygenase-mediated diseases, comprising administering to a patient in need thereof a non-toxic therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition described above.

State of the art

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat arthritis and pain. These agents act by inhibiting the production of prostaglandin, which plays an important role in the inflammatory process. The synthesis of prostaglandin is inhibited by blocking the cyclooxygenase (COX) enzyme (Vane J. R. Nature [New Biol.] 1971, 231-232). However, these NSAIDs, as it was found, although they reduce inflammation and the associated symptoms induced by prostaglandin, also act on prostaglandin, which regulates other necessary processes, causing side effects [Allison M. C., et al., J. Med. 1992, 327, 749]. Side effects of NSAIDs include hypersecretion and heartburn, platelet aggregation blockade, inhibition of uterin, contractility, inhibition of prostaglandin, which regulates renal function and allergic reactions.

It has recently been discovered that there are two isoforms of the cyclooxygenase enzyme, namely COX-1 and COX-2. Although COX-1 is the main isoform found in the blood vessels, stomach, and kidneys, COX-2 is produced during inflammation. Therefore, selective inhibition of the COX-2 enzyme may be useful for treating inflammation without the occurrence of side effects due to inhibition of COX-1.

On the other hand, leukotrienes are also mediators of inflammation and related diseases. Leukotrienes (LTB4, LTC4, LTD4, etc.) are produced by 5-lipoxygenase-mediated oxidation of arachidonic acid. Therefore, inhibition of the 5-lipoxygenase (5-LO) enzyme may also be useful in treating inflammation and related diseases. Consequently, it is possible to treat inflammation with agents that can selectively inhibit COX-2 or 5-LO, or both, without the possible side effects that occur with ongoing treatment with conventional NSAIDs.

Recently, it has been shown that an increase in the expression of COX-2 occurs in colon tumors. Therefore, agents that can inhibit COX-2 can also be used to treat cancer.

Studies have shown that brain tissue in Alzheimer's patients often have high levels of COX-2. This shows the suitability of using COX-2 inhibitors for treating Alzheimer's disease and for improving memory.

Some heterocyclic compounds, their derivatives and their analogs, useful for treating inflammation, have been reported. Some of these compounds described in the prior art are listed below.

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

where R ¹ represents an alkyl or a group NR ⁴ R ⁵ where R ⁴ and R ⁵ each independently represents hydrogen or an alkyl or benzyl group; R ² represents naphthyl, tetrahydronaphthyl, unsubstituted phenyl or phenyl group substituted by 1-3 halogen atoms, alkyl, hydroxy, alkoxy or trifluoromethyl groups, and R ³ represents hydrogen or an alkyl group. Examples of these compounds are given in formula (IIb)

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

where R ¹ represents hydrogen, alkoxycarbonyl, carboxy, halogen, alkyl, phenyl or alkanoyl; R ² , R ³ and R ⁴ are hydrogen, alkyl, alkoxy or halogen; X represents alkyl or NH ₂ .

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

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

where —YZ— is selected from the group consisting of —CH ₂ CH ₂ CH ₂ -, —C (O) CH ₂ CH ₂ -, —CH ₂ CH ₂ C (O) -, CR ⁵ (R ⁵ ) —OC ( O) -, -C (O) -O-CR ⁵ (R ^{5 '} ), CH ₂ -NR ³ -CH ₂ -, CR ⁵ (R ⁵ ') -NR ³ -C (O) -, -CR ⁴ = CR ^4'- S-, -S-CR ⁴ = CR ^4'- , -SN = CH-, -CH = NS-, -N = CR ⁴ -O-, -O-CR ⁴ = N-, - N = CR ⁴ -NH-, -N = CR ⁴ -S-, -S-CR ⁴ = N-, -C (O) -NR ³ -CR ⁵ (R ^{5 '} ) -, -NR ³ -CH = CH-, provided that R ^{1 is} not —S (O) ₂ Me, —CH = CH — NR ³ -, provided that R is not —S (O) ₂ Me; when side b is a double bond and sides a and c are single bonds and XYZ- is selected from the group consisting of = CH-O-CH =, = CH-NR ³ -CH =, = NS-CH =, = CH-SN =, = NO-CH =, = CH-ON =, = NSN =, = NON =, when sides a and c are double bonds and side b is a simple bond; R 'is selected from the group consisting of S (O) ₂ CH ₃ , S (O) ₂ NH ₂ , S (O) ₂ NHC (O) CF ₃ , S (O) (NH) CH ₃ , S (O) (NH) NH ₂ , S (O) (NH) NHC (O) CF ₃ , P (O) (CH ₃ ) OH and P (O) (CH ₃ ) NH ₂ ; R ² selected from the group consisting of (C ₁ -C ₆ ) alkyl; (C ₃ -C ₇ ) cycloalkyl; mono, di or trisubstituted phenyl, where the substituent is selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, CN, CF ₃ , (C ₁ -C ₆ ) alkyl , N ₃ , -CO ₂ H, -CO ₂ - (C ₁ -C ₄ ) alkyl, -C (R ⁵ ) (R ⁶ ) -OH, -C (R ⁵ ) (R ⁶ ) -O- (C ₁ -C ₄ ) alkyl; and - (C ₁ -C ₆ ) alkyl-CO ₂ -R ⁵ ; mono, di or trisubstituted heteroaryl, where heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is S, O or N and optionally 1, 2, 3 or 4 additional N atoms, said substituents are selected from a group consisting of hydrogen, halogen, including fluorine, chlorine, bromine and iodine, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio, CN, CF ₃ , N ₃ , -C (R ⁵ ) (R ⁶ ) -OH and -C (R ⁵ ) (R ⁶ ) -O- (C ₁ -C ₄ ) alkyl; R ^{3 is} selected from the group consisting of hydrogen, CF ₃ , CN, (C ₁ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) alkyl, —C (O) - (C ₁ -C ₆ ) alkyl, and optionally substituted - (C ₁ -C ₅ ) alkyl-Q, - (C ₁ -C ₃ ) alkyl-O- (C ₁ -C ₃ ) alkyl-Q, - (C ₁ -C ₃ ) alkyl-S- (C ₁ -C ₃ ) alkyl-Q, - (C ₁ -C ₅ ) alkyl-OQ or - (C ₁ -C ₅ ) alkyl-SQ, where the substituents are on alkyl and the substituent is (C ₁ -C ₃ ) alkyl; or R ³ is —Q; R ⁴ and R ^{4 are} each independently selected from the group consisting of hydrogen, CF ₃ , CN, (C ₁ -C ₆ ) alkyl, -Q, -OQ, -SQ, and optionally substituted (C ₁ -C ₅ ) alkyl- Q, -O- (C ₁ -C ₅ ) alkyl-Q, -S- (C1-C5) alkyl-Q, - (C ₁ -C ₃ ) alkyl-O- (C ₁ -C ₃ ) alkyl-Q , - (C ₁ -C ₃ ) alkyl-S- (C ₁ -C ₃ ) alkyl-Q, - (C ₁ -C ₅ ) alkyl-OQ or - (C ₁ -C ₅ ) alkyl-SQ, where the substituents located on alkyl, and the substituent is (C ₁ -C ₃ ) alkyl; and R ⁵ , R ^{5 ′} , R ⁶ , R ⁷ and R ^{8 are} each independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, or R ⁵ , R ^{5 ′} , R ⁶ , R ⁷ and R ⁸ together with the carbon to which they are attached, form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms. Q represents CO ₂ H, CO ₂ - (C ₁ -C ₄ ) alkyl, tetrazolyl-5-yl, C (R ⁷ ) (R ⁸ ) (OH) or C (R ⁷ ) (R ⁸ ) -O- (C ₁ -C ₄ ) alkyl; provided that when XYZ is S-CR ⁴ = CR ^{4 ′} , then R ⁴ and R ^{4 ′} are other than CF ₃ .

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

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

where A is a 5- or 6-membered ring substituent selected from partially unsaturated heterocyclic and carbocyclic rings, A may optionally be substituted with a radical selected from acyl, halogen, alkyl, haloalkyl, cyano, nitro, carboxyl, alkoxy, oxo, aminocarbonyl alkoxycarbonyl, carboxyalkyl, cyanoalkyl and hydroxyalkyl; Y represents a radical selected from oxy, thio, sulfinyl, sulfonyl, alkyl, alkenyl, alkynyl, alkyloxy. alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, hydroxyalkyl, hydroxyalkyloxy, gidroksialkiloksialkila, gidroksialkiltio, gidroksialkiltioalkila, oksiminoalkoksi, oksiminoalkoksialkila, (alkyl) oksiminoalkoksi, (alkyl) oksiminoalkoksialkila, oksiminoalkiltio, oksiminoalkiltioalkila, (alkyl) oksiminoalkiltio, (alkyl) oksiminoalkiltioalkila, karbonilalkiloksi, carbonylalkyloxyalkyl, carbonylalkylthio, carbonylalkylthioalkyl, heterocyclo, cycloalkenyl, aralkyl, heterocycloalkyl, acyl, alkylthioalkyl, alkyloxy hernia, alkenylthio, alkynylthio, alkenyloxy, alkynyloxy, alkeniltioalkila, alkeniloksialkila, alkiniloksialkila, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkilarilalkiniloksi, alkilarilalkeniloksi, alkilarilalkiniltio, alkilarilalkeniltio, haloalkylcarbonyl, alkoxyalkyl, alkilaminokarbonilalkila, geteroaralkoksialkila, heteroaryloxyalkyl, geteroariltioalkila, geteroaralkiltioalkila, heteroaralkoxy, geteroaralkiltio, heteroaryloxy, heteroarylthio, arylthioalkyl, aryloxyalkyl, haloaryloxyalkyl, aralkylthioal hernia, aralkoxyalkyl, alkoksiaralkoksialkila, alkoxycarbonylalkyl, alkoksikarboniltsianoalkenila, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N, N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, tsikloalkilaminokarbonila, geterotsikloaminokarbonila, karboksialkilaminokarbonila, alkylcarbonylalkyl, aralkoksikarbonilalkilaminokarbonila, galogenaralkila, karboksigalogenalkila, alkoksikarbonilgalogenalkila, aminocarbonylhaloalkyl, alkylaminocarbonylhaloalkyl, N-alkylamino, N, N-dialkylamino, N-ari amino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl, N, N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aminoalkoxy, aminoalkoksialkila, aminoalkiltio, aminoalkiltioalkila, cycloalkyloxy, tsikloalkilalkiloksi, cycloalkylthio, tsikloalkilalkiltio, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N, N-dialkylaminosulfonyl, N -alkyl-N-arylaminosulfonyl, or Y represents the following groups

Ar is selected from aryl and heteroaryl, Ar may be optionally substituted with one or two substituents selected from halogen, hydroxyl, mercapto, amino, nitro, cyano, carbamoyl, alkyl, alkenyloxy, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonyl, alkylamino, dialkylamino, , alkoxycarbonyl, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, alkanoylamino, cyanoalkoxy, carbamoylalkoxy, alkoxycarbonylalkoxy and

where R ¹ represents one or more substituents selected from heterocycle, cycloalkyl, cycloalkenyl and aryl, R ¹ may optionally be substituted in the substituted position by one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halogen, alkoxy and alkylthio; R ² selected from alkyl and amino; where R ³ and R ⁴ together form a group of formula -B-X-B ¹ , which, together with the carbon atom to which B and B ^{1 are} attached, form a ring having 6 ring atoms, where B and B ¹ , which may be the same or different, each is alkylene, and X is hydroxy, and the ring may include one, two or three substituents, which may be the same or different, selected from hydroxyl, alkyl, alkoxy, alkenyloxy and alkynyloxy; where R ^{5 is} selected from hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyl, acyl and cyano; where R ⁶ selected from hydrido, alkyl, aryl and aralkyl; where R ⁷ selected from alkyl, alkoxy, alkenyl and alkynyl; where R ⁸ represents an oximino optionally substituted with alkyl; where n is 0 or 1; provided that Ar is substituted

where R ³ , R ⁴ R ⁵ , R ⁸ and n are as defined above.

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

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

where R ¹ represents halogenated; R ² is aryl optionally substituted in an appropriate position by one or more radicals independently selected from alkylsulfinyl, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkyl, amino, alkylamino, arylamino, nitro, halogen, alkoxy and alkyl ; R ³ is aryl, suitably substituted with a radical selected from alkylsulfonyl and sulfamyl, and R ^{4 is} selected from halogen, alkoxy and alkynyloxy.

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

(vi) DE 19533643 describes compounds of formula (IIk)

where A represents O, S or NH; R ¹ represents an optionally substituted cycloalkyl, aryl or heteroaryl; R ² represents hydrogen, optionally substituted alkyl, aralkyl, aryl, heteroaryl or (CH ₂ ) _n —X; Z represents CH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₂ CH = CH, CH ₂ CO, NHCO, NHCH ₂ , N = CH, NHCH, CH ₂ CH ₂ NH, CH = CH, C = O, S (O) _m or optionally substituted NH; m is 0-2; n is 0-8; X is halogen, NO ₂ optionally substituted with OH, COH, COOH, COOH, CONHOH, CONH ₂ , SH, S (O) H, SO ₂ H, NH ₂ , NHCOH or NHSO ₂ H or CN; R ⁶ is optionally substituted (C ₁ -C ₄ ) alkyl.

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

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

where R ^{2 is} selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxy, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonylalkylcarbonylalkylalkyl, aralkoxycarbonylalkylalkylalkyl, where R ³ selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen; R ^{4 is} selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclyl; R ⁴ is an optionally substituted one or more radicals selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxy carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfamyl, heterocycle and amino; with the proviso that R ² and R ³ are not simultaneously hydridos; also provided that R ^{2 is} not carboxyl or methyl when R ³ is hydrido and when R ⁴ is phenyl; also provided that R ^{4 is} not triazolyl when R ² is methyl; also provided that R ^{4 is} not aralkenyl when R ² is carboxyl, aminocarbonyl or ethoxycarbonyl; also provided that R ^{4 is} not phenyl when R ² is methyl and R ³ is carboxyl; and provided that R ^{4 is} not unsubstituted thienyl when R ² is trifluoromethyl.

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

(viii) WO 96/19462 describes compounds of formula (IIo)

where one of R, R ¹ represents methylsulfonylphenyl, aminosulfonylphenyl or alkylaminosulfonylphenyl, and the other represents 5-7-carbon cycloalkyl, optionally substituted by alkyl, thienyl or furyl, optionally substituted by alkyl or halogen; R ² represents lower alkyl.

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

Object of the invention

To develop new compounds for the treatment and / or prophylaxis of diseases or conditions mediated with cyclooxygenase, more specifically COX-2 and other related diseases, such as pain, fever or inflammation, for inhibiting prostanoid-induced smooth muscle contraction, for the treatment of Alzheimer's disease, colon cancer, for the treatment of pain, fever and inflammation associated with hypothermia, flu, viral infections, for the treatment of arthritis such as rheumatoid arthritis, osteoarthritis, gouty arthritis juvenile arthritis, spondylitis arthritis; systemic lupus erythematosus, skin inflammatory diseases such as eczema, burns, dermatitis, psoriasis; pain in the lower back and neck, dysmenorrhea, headache, toothache, sprain, sprains, myositis, neuralgia, synovitis, bursitis, tendovaginitis, injuries from surgical and dental procedures, postoperative inflammation, including ophthalmic surgery such as cataract removal and surgical Operations aimed at correcting refraction, with better efficiency, activity and lower toxicity, new compounds have been developed that are effective for the treatment of the above diseases. Research in this direction has led to the development of compounds of general formula (I).

The main objective of the present invention is, therefore, the preparation of new compounds and their derivatives, their analogues, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or mixtures thereof.

Another objective of the present invention is to obtain new compounds and their derivatives, their analogues, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having increased activity, without toxic effects or with reduced toxic effects.

Another objective of the present invention is to develop a method for producing new compounds and their derivatives of formula (I), as defined above, their analogues, their tautomeric forms, their stereoisomers, their regioisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.

The next objective of the present invention is to obtain pharmaceutical compositions containing compounds of General formula (I), their analogues, their derivatives, their tautomers, their stereoisomers, their regioisomers, their polymorphs, their salts, solvates or their mixtures in combination with pharmaceutically acceptable carriers, solvents , diluents and other media commonly used in the preparation of such compositions, optionally containing one or more ingredients, such as another analgesic agent, like acetaminophen, phenacetin, sweat nizing agent, such as caffeine, H ₂ antagonist, aluminum or magnesium hydroxide, simethicone, decongestant, such as phenylephrine, phenylpropanolamine, pseudohedrine, oxymethazoline, epinephrine, nefazolin, propylhexadrine or livedesoxyephedrine, xylomatamine non-sedative, antioxidant, antioxidant, antioxidant, antioxidant, antioxidant such as dextromethorphan, carbetapentane, karamifen, hydrocodeine and codeine and the like, or a diuretic.

The present invention also relates to a method for treating cyclooxygenase-mediated diseases, comprising administering to a patient in need thereof a non-toxic therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition described above.

The present invention also relates to new intermediates of the formulas (I-1), (I-3), (I-5), (I-7), (II-1), (II-2) and (II-4) .

SUMMARY OF THE INVENTION

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

where R ¹ represents an amino or substituted or unsubstituted group selected from alkyl, alkylamino, acylamino, cycloalkyl, cyclic amino, carbethoxycarbonylalkyl, hydrazino, hydrazido, amino acid residue, aryl, heteroaryl or —N = CR (NR) ₂ , where R represents represents hydrogen or a lower alkyl group; R ² represents halogen, hydroxy, cyano, nitro, azido, formyl, oxyalkyl, thio or a substituted or unsubstituted group selected from amino, alkyl, alkoxy, hydrazino, hydrazinoalkyl, hydrazido, hydrazidoalkyl, amino acid residue, alkylamino acid residue, acyl, carbonylalkylalkyl , haloalkyl, aminoalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, aralkoxyalkyl, carboxamidoalkyl, carbonylamino noy group or when the group -S (= O) _m -R ¹ and R ² are on adjacent carbon atoms, R ¹ and R ² together with the atoms to which they are attached may also form a substituted or unsubstituted 5-7-membered a cyclic structure containing carbon atoms, a sulfur atom, and may optionally contain one or two heteroatoms selected from O, S or N; R ³ represents hydrogen, a halogen atom, hydroxy, nitro, cyano, azido or a substituted or unsubstituted group selected from hydrazino, hydrazinoalkyl, hydrazido, hydrazidoalkyl, amino acid residues, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, acylamino or amino groups; R ⁴ and R ⁵ may 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, hydrazinoalkyl, hydrazido , hydrazidoalkyl, amino acid residues, aminoacyl, carboxyalkyl, carboxyalkenyl, aryl, aryloxy, aralkyl, aralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroaryl, heteroaryloxy. heteroaralkyl, heteroaralkoxy, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroaralkylcarbonyl, heteroaralkoxycarbonyl, heterocyclylcarbonyl, aminocarbonyl, aminocarbonylalkyl, carbonylamino, cycloalkyl acyloalkyl or partially saturated alkyl or alkylalkyl, or partially saturated or aromatic, non-condensed or condensed a 5-7 membered heterocyclic ring; R ⁶ represents hydrogen, halogen, hydroxy, amino, cyano, nitro, thio, hydroxylamino or a substituted or unsubstituted group selected from alkyl, alkoxy, carboxyalkyl; the furanone ring may be condensed with R ⁴ , if possible; R ⁵ and R ⁶ together can be = C (R ^a ) (R ^b ), where R ^a and R ^b can be the same or different and independently represent hydrogen, (C ₁ -C ₆ ) alkyl or aryl; = O or —NR ⁷ where R ⁷ represents hydrogen, aryl or heteroaryl group; X represents oxygen or NR ⁸ , where R ⁸ represents hydrogen or a substituted or unsubstituted group selected from (C ₁ -C ₆ ) alkyl, aryl, aralkyl, heteroaryl, heteroalkyl, aralkenoyl, aralkanoyl, and m is an integer in the range from 0 to 2.

DETAILED DESCRIPTION OF THE INVENTION

Suitable groups representing R ¹ may be selected from an amino, substituted or unsubstituted linear or branched (C ₁ -C ₆ ) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like; (C ₁ -C ₆ ) alkylamino groups such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino and the like, which may be substituted; acylamino groups such as NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₆ H ₅ and the like, which may be substituted; (C ₃ -C ₈ ) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which may be substituted; a cyclic amino group such as aziridine, pyrrolidine, piperidine and the like, the cyclic amino group may be substituted; a carboethoxycarbonyl (C ₁ -C ₆ ) alkyl group such as carboethoxycarbonylmethyl, carboethoxycarbonylethyl, carboethoxycarbonylpropyl and the like, a carboethoxycarbonyl (C ₁ -C ₆ ) alkyl group may be substituted; hydrazino, 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; an aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; a 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 a (C ₁ -C ₆ ) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.

Suitable groups representing R ² may be selected from a halogen atom such as chlorine, fluorine, bromine or iodine; hydroxy, cyano, nitro, azido, formyl, oxime (C ₁ -C ₆ ) alkyl groups such as oxymethyl, oxymethyl, oximpropyl and the like; thio, an amino group which may be substituted; substituted or unsubstituted linear or branched (C ₁ -C ₆ ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like ; (C ₁ -C ₆ ) alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; hydrazino, which may be substituted; hydrazino (C ₁ -C ₆ ) alkyl groups such as hydrazinomethyl, hydrazinoethyl, hydrazinopropyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazido (C ₁ -C ₆ ) alkyl, such as hydrazidomethyl, hydrazidoethyl, hydrazidopropyl and the like, which may be substituted; an amino acid residue, where the amino acid is selected from glycine, alanine, phenylalanine, lysine and the like, which may be substituted; (C ₁ -C ₆ ) alkyl amino acid residue, where the amino acid is as defined above, which may be substituted; an acyl group such as acetyl, propanoyl, benzoyl and the like, which may be substituted; carbonyloxy (C ₁ -C ₆ ) alkyl groups such as carbonyloxymethyl, carbonyloxyethyl, carbonyloxypropyl and the like, which may be substituted; halogen (C ₁ -C ₆ ) alkyl, such as chloromethyl, bromoethyl, chlorpropyl, chlorisopropyl and the like, which may be substituted; amino (C ₁ -C ₆ ) alkyl, such as aminomethyl, aminoethyl, aminopropyl, aminoisopropyl and the like, which may be substituted; halogen (C ₁ -C ₆ ) alkoxy, such as chloromethoxy, bromethoxy, chlorpropoxy, brompropoxy and the like, which may be substituted; hydroxy (C ₁ -C ₆ ) alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and the like, which may be substituted; alkoxy (C ₁ -C ₆ ) alkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; thio (C ₁ -C ₆ ) alkyl, such as thiomethyl, thioethyl, thiopropyl, thioisopropyl and the like, which may be substituted; (C ₁ -C ₆ ) alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio and the like, which may be substituted; (C ₁ -C ₆ ) alkylsulfinyl, such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, butylsulfinyl and the like, (C ₁ -C ₆ ) alkylsulfinyl group may be substituted, (C ₁ -C ₆ ) alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like, (C ₁ -C ₆ ) alkylsulfonyl group may be substituted; an aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl, such as benzyl, phenethyl, C ₆ H ₅ CH ₂ CH ₂ CH ₂ , naphthylmethyl and the like, the aralkyl group may be substituted; aryloxy groups such as phenoxy, naphthyloxy and the like, the aryloxy group may be substituted; aralkoxy groups such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, which may be substituted; an aryloxyalkyl group such as C ₆ H ₅ OCH ₂ , C ₆ H ₅ OCH ₂ CH ₂ , naphthyloxymethyl and the like, which may be substituted; an aralkoxyalkyl group such as C ₆ H ₅ CH ₂ OCH ₂ , C ₆ H ₅ CH ₂ OCH ₂ CH ₂ and the like, which may be substituted; carboxamido (C ₁ -C ₆ ) alkyl, such as carboxamidomethyl, carboxamidoethyl, carboxamidopropyl and the like, carboxamido (C ₁ -C ₆ ) alkyl group may be substituted; carbonylamino (C ₁ -C ₆ ) alkyl groups such as carbonylaminomethyl, carbonylaminoethyl, carbonylaminopropyl and the like, carbonylamino (C ₁ -C ₆ ) alkyl may be substituted.

When R ¹ and R ² together form a cyclic structure, R ¹ and R ² together represent substituted or unsubstituted —NH — C (═O) - (CH ₂ ) n—, —CH ₂ - (CH ₂ ) _n -, - (CH ₂ ) _n -C (= O) -, -CH ₂ -C (= O) -CH ₂ -, -NH- (CH ₂ ) _n -, -NH-C (= O) -, -NH- (CH ₂ ) _n -C (= O) -, - (CH ₂ ) _n -C (= O) -NH-, -NH- (CH ₂ ) _n -O-, -NH- (CH ₂ ) _n - S-, -CH ₂ - (CH ₂ ) _n -O-, -CH ₂ - (CH ₂ ) _n -S-, where n is an integer in the range 1-2.

The substituents on R ¹ and R ² may be selected from hydroxy, linear or branched (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, aryl, aralkyl, aralkoxy, acyl, heteroaryl, such as pyridyl, furyl, thiophenyl oxazolyl and the like; heteroalkyl, such as pyridylmethyl, pyridylethyl, furanmethyl, furanethyl and the like; heterocyclyl such as morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, dihydro-3-oxo-1,1-dioxo-benzo [b] isothiazolyl, benzoisothiazolyl, benzothiazolyl and the like; sulfonyl, (C ₁ -C ₆ ) alkylsulfinyl, arylsulfinyl such as phenylsulfonyl, naphthylsulfonyl and the like; (C ₁ -C ₆ ) alkylsulfonyl, arylsulfonyl, such as phenylsulfinyl, naphthylsulfinyl 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 groups.

Suitable groups representing R ³ may be selected from hydrogen, a halogen atom such as chlorine, fluorine, bromine or iodine; hydroxy, nitro, cyano, azido, hydrazino, which may be substituted; hydrazino (C ₁ -C ₆ ) alkyl groups such as hydrazinomethyl, hydrazinoethyl, hydrazinopropyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazido (C ₁ -C ₆ ) alkyl, such as hydrazidomethyl, hydrazidoethyl, hydrazidopropyl 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 (C ₁ -C ₆ ) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl and the like, which may be substituted ; (C ₁ -C ₆ ) alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; hydroxy (C ₁ -C ₆ ) alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and the like, which may be substituted; A (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and the like, which may be substituted; acylamino groups such as NHCOCH ₃ , NHCOC ₂ H ₅ , NHCOC ₃ H ₇ , NHCOC ₆ H ₅ and the like, which may be substituted; an amino group which may be substituted.

Suitable groups representing R ⁴ and R ⁵ may be selected from hydrogen, a halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, cyano, nitro, thio, hydroxylamino, substituted or unsubstituted linear or branched (C ₁ -C ₆ ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- pentyl, isopentyl, hexyl and the like; (C ₁ -C ₆ ) alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, (C ₁ -C ₆ ) alkoxy groups may be substituted; an acyl group such as formyl, acetyl, propanoyl, benzoyl and the like; an acyl group may be substituted; an acyloxy group such as OSOMe, OCOEt, OCOPh and the like, the acyloxy group may be substituted; amino groups which may be substituted; hydrazino, which may be substituted; hydrazino (C ₁ -C ₆ ) alkyl groups such as hydrazinomethyl, hydrazinoethyl, hydrazinopropyl and the like, which may be substituted; hydrazido, which may be substituted; hydrazido (C ₁ -C ₆ ) alkyl, such as hydrazidomethyl, hydrazidoethyl, hydrazidopropyl 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, aminopropanoyl, aminobutanoyl and the like, which may be substituted; carboxy (C ₁ -C ₆ ) alkyl, such as carboxymethoxy, carboxyethyl, carboxypropyl and the like, which may be substituted; carboxy (C ₂ -C ₆ ) alkenyl, such as carboxyethenyl, carboxypropenyl, carboxybutenyl and the like, which may be substituted; an aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aryloxy groups such as phenoxy, naphthyloxy and the like, the aryloxy group may be substituted; an aralkyl group such as benzyl, phenethyl, C ₆ H ₅ CH ₂ CH ₂ CH ₂ , naphthylmethyl and the like, the aralkyl group may be substituted; aralkoxy groups such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, which may be substituted; (C ₁ -C ₆ ) alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like, (C ₁ -C ₆ ) alkoxycarbonyl may be substituted; aryloxycarbonyl, such as phenoxycarbonyl, naphthyloxycarbonyl and the like, which may be substituted; an aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; aminocarbonyl, which may be substituted; carbonylamino, which may be substituted; aminocarbonyl (C ₁ -C ₆ ) alkyl, such as aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl and the like, aminocarbonyl (C ₁ -C ₆ ) alkyl may be substituted; (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy groups such as methylaminomethoxy, ethylaminoethoxy, methylaminoethoxy, ethylaminomethoxy, propylaminoethoxy and the like, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkoxy group substituted; (C ₁ -C ₆ ) alkylaminoacyl groups such as methylaminoacetyl, ethylaminopropanoyl, methylaminopropanoyl, ethylaminoacetyl and the like, (C ₁ -C ₆ ) alkylaminoacyl group may be substituted; (C ₃ -C ₈ ) cycloalkylacylamino such as cyclopropylacylamino, cyclobutylacylamino, cyclobutylacylamino and the like, (C ₃ -C ₈ ) cycloalkylaminoacyl may be substituted; substituted or unsubstituted carbocyclic groups such as phenyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like; heteroaryl and heterocyclic groups, such as pyrrolyl, pyrrolidinyl, furyl, dihydrofuryl, tetrahydrofuryl, furanonyl, benzofuryl, dihydrobenzofuryl, benzofuranonyl, thienyl, benzothienyl, dihydrobenzodiazolazoleazoleazoleazoleazole-aziazolazole , thiadiazolyl, triazolyl, tetrazolyl, indolyl, azaindolyl, indolinyl, dihydroindolinyl, dihydroindolinolyl, azaindolinyl, pyranyl, benzopyranyl, dihydrobenzopyranyl, tetrahydrobenzopyranyl, diazine l, triazinyl, tetrazinyl, pyridyl, piperidinyl, piperidinone, pyridazinyl, pyrazinyl, piperazinyl, morpholinyl, quinolinyl, dihydroquinolinyl, oxazinyl, benzoxazinyl, digidrobenzoksazinil, thiazinyl, benzothiazinyl, digidrobenzotiazinil, quinazolinyl, dihydroquinazolinyl, phthalazinyl, dihydrophthalazine, hinaoksalinil, dihydrobenzothienyl-1- oxide, dihydrobenzothienyl-1,1-dioxide, which may be substituted; heterocyclylcarbonyl groups such as pyrrolidinylcarbonyl, morpholinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl and the like, the heterocyclic group may be substituted; a heteroaryl carbonyl group such as a pyridylcarbonyl, thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, oxazolylcarbonyl, thiazolylcarbonyl, oxadiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl and the like, the heteroaryl group may be substituted; heteroaryloxy, heteroaralkyl such as pyridylmethyl, pyridylethyl, furanmethyl, furanethyl and the like; heteroaralkoxy, heteroaralkylcarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl and heteroaralkyl groups are as defined above that may be substituted; carboxylic acid or its derivatives, such as amides, like CONH ₂ , CONHMe, CONMe ₂ , CONHEt, CONEt ₂ , CONHPh and the like.

Suitable substituents for the groups representing R ⁴ and R ⁵ are selected from a halogen atom such as fluoro, chloro, bromo or iodo; hydroxy, cyano, nitro, optionally halogenated (C ₁ -C ₆ ) alkyl, optionally halogenated (C ₁ -C ₃ ) alkoxy, acyl, amino, acylamino, (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl such as morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and the like; heteroaryloxy, heteroaralkyl, heteroaryloxy, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonylamino, heteroaralkoxycarbonylamino, acyloxy, (C ₁ -C ₆ ) alkoxycarbonyl, aryloxycarbonyl. aralkoxycarbonyl, mono (C ₁ -C ₆ ) alkylamino such as methylamino, ethylamino, isopropylamino and the like, (C ₁ -C ₆ ) dialkylamino such as dimethylamino, methylethylamino and the like; arylamino, such as phenylamino, naphthylamino and the like; aralkylamino such as benzylamino, phenethylamino and the like; amino (C ₁ -C ₆ ) alkyl, such as aminomethyl, aminoethyl, aminoisopropyl and the like; hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, such as methoxymethyl, methoxyethyl, ethoxypropyl and the like; aryloxy (C ₁ -C ₆ ) alkyl such as phenyloxymethyl, phenyloxyethyl, naphthyloxymethyl, naphthyloxyethyl and the like; aralkoxy (C ₁ -C ₆ ) alkyl such as benzyloxymethyl, benzyloxyethyl, phenethoxymethyl, phenethoxyethyl and the like; (C ₁ -C ₆ ) alkoxycarbonylamino, such as methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino and the like; aryloxycarbonylamino, such as phenyloxycarbonylamino, naphthyloxycarbonylamino, aralkoxycarbonylamino, such as benzyloxycarbonylamino, phenyloxycarbonylamino and the like; thio, thio (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylsulfinyl, such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, butylsulfinyl and the like; (C ₁ -C ₆ ) alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like; sulfonic acid or its derivatives, such as SO ₂ NH ₂ , SO ₂ NHMe, SO ₂ NMe ₂ , SO ₂ NHEt, SO ₂ NEt ₂ and the like; or a carboxylic acid or its derivatives, such as amides, such as CONH ₂ , CONHMe, CONMe ₂ , CONHEt, CONEt ₂ , CONHPh and the like; substituents for the groups are the same as defined for R ⁴ and R ⁵ .

Suitable R ⁶ groups are selected from hydrogen, a halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, amino, cyano, nitro, thio, hydroxylamino, linear or branched (C ₁ -C ₆ ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl , isopentyl, hexyl and the like, (C ₁ -C ₆ ) alkyl group may be substituted; (C ₁ -C ₆ ) alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, (C ₁ -C ₆ ) alkoxy group may be substituted; carboxy (C ₁ -C ₆ ) alkyl, such as carboxymethyl, carboxyethyl, carboxypropyl and the like, carboxy (C ₁ -C ₆ ) alkyl may be substituted.

Suitable groups representing R ^a and R ^b are selected from hydrogen or a (C ₁ -C ₆ ) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like; an aryl group such as phenyl, naphthyl and the like.

Suitable groups representing R ⁷ are selected from hydrogen, an aryl group such as phenyl, naphthyl and the like; heteroaryl groups such as pyridyl, furyl, thiophenyl, benzothiazolyl, purinyl, benzimidazoyl, pyrimidinyl, tetrazolyl and the like.

Suitable ring structures formed by the condensation of R ⁴ with furanone can be selected from 2,3a, 4,5-tetrahydronaphtho [2,1-b] furan-2-one; 4-thioxo-2,3a, 4,5-tetrahydronaphtho [2,1-b] furan-2-one; 4-imino-2,3a, 4,5-tetrahydronaphtho [2,1-b] furan-2-one; 3a, 4,5,6-tetrahydronaphtho [2,1-b] furan-2-one; 2,3a-dihydronaphtho [2,1-b] furanone; 2,3a, 4,5-tetrahydronaphtho [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-one; 3a, 4-dihydro-2H-furo [2,3-c] chromene-2,4-dione; 2,3a, 4,5-tetrahydro-2H-furo [2,3-c] chromen-2-one; 4-thioxo-2,3a, 4,5-tetrahydro-2H-furo [2,3-c] chromen-2-one; 4-imino-2,3a, 4,5-tetrahydro-2H-furo [2,3-c] chromen-2-one; 2,3a, 4,5-tetrahydro-2H-furo [2,3-c] chromene-2,4-dione; 2,3a, 4,5-tetrahydrofuro [2,3-c] quinolin-2-one; 2,3a, 4,5-tetrahydrofuro [2,3-c] quinoline-2,4-dione; 8,8a-dihydro-2H-indeno [2,1-b] furan-2-one; 4-thioxo-8,8a-dihydro-2H-indeno [2,1-b] furan-2-one; 4-imino-8,8a-dihydro-2H-indeno [2,1-b] furan-2-one; 2.8a-dihydrobenzo [4,5] thieno [2,3-b] furan-2-one; 2,8a-dihydrobenzo [b] furo [3,2-d] furan-2-one; 8.8a-dihydro-2H-furo [2,3-b] indol-2-one; 8,8a-dihydro-2H-indeno [2,1-b] furan-2-one; 3a, 4,5,6-tetrahydro-2H-benzo [3,4] cyclohepta [b] furan-2-one; 3a, 4,5,8-tetrahydro-2H-indeno [5,4-b] furan-2-one; 4,5,5a, 7-tetrahydro-1H-furo [2,3-g] indol-7-one; 4,5,5a, 7-tetrahydrothieno [2 ', 3': 3,4] benzo [b] furan-7-one; 4,5,5a, 7-tetrahydrofuro [2 ', 3': 3,4] benzo [b] furan-7-one.

Suitable groups representing X are selected from oxygen or NR ⁸ , where R ⁸ is hydrogen or a linear or branched (C ₁ -C ₆ ) alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, n-pentyl, isopentyl, hexyl and the like, (C ₁ -C ₆ ) alkyl group may be substituted; an aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; an aralkyl group such as benzyl, phenethyl and the like, the aralkyl group may be substituted; a heteroaryl group such as pyridyl, furyl, thiophenyl, benzothiazolyl, purinyl, benzimidazoyl, pyrimidinyl, tetrazolyl and the like, the heteroaryl group may be substituted; a heteroaralkyl group such as pyridylmethyl, pyridylethyl, furanmethyl, furanethyl and the like, the heteroaralkyl group may be substituted; an aralkenoyl group such as phenylpropenoyl, phenylbutenoyl, phenylpentenoyl and the like, the aralkenoyl group may be substituted; an aralkanoyl group such as phenylpropanoyl, phenylbutanoyl, phenylpentanoyl and the like, the aralkanoyl group may be substituted.

The substituents on R ³ , R ⁶ and R ⁸ may be selected from nitro, a 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, hydrabamine, isopropylamine, methylglucamine, morpholine prine, , purines, theobromine, triethylamine, trimethylamine, tripropylamine, trimethamine, diethanolamine, meglumine, ethylenediamine, N, N'-diphenylethylenediamine, N, N'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, cholinhydroxide, dicyclomethylamine, dicyclohexylamine, dicyclohexylamine, dicyclohexylamine, dicyclohexylamine, trials amine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine, and the like; chiral bases such as alkylphenylamine, glycine, phenyl glycine 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, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts, among which sulphates, nitrates, phosphates, perchlorates, borates, halides, acetates, tartrates, maleates, citrates, succinates, palmates, methanesulfonates, benzoates, salicylates, hydroxy naphthoates, benzosulfonates, glycine ascorbates, are suitable, and the like. Pharmaceutically acceptable solvates may be hydrates or those containing other crystallization solvents, such as alcohols.

Representatives of the compounds obtained in accordance with the method of the present invention can be selected from:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4- (4-methylsulfanyl-3-fluorophenyl) -3- (4-methylsulfanylphenyl) -2,5-dihydro-2-furanone;

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

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

4- (4-methylsulfanyl-3-fluorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone;

4- (4-methylsulfonyl-3-fluorophenyl) -3-phenyl-2,5-dihydro-2-furanone;

4- (4-methylsulfonyl-3-chlorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone;

4- (4-methylsulfonyl-3-fluorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone;

4- (2-fluoro-4-methylsulfanylphenyl) -3- (4-trifluoromethylphenyl) -2,5-dihydro-2-furanone;

4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-trifluoromethylphenyl) -2,5-dihydro-2-furanone;

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

4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone;

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

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

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

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

4- (4-methylsulfonyl-3-fluorophenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone;

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

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

4- (2-fluoro-4-methylsulfanylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone;

4- (4-methylsulfonyl-3-chlorophenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone;

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

4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone;

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

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

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

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

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

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

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

4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -2,5-dihydro-2-furanone;

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

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

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

4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone;

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

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

4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone;

4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone;

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

4- (3-methyl-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone;

4- (3-bromomethyl-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone;

2- {5- [4- (4-fluorophenyl) -2,2-dimethyl-5-oxo-2,5-dihydro-3-furanyl] -2-methylsulfonylbenzyl} -2,3-dihydrobenzo [d] isothiazole- 3-oxo-1,1-dioxide;

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

5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -2,5-dihydro-2-furanone;

3- (4-fluorophenyl) -5,5-dimethyl-4- (4-methylsulfonyl-3-morpholinomethylphenyl) -2,5-dihydro-2-furanone;

5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone;

3- (3,4-difluorophenyl) -4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone;

3- (3,5-difluorophenyl) -4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone;

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

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

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

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

5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-methoxy-3-methylphenyl) -2,5-dihydro-2-furanone;

5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone;

3- (3,4-difluorophenyl) -5-ethyl-4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone;

3- (3,4-difluorophenyl) -5-ethyl-4- (2-fluoro-4-methylsulfonylphenyl) -5-hydroxy-2,5-dihydro-2-furanone;

4- (3-fluoromethyl-4-methylsulfonylphenyl) -3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone;

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

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

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

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

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

5-ethyl-4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5-hydroxy-2,5-dihydro-2-furanone;

5-ethylidene-4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -2,5-dihydro-2-furanone;

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

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

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

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

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

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

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

4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5-methoxy-5-methyl-2,5-dihydro-2-furanone;

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

4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5-methoxy-5-methyl-2,5-dihydro-2-furanone;

1- (4-fluorophenyl) -4- (3-methyl-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-1H-2-azolone;

3- (2-fluoro-4-methylsulfonylphenyl) -1- (4-fluorophenyl) -4-phenyl-2,5-dihydro-1H-2,5-azoldione.

Accordingly, compounds of general formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, and m are as previously defined, can be prepared by any of the following methods shown in Scheme I :

The interaction of the compounds of formula (I-1) with the compound (I-2), or the interaction of the compounds of the formula (I-3) with the compound of the formula (I-4), or the interaction of the compounds of the formula (I-5) with the compound of the formula (I-6) ), or the interaction of a compound of formula (I-7) with a compound of formula (I-8), where L ¹ represents B (OR) ₂ , where R represents hydrogen or a (C ₁ -C ₆ ) alkyl group, L ² represents represents a halogen atom such as chlorine, bromine or iodine or other leaving groups such as ZnCl ₂ or 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, dimethyl sulfoxide (DMSO), dichloromethane (DCM) ), water and the like, or mixtures thereof. The reaction can be carried out in an inert atmosphere, using inert gases such as He, N ₂ , Ar and the like. The reaction can be carried out in the presence of a catalyst, such as bis (triphenylphosphine) palladium (II) chloride, 1,4-bis (diphenylphosphine butane) palladium (II) chloride, bis (dibenzylideneacetone) palladium (o), palladium acetate, acetate-three (o -tolyl) phosphine palladium, bis (acetonitrile) palladium (II) chloride, carbon palladium + triphenylphosphine, tetrakis (triphenylphosphine) palladium (o) and the like. The amount of catalyst used can range from 0.1% mol to 50% mol, preferably from 1 to 10% mol. The reaction can be carried out in the presence of a base, such as alkali metal carbonates, such as sodium carbonate or potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; organic bases such as triethylamine, pyridine, dimethylaminopyridine (DMAP) or diisopropylethylamine and the like. The amount of base may be in the range of 1 to 20 equivalents, preferably the amount of base is in the range of 1 to 5 equivalents. Phase transfer catalysts such as tetraalkylammonium halide, benzyltriethylammonium halide, benzyltributylammonium halide, tetraalkylammonium bisulfate, benzyltriethylammonium bisulfate or benzyltributylammonium bisulfate can be used. The amount of phase transfer catalyst used may range from 0.01 equivalent to 1 equivalent, preferably from 0.05 to 0.5 equivalent. The reaction temperature may range from 0 ° C. to the boiling point of the solvent, preferably from 30 ° C. to the boiling point of the solvent. The reaction time may range from 0.5 to 76 hours, preferably from 6 hours to 24 hours.

In another aspect of the present invention, the compounds of general formula (I), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, and m are as previously defined, can be prepared by any of the following methods, shown in Scheme II below:

The reaction of a compound of formula (II-1), where all the symbols are as defined above, with carbon monoxide and water to produce a compound of the formula (I), where X is oxygen, and all other symbols are as previously defined, can carried out in the presence of a suitable palladium catalyst such as PdCl ₂ , Pd (OAc) ₂ , (PPh ₃ ) PdCl ₂ and the like. The amount of catalyst may range from 0.01% mol to 5% mol, preferably 2.0% mol. The reaction can be carried out in the presence of aqueous mineral acids, such as HCl or HBr; protic solvents such as EtOH, iso-PrOH or BuOH. The reaction temperature may range from -78 ° C to 300 ° C, preferably at a temperature in the range of 20 ° C to the boiling point of the solvent used, and the reaction can be carried out in a pressure range of 50 to 150 atmospheres of carbon monoxide. The duration of the reaction can range from 2 to 80 hours.

Alternatively, a compound of formula (I), where X is oxygen, and all symbols are as previously defined, can be obtained by reacting a compound of formula (II-1), where all symbols are as previously defined, with carbonyl complexes of the transition metal, such as Rh ₄ (CO) ₁₂ or Rh ₆ (CO) ₁₆ . The reaction can be carried out in the presence of solvents such as THF, acetone, acetonitrile, benzene, toluene, EtOH, MeOH and the like, or mixtures thereof. The reaction can be carried out in the presence of a base such as trialkylamine, for example triethylamine, diisopropylethylamine and the like. The temperature may range from 30 ° C to 300 ° C, preferably at a temperature in the range from 50 ° C to 150 ° C at a pressure of from 20 to 300 atmospheres. The reaction can be carried out in an inert atmosphere using inert gases such as N ₂ , Ar or He. The duration of the reaction can range from 2 to 80 hours.

The reaction of the compounds of formula (II-2), where L ³ represents a halogen atom, such as chlorine, bromine or iodine, and all other symbols are as defined above, with the compound of formula (II-3), where X represents oxygen or NR ⁸ and R ⁴ is as previously defined, or a reaction of a compound of formula (II-4), wherein X is oxygen or NR ⁸ , and all other symbols are as previously defined, with a compound of formula (II- 5), where L ⁴ represents a hydroxy, a halogen atom such as chlorine, bromine or iodine, to obtain a compound of the formula ( I), where all symbols are as previously defined, can be carried out in the presence of a base such as triethylamine (TEA), diisopropylamine, diisopropylethylamine, pyridine, piperidine, DMAP, 1,8-diazabicyclo [5.4.0] undec-7- ene (DBU), lithium diisopropylamide (LDA), potassium bis (trimethylsilyl) amide, Na ₂ CO ₃ , K ₂ CO ₃ , NaOH, KOH, NaOMe, NaOEt, NaO-iso-Pr, tert-BuOK, NaH, KH and the like. The amount of base may be in the range of 1 to 5 equivalents, preferably the amount of base is in the range of 2 to 3 equivalents. The reaction can be carried out using solvents such as THF, N-methylpyrrolidine, acetonitrile, propionitrile, acetone, 2-butanone, DMSO, DMF, dimethylamine (DMA), DCM, CHCl ₃ and the like, or mixtures thereof. The reaction can be carried out in an inert atmosphere, which can be provided using inert gases such as He, N ₂ , Ar and the like. The reaction temperature may range from 0 ° C to 150 ° C, preferably at a temperature in the range from 20 ° C to the boiling point of the solvent used. The reaction time may range from 2 to 50 hours, preferably from 2 to 20 hours. In the case of incomplete dehydrogenation, the resulting compound is further dehydrogenated.

Alternatively, the reaction of a compound of formula (II-2), where L ³ represents a halogen atom such as chlorine, bromine or iodine, and all other symbols are as defined above, with a compound of formula (II-3), where X represents is oxygen or NR ⁸ and R ⁴ is as previously defined, or a reaction of a compound of formula (II-4), where X is oxygen or NR ⁸ and all other symbols are as previously defined with a compound of formula (II -5), wherein L ⁴ represents a hydroxy, a halogen atom such as chlorine, bromine or iodine, to give comp neniya of formula (I), wherein all symbols are as defined earlier may be carried out in the presence of 2 equivalents of N, N'-dicyclohexylcarbodiimide (DCC) + 0.5 equivalents of DMAP or carboxymethylcellulose (CMC) + DMAP. The reaction can be carried out in the presence of solvents such as DCM, CHCl ₃ , benzene, toluene, xylene and the like, or mixtures thereof. The reaction temperature may be from room temperature to the boiling point of the solvents used. The duration of the reaction may be in the range from 2 to 12 hours

In accordance with another aspect of the present invention, a compound of formula (I), wherein R ¹ is an amino group, m is 2, and all other symbols are as defined above, can be obtained by conversion of a compound of formula (I), where R ¹ is a lower alkyl group, m is 2 and all other symbols are as previously defined in the presence of a Grignard reagent such as MeMgCl, MeMgBr, EtMgCl, or a base such as nBuLi, LiNH ₂ or LDA. The reaction may be carried out in the presence of a trialkylborane such as triethylborane or tributylborane in the presence of a solvent such as dioxane, diethyl ether, diisobutyl ether, diphenyl ether, THF and the like, or mixtures thereof. The reaction can be carried out in an inert atmosphere using Ar, N ₂ or He. The reaction can be carried out at a temperature in the range of −78 ° C. to the boiling point of the solvent used, preferably at 0 ° C. to the boiling point of the solvent used. The reaction may be more effective in anhydrous conditions. The reaction time may 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 ranges from 0 ° C to the boiling point of the solvent, preferably from 0 ° C to 50 ° C. The duration of the reaction can be from 2 to 20 hours, preferably from 2 to 10 hours.

In accordance with another aspect of the present invention, a compound of formula (I), where all the symbols are as previously defined and m is 0, can be obtained by reconstituting a compound of the formula (I) where all the symbols are as previously defined and m has a value of 1 or 2. Reduction can be carried out using reagents such as LAH, HI, Bu ₃ SnH, TiCl ₂ , MeSiCl ₃ , Nal, PCl ₃ , H ₂ -Pd-C, acetyl chloride, PPh ₃ , tert-BuBr and Tris (dimethylamino) phosphine-I ₂ . Recovery can also be carried out using diisobutylaluminum hydride [(ISO-Bu) ₂ AlH], LAH in accordance with the method described in J. Org. Chem. 48, (1983) 1617.

In another embodiment of the present invention, a compound of formula (I), where all the symbols are as previously defined, and m is 1 (sulfoxide), or m is 2 (sulfone), can be obtained by oxidizing a compound of formula (I), where all symbols are as previously defined, and m is 0, a suitable oxidizing agent. The oxidation of the compound of formula (I), where m is 0, can be carried out in the presence of an oxidizing agent, such as 30% H ₂ O ₂ , m-CPBA, oxone (potassium peroxymonosulphate), NalO ₄ , KMnO ₄ , sodium perborate, magnesium monoperoxyphthalate hexahydrate and the like. The amount of reagent varies from 2 mol to 20 mol, preferably from 4 to 10 mol. The reaction may be effective in the presence of a solvent such as CHCl ₃ , tert-butanol, CH ₂ Cl ₂ , acetone, CH ₃ COOH and the like, or mixtures thereof. Water can be used as a co-solvent. The reaction can be carried out in an inert atmosphere using He, Na or Ar. The reaction can be carried out at a temperature in the range from 0 ° C to 150 ° C, preferably in the range from 30 ° C to 120 ° C. The duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

In another embodiment of the present invention, a compound of general formula (II-2) wherein L ³ is a halogen atom, R ¹ and R ² together with the atoms to which they are attached form a ring and the ring is selected from dihydrothiophene, R ⁵ , R ⁶ are hydrogen itself and R ³ is as previously defined, can be obtained by the method shown in Scheme III:

The oxidation of the compounds of formula (II-2a), where R ³ is as defined above, to obtain the compounds of formula (II-2b), where R ³ is as defined above, can be carried out using oxidizing agents such as hydrogen peroxide, potassium permanganate, meta-chloroperbenzoic acid (m-CPBA), NaIO ₄ , tert-BuOCl, sodium perborate, potassium hydrosulfate and the like. The amount of oxidizing agent used may vary from 1 to 20 equivalents, preferably 2-10 equivalents. The reaction can be carried out in the presence of solvents such as glacial acetic acid, propionic acid, water and the like, or mixtures thereof. The reaction can be carried out in an inert atmosphere, which is provided by the use of inert gases such as He, N or Ar. The reaction temperature may range from 20 ° C. to the boiling point of the solvent used, preferably from 50 ° C. to the boiling point of the solvent used. The duration may vary from 15 minutes to 15 hours, preferably from 15 minutes to 3 hours.

The reduction of the compound of formula (II-2b) as defined above to the compound of formula (II-2c), where R ³ is as defined above, can be carried out using a 5-10% Pd-C catalyst, Raney nickel, Pt / C nickel boride and the like. The amount of catalyst may vary from 0.01 to 1.0% by weight, preferably in the range from 0.01 to 0.50% by weight. The reaction can be carried out in the presence of solvents such as acetic acid, methanol, ethanol and the like, or mixtures thereof. The reaction can be carried out in an atmosphere of H ₂ , the pressure varies from 1 to 20 atmospheres, preferably from 1 to 10 atmospheres. The reaction can be carried out in an inert atmosphere, which is achieved by using inert gases such as He, N ₂ or Ar. The reaction temperature may range from 15 to 100 ° C, preferably from 15 to 50 ° C. The duration of the reaction can vary from 0.5 to 20 hours, preferably from 0.5 to 5 hours.

The reduction of a compound of formula (II-2c) as defined above to a compound of formula (II-2d), where R ³ is as defined above, can be carried out using reducing agents such as LAH, HI, Bu ₃ SnH, TiCl ₂ . MeSiCl ₃ , Nal, PCl ₃ , H ₂ -Pd / C, PPh ₃ , tert-BuBr, Tris (dimethylamino) phosphine-I ₂ and the like. The amount of reducing agent may vary from 0.5 to 10 equivalents, preferably from 1 to 5 equivalents. The reaction can be carried out in the presence of solvents such as (C ₁ -C ₈ linear or branched) alkyl ether, THF, dioxane and the like. The reaction can be carried out in an inert atmosphere, which is achieved by using inert gases such as He, N ₂ or Ar. The reaction temperature can range from 0 ° C. to the boiling point of the solvent used, and the reaction time is from 1 to 80 hours, preferably from 1 to 24 hours. The reaction can be carried out under anhydrous conditions.

The reaction of a compound of formula (II-2d) as defined above with acetyl chloride to produce a compound of formula (II-2e), where R ³ is 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 amount of acetyl chloride may vary from 1 to 10 equivalents, preferably from 1 to 5 equivalents. The reaction can be carried out using catalysts such as AlHal ₃ (where Hal is F, Cl or Br). The amount of catalyst may range from 1 to 10 equivalents, preferably from 1 to 5 equivalents. The reaction can be carried out in an inert atmosphere, which is provided by the use of inert gases such as He, Na or Ar. The reaction temperature may range from -20 ° C to the boiling point of the solvent used, preferably from -20 ° C to 50 ° C. The duration of the reaction can vary from 1 to 80 hours, preferably from 4 to 24 hours.

The oxidation of a compound of formula (II-2e) above to produce a compound of formula (II-2f), where R ³ is as defined above, can be carried out using oxidizing agents such as hydrogen peroxide, potassium permanganate, m-CPBA, NalO ₄ , tert-BuOCl, sodium perborate, potassium hydrosulfate and the like. The amount of oxidizing agent used may vary from 1 to 20 equivalents, preferably 2-10 equivalents. The reaction can be carried out in the presence of solvents such as glacial acetic acid, propionic acid, water and the like, or mixtures thereof. The reaction can be carried out in an inert atmosphere, which is achieved by using inert gases such as He, N ₂ or Ar. The reaction temperature may range from 20 ° C. to the boiling point of the solvent used, preferably from 50 ° C. to the boiling point of the solvent used. Duration may vary from 15 minutes to 15 hours, preferably from 15 minutes to 3 hours.

The reaction of a compound of formula (II-2f) above to produce a compound of formula (II-2), wherein L ³ is a halogen atom and all other symbols are as defined above, can be carried out using a halogenating 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 may vary from 15 ° C. to the boiling point of the solvent used, preferably from 15 to 75 ° C. The duration of the reaction can vary from 1 to 20 hours, preferably from 1 to 10 hours.

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

In the preparation of a compound of formula (I) through an intermediate, conventional functional group transformations, such as hydrolysis, reduction, or oxidation, can be carried out.

Some transformations of the functional group are illustrated by the following examples.

Compounds of formula (I) having CONH ₂ groups can be converted to CN by the method described in WO 99/15505.

Similarly, a compound of formula (I) having a CO ₂ Et group can be converted to CH ₂ OH by the method described in WO 95/15316.

Pharmaceutically acceptable salts are prepared by reacting a compound of formula (I) with a base in an amount of 1 to 4 equivalents, such as sodium hydroxide, sodium methoxide, sodium hydride, potassium tert-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents, such as ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, etc. A solvent mixture may be used. Organic bases such as lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives, etc. can also be used. Alternatively, the acid addition salts used are obtained by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxy naphtha, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like, in solvents such as ethyl acetate, ether, s irty, acetone, THF, dioxane, etc. A solvent mixture may also be used. Salts of amino acid groups and other groups can be obtained by the reaction of the compounds of formula (I) with the corresponding groups in solvents such as alcohols, ketones, esters, etc. A solvent mixture may be used.

The stereoisomers of the compounds of formula (I) that are part of the present invention can be obtained using the reagents in their individual enantiomeric form in the method, if possible, or when carrying out the reaction in the presence of reagents or catalysts in their individual enantiomeric form, or by splitting the mixture of stereoisomers conventional methods. Some of the preferred methods include digestion with microorganisms, digestion of diastereoisomeric salts prepared with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, or chiral bases such as brucine, cinnamon alkaloids and their derivatives, and the like.

The regioisomers of a compound of formula (I) can be prepared by modifying the reaction conditions using reagents such as an acid instead of a base or a base instead of an acid, or by reaction with the free base of hydrazine instead of its salt with diketone. The molar ratio can also change the formation of regioisomer.

Various polymorphs of a compound of general formula (I) forming part of the present invention can be obtained by crystallization of a compound of formula (I) under various conditions. For example, using various commonly used solvents or mixtures thereof for recrystallization; crystallization at various temperatures; various cooling methods, from very fast to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or slow cooling. The presence of polymorphs can be determined by a solid breakdown of NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, X-ray force data, or by any other means.

Pharmaceutically acceptable solvates of the compounds of formula (I) forming part of this invention can be prepared 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 various crystallization methods.

The compounds of general formula (I) are useful as a partial or complete substitute for NSAIDs in compositions or compositions where they are administered with other agents or ingredients. The present invention also includes pharmaceutical compositions for treating cyclooxygenase-mediated diseases as previously defined, comprising a non-toxic therapeutically effective amount of a compound of formula (I) as defined above, and a pharmaceutically acceptable carrier, and optionally containing one or more other therapeutic ingredients, such as another analgesic agent such as acetaminophen, phenacetin, potentiating agent such as caffeine, H ₂ antagonist, aluminum or magnesium hydroxide, Sime icons, decongestant, such as phenylephrine, phenylpropanolamine, pseudo-ephedrine, oxymetazoline, epinephrine, nefazolin, propylhexadrine or livodesoxyephedrine, xylomatazoline, a sedative or non-sedative antihistamine, an anti-cough agent such as dextromethorphan, carbamenpentane, and carbetapentane diuretic. The present invention also includes a method for treating cyclooxygenase-mediated diseases, comprising administering to a patient in need thereof a non-toxic therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition 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, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions suitable for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, perfumes, colorants and preservatives for obtaining pharmaceutically excellent and enjoyable drugs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable additives that are suitable for tablet production. These additives may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or gum arabic; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to slow the disintegration and adsorption in the gastrointestinal tract and, thus, to provide a prolonged action for a longer period. For example, materials such as glyceryl monostearate or glyceryl distearate can be used for these purposes. They can also be coated by methods described in US 4,256,108; 4,166,452 and 4,265,874, for the preparation of controlled release osmotic therapeutic tablets.

Compositions for oral administration can also be presented in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredients are mixed with an aqueous or oily medium, for example peach oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture with additives suitable for preparing aqueous suspensions. Such additives are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth resin and gum arabic; dispersing or moisturizing agents may be natural phosphatides, for example lecithin or condensation products of alkylene oxide with fatty acids, for example polyoxyethylene stearate or products of condensation of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene ethylene cetanol or products of condensation of ethylene oxide and non-fatty acids, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty hexitol acids and anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more perfumes and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example wax, paraffin wax or cetyl alcohol. Sweetening agents such as those indicated above and perfumes may be added to provide a pleasant oral administration. These compositions may be retained by the administration of antioxidants such as ascorbic acid.

Dispersion powders and granules suitable for the preparation of an aqueous suspension with the addition of water provide the active ingredient in admixture with a dispersing or moisturizing agent, a suspending agent and one or more preservatives. Suitable dispersing or moisturizing agents and suspending agents are those mentioned above. Additional additives may also be present, for example, sweetening agents, perfumes and coloring agents.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil, or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example soybeans, lecithin and ethers, or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and perfumes.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain emollients, preservatives and perfumes and colorants. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated in accordance with the prior art using such suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable composition may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanedione. 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 usually used as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, can be used for injection.

The compounds of formula I can also be administered as suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritant supplement that is solid at ordinary temperature and becomes liquid at rectal temperature and then melts in the rectal cavity to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of formula (I) are used (for the purpose of such application, topical applications may include rinsing for the teeth and gargling for the throat).

Dose levels in the range of about 0.01 mg to about 140 mg / kg of body weight per day are useful for treating the above diseases, or alternatively about 0.5 mg to about 7 g to the patient per day. For example, inflammation can be effectively treated by administering from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g to the patient per day, preferably from 2.5 mg to 1 g to the patient per day.

The amount of active ingredient that can be combined with carrier materials to produce a unit dosage form may vary depending on the object being treated 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 combined with a suitable and standard amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. A unit dosage form usually contains between about 1 mg to about 500 mg of the active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg.

It is clear, however, that the particular dose level for any given patient depends on various factors, including age, body weight, general health, gender, nutrition, time of administration, route of administration, rate of excretion, combination with drugs, and severity of the particular disease being treated .

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

Information confirming the possibility of carrying out the invention

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

Cooking 1:

3-fluoroanisole

To an ice-cooled solution (~ 0 ° C) of 3-fluoroaniline (50 g, 450.45 mmol) in 6N hydrochloric acid (200 ml) is added very slowly and dropwise 150 ml of an ice-cold aqueous solution (~ 5 ° C) of NaNO ₂ (37.3 g, 540.58 mmol). The temperature of the reaction mixture is maintained strictly within the range of 0-5 ° C. by adding from time to time each time ice and salt into the space around the reaction flask. Then, a diazotizing solution of 3-fluoroaniline is added very slowly (no more than 2 ml at a time) to an aqueous solution of potassium ethyl xanthate (101.5 g, 634.37 mmol in 100 ml of H ₂ O) at 40-45 ° C. Addition is carried out over 1.5 hours. Then the reaction mixture is stirred for 1 hour at 40-45 ° C. The aqueous layer is decanted from an orange-colored oil, which is extracted with chloroform (3 × 100 ml). The combined organic layers were washed with 5N NaOH solution (2 × 50 ml) and then with water (2 × 100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under low vacuum. The crude oil thus obtained is used in the next step.

To a solution of the product obtained above in ethanol (250 ml), KOH in granules (37.91 g, 675.63 mmol) was carefully added. Then the mixture is heated to 85-90 ° C in nitrogen atmosphere with vigorous stirring for 27 hours. After that, ethanol was removed under low vacuum and the resulting residue was dissolved in acetone (200 ml). The reaction mixture was cooled to ~ 10 ° C, methyl iodide (127.87 g 900.87 mmol) was added slowly and dropwise. After stirring for 12 hours at room temperature, the solvent was distilled off in vacuo and petroleum ether (200 ml) was added to the residue. 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 ° C at 40 mm Hg, which gives 31 g of the title compound (49% yield) as an oil.

¹ H NMR (CDCl ₃ , 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).

Cooking 2:

2-fluorothioanisole

2-Fluorothioanisole is obtained in 71% yield from 2-fluoroaniline (30 g, 270.27 mmol) using NaNO ₂ (22.37 g, 324.49 mmol), potassium ethyl xanthate (43.51 g, 271.4 mmol) and methyl iodide (76.72 g, 540.21 mmol) , in accordance with the procedure described in preparation 1.

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

Cooking 3:

2,3-dimethylthioanisole

2,3 - Dimethylthioanisole is obtained in 78% yield from 2,3-dimethylaniline (5 g, 41.32 mmol) using NaNO ₂ (5.13 g, 74.37 mmol), potassium ethyl xanthate (7.90 g, 49.28 mmol) and methyl iodide (6.10 g , 42.95 mmol), in accordance with the procedure described in preparation 1.

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

Cooking 4:

2-chlorothioanisole

2-Chlorothioanisole was obtained in 89% yield from commercially available 2-chlorothiophenol (4.0 g, 27.6 mmol) using methyl iodide (4.66 g, 32.81 mmol), in accordance with the procedure described in Preparation 1.

¹ H NMR (CDCl ₃ , 200 MHz): δ 7.3 1-6.92 (m, 4H), 2.46 (s, 3H).

Cooking 5:

2-fluoro-4-methylsulfanylacetophenone

To a suspension of AlCl ₃ (45 g, 339 mmol) in dichloromethane (150 ml) was added dropwise acetyl chloride (24.2 ml, 339 mmol) at 0 ° C. The mixture is stirred for 0.5 hours at 25 ° C. until a clear solution forms. To the resulting solution, a solution of 3-fluorothioanisole (37 g, 260.5 mmol) in dichloromethane (50 ml) was slowly added at 0 ° C. The duration of the addition is 30 minutes. Then the mixture was stirred for 3 hours at 25 ° C, poured onto ice (500 g), extracted with chloroform (3 × 100 ml). The combined organic layers were washed with water (2 × 100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a crude product. The specified product is purified using a chromatographic column on silica gel using 1% EtOAc - petroleum ether as eluent, which gives 14 g (29% yield) of the title compound as a light brown solid, mp: 61-62 ° C. .

¹ H NMR (CDCl ₃ , 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).

Cooking 6:

3-fluoro-4-methylsulfanylacetophenone

3-Fluoro-4-methylsulfanylacetophenone is obtained in 22% yield from 2-fluorothioanisole (9 g, 63.38 mmol) using acetyl chloride (5.97 g, 76.05 mmol) and AlCl ₃ (10.11 g, 75.82 mmol), in accordance with the procedure described in preparation 5.

¹ H NMR (CDCl ₃ , 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).

Cooking 7:

2,3-dimethyl-4-methylsulfanylacetophenone

2,3-Dimethyl-4-methylsulfanylacetophenone is obtained in 28% yield from 2,3-dimethylthioanisole (7.5 g, 49.01 mmol) using acetyl chloride (4.60 g, 58.59 mmol) and AlCl ₃ (7.80 g, 58.49 mmol), in accordance with the procedure described in preparation 5.

¹ H NMR (CDCl ₃ , 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).

Cooking 8:

3-chloro-4-methylsulfanylacetophenone

3-Chloro-4-methylsulfanylacetophenone was obtained in 69% yield from 2-chlorothioanisole (5.0 g, 31.54 mmol) using acetyl chloride (2.7 ml, 37.83 mmol) and AlCl ₃ (4.56 g, 34.19 mmol), in accordance with the procedure described in preparation 5.

¹ H NMR (CDCl ₃ , 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).

Cooking 9:

2-Bromo-1- (2-fluoro-4-methylsulfanylphenyl) -1-ethanone

To a solution of 2-fluoro-4-methylsulfanylacetophenone (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 a solution of bromine (3.18 ml, 61.72 mmol) in acetic acid (4 ml) is added very slowly. Stirring is continued for another 3 hours until bromine staining disappears. Water (300 ml) was added to the resulting mixture, the solid was separated, filtered and dried in vacuo. The powder thus obtained was treated with petroleum ether (20 ml) to remove coloring impurities, and then filtered to give 13.3 g of the title compound in 78% yield as a pale brown solid. Mp 55-59 ° C.

¹ H NMR (CDCl ₃ , 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).

Cooking 10:

2-Bromo-1- (3-fluoro-4-methylsulfanylphenyl) -1-ethanone

2-Bromo-1- (3-fluoro-4-methylsulfanylphenyl) -1-ethanone is obtained in 67% yield from 2-fluoro-4-methylsulfanyl 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.

¹ H NMR (CDCl ₃ , 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) .

Cooking 11:

2-Bromo-1- (2,3-dimethyl-4-methylsulfanylphenyl) -1-ethanone

2-Bromo-1- (2,3-dimethyl-4-methylsulfanylphenyl) -1-ethanone is obtained in 79% yield from 2,3-dimethyl-4-methylsulfanylacetophenone (1.8 g, 9.2 mmol) using bromine (0.45 ml, 8.73 mmol), in accordance with the procedure described in preparation 9.

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

Cooking 12:

2-Bromo-1- (3-chloro-4-methylsulfanylphenyl) -1-ethanone

2-Bromo-1- (3-chloro-4-methylsulfanylphenyl) -1-ethanone is obtained in 55% yield from 3-chloro-4-methylsulfanylacetophenone (6.6 g, 33 mmol) using bromine (1.60 ml, 31.01 mmol), in accordance with the procedure described in preparation 9.

¹ H NMR (CDCl ₃ , 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).

Cooking 13:

Benzothiophene-1,1-dioxide

To a solution of benzothiophene (10 g, 74.6 mmol) in glacial acetic acid (18.65 ml) was added a 30% aqueous solution of H ₂ O ₂ (37.31 ml, 329.20 mmol) and heated at the boil under reflux for 0.5 hours. The reaction mixture was slowly cooled to 10-15 ° C, filtered, washed with chilled water (15 ml) and dried to obtain the title compound as a white solid (12 g, 97%). Mp 129-130 ° C.

¹ H NMR (CDCl ₃ , 200 MHz ): 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).

Cooking 14:

2,3-dihydrobenzothiophene-1,1-dioxide

To a solution of benzothiophene-1,1-dioxide (10 g, 60.24 mmol) obtained in Preparation 13, dissolved in glacial acetic acid (400 ml), 5-10% Pd-C (100 mg, 0.01% by weight) was charged and hydrogenate using gaseous H ₂ for 5 hours. The reaction mixture was filtered using a pad of celite, and the filtrate was poured into ice water (500 ml), extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and evaporated to give a thick substance, which was chromatographed on a silica gel column using ethyl acetate : petroleum ether (10:90) to give the title compound (10 g, 99%). Mp 91-92 ° C.

¹ H NMR (CDCl ₃ , 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).

Cooking 15:

2,3-dihydrobenzothiophene

To 2,3-dihydrobenzothiophene-1,1-dioxide (10 g, 59.52 mmol) obtained in preparation 14 under argon atmosphere, lithium aluminum hydride (5.65 g, 148.80 mmol) and THF (100 ml) are added and heated to reflux refrigerator for 4-5 hours. The reaction mixture was cooled to 10 ° C. and water was slowly added dropwise, quenching the excess lithium aluminum hydride. THF is removed under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added and stirred. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried (Na ₂ SO ₄ ) and evaporated to give the material as a crude product, which was chromatographed on a silica gel column using 2% ethyl acetate and petroleum ether as an eluent to give the title compound as a viscous liquid.

¹ H NMR (CDCl ₃ , 200 MHz): δ 7.26-7.01 (m, 4H), 3.39-3.26 (m, 4H).

Cooking 16:

5-acetyl-2,3-dihydrobenzothiophene

The 2,3-dihydrobenzothiophene (8 g, 58.8 mmol) obtained in Preparation 15 is slowly added to a suspension of anhydrous aluminum chloride (11.77 g, 88.2 mmol) and acetyl chloride (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 onto crushed ice. It was then extracted with dichloromethane (2 × 50 ml), dried (Na ₂ SO ₄ ) and evaporated to give the title compound as a viscous liquid (10 g, 96%).

¹ H NMR (CDCl ₃ , 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).

Cooking 17:

5-acetyl-2,3-dihydrobenzothiophene-1,1-dioxide

To a solution of 5-acetyl-2,3-dihydrobenzothiophene (8 g, 44.9 mmol) obtained in preparation 16 in glacial acetic acid (16 ml) was added a 30% aqueous solution of H ₂ O ₂ (22, 92 ml, 202.2 mmol ) and heated at the boil under reflux for 1 hour. After cooling to 20 ° C., the precipitated solid was filtered off and washed with water to obtain the title compound (9 g, 96%). Mp 54-56 ° C.

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

Cooking 18:

5-bromoacetyl-2,3-dihydrobenzothiophene-1,1-dioxide

To a solution of 5-acetyl-2,3-dihydrobenzothiophene-1,1-dioxide (8 g, 38.1 mmol) (obtained in preparation 17) dissolved in acetic acid (45 ml) under argon atmosphere, an aqueous solution of HBr (0.5 ml, 47%), bromine (5.84 g, 36, 54 mmol) at 15-20 ^C C and the reaction mixture was stirred for about 0.5 hours. Then additional bromine (4.84 g) is slowly added and stirring is continued for another 10 hours at 25-30 ° C. The argon supply was stopped and the reaction mixture was kept open in a stream of air in a boiling cup to free free bromine. The solid that separated out was filtered off and washed with acetic acid (2 × 10 ml), then with petroleum ether, which afforded the title compound (10 g, 91%). Mp 68-70 ° C.

¹ H NMR (CDCl ₃ , 200 MHz): 8.06 (d, J = 8.20 Hz, m), 8.00 (s, 1H), 7.86 (d. J = 8.40 Hz, 1H), 4.44 (s, 2H), 3.62 -3.40 (dt, J = 5.40 Hz, 4H).

Cooking 19:

2- (4-Fluoroaniline) -1- (3-methyl-4-methylsulfonylphenyl) -1-ethanone

To a mixture of p-fluoroaniline (1.14 g; 10.3 mmol) and NaHCO ₃ (0.865 g, 10.3 mmol) in ethanol (25 ml) was added 2-bromo-1- (3-methyl-4-methylsulfonyl) acetophenone (3 g, 10.3 mmol) in a nitrogen atmosphere at 25 ° C. The mixture was vigorously stirred for 3.5 hours at the same temperature and then diluted with water (100 ml). The solid that separated out was filtered off, washed with water (2 × 25 ml), then with petroleum ether (2 × 10 ml) and dried in vacuo, which afforded 2.9 g of the title compound in 88% yield.

¹ H NMR (CDCl ₃ , 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).

Cooking 20:

2- (4-Fluoroaniline) -1- (2-fluoro-4-methylsulfonylphenyl) -1-ethanone

2- (4-Fluoroaniline) -1- (3-methyl-4-methylsulfonylphenyl) -1-ethanone is obtained in 95% yield using p-fluoroaniline (0.22 g, 1.96 mmol) and 2-bromo-1- (2- fluoro-4-methylsulfanylphenyl) -1-ethanone (0.6 g, 1.96 mmol), in accordance with the procedure described in preparation 19.

¹ H NMR (CDCl ₃ , 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).

Cooking 21:

N ¹ - (4-Fluorophenyl) -N ¹ - (3-methyl-4-methylsulfonylphenyl) -2-oxoethyl] -2-phenylacetamide

To a solution of 2- (4-fluoroaniline) -1- (3-methyl-4-methylsulfonylphenyl) -1-ethanone (1.5 g, 4.67 mmol) (prepared in Preparation 19) in anhydrous THF (15 ml) phenacyl chloride (very slowly) is added 0.722 g, 0.62 mmol) in a nitrogen atmosphere at 25 ° С. The mixture was stirred for 2 hours and diluted with water (25 ml). The solid was separated, filtered, washed with water (2 × 15 ml), then with petroleum ether (2 × 5 ml) and dried in vacuo to give 1.6 g of the title compound in 78% yield.

¹ H NMR (CDCl ₃ , 200 MHz): δ 8.14-8.10 (d, J = 8.8 Hz, 1H), 7.89-7.86 (m, 3H), 7.39-7.00 (m, 9H), 5.04 (s, 2H) 6.57 (s, 2H); 3.08 (s, 3H); 2.75 (s, 3H).

Cooking 22:

N ¹ - (4-Fluorophenyl) -N ¹ - [2- (2-fluoro-4-methylsulfonylphenyl) -2-oxoethyl] -2-phenylacetamide

N ¹ - (4-Fluorophenyl) -N ¹ - [2 (3-methyl-4-methylsulfonylphenyl) -2-oxoethyl] -2-phenylacetamide are obtained in 93% yield from 2- (4-fluoroaniline) -1- (2 -fluoro-4-methylsulfonylphenyl) -1-ethanone (0.55 g, 1.84 mmol) and phenacyl chloride (0.285 g, 1.84 mmol), in accordance with the procedure described in preparation 21.

¹ H NMR (CDCl ₃ , 200 MHz): δ 8.18-8.11 (m, 1H), 7.84-7.73 (m, 2H), 7.35-7.04 (m, 9H), 4.95 (s, 2H), 3.56 (s, 2H), 3.08 (s, 3H).

Example 1:

3- (4-Fluorophenyl) -4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone

Stage 1:

Preparation of 2- (2-fluoro-4-methylsulfanylphenyl) -2-hydroxyethyl-2- (4-fluorophenyl) acetate

To a solution of 4-fluorophenylacetic acid (7.6 g, 49.3 mmol) in DMF (30 ml) was added an aqueous solution of KOH (2.7 g, 48.11 mmol in 5 ml of water), and the mixture was stirred at 25 ° C for 30 minutes. To the resulting mixture was added a solution of 2-bromo-1- (2-fluoro-4-methylsulfanylphenyl) -1-ethanone (13 g, 49.3 mmol) in DMF (100 ml) and stirring was continued for another hour at 25 ° C. Then water (500 ml) was added to the solution, the precipitated solid was filtered off and dried in vacuo. The crude solid was treated with isopropanol and filtered to give 15 g of the title compound in 90% yield as a pale brown solid. Mp 78-81 ° C.

¹ H NMR (CDCl ₃ , 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-fluorophenyl) -4- (2-fluoro-4-methylsulfanyylphenyl) -2,5-dihydro-2-furanone.

To a solution of 2- (2-fluoro-4-methylsulfanylphenyl) -2-hydroxyethyl-2- (4-fluorophenyl) acetate (12 g, 35.7 mmol) (obtained in step 1) in acetonitrile (100 ml) was added dropwise 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) (11 ml, 71.5 mmol) at 25 ° C in a nitrogen atmosphere. The mixture is stirred for 30 minutes at the same temperature. Water (200 ml) was added to the resulting mixture, followed by an additional 2N HCl (200 ml). The mixture was then extracted with EtOAc (2 × 250 ml), the organic layers were collected, combined, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel column chromatography using 10% EtOAc-petroleum ether, which afforded 5 g of the title compound in 44% yield as a white solid. Mp 118-122 ° C.

¹ H NMR (CDCl ₃ , 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:

Preparation of 3- (4-fluorophenyl) -4- (2-fluoro-4-methylsulfonylphenyl) -2.5-dihydro-2-furanone.

To a solution of 3- (4-fluorophenyl) -4- (2-fluoro-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone (6 g, 18.8 mmol) (obtained in stage 2) in acetone (150 ml) add a solution of 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 was removed under low vacuum and then water (200 ml) was added to the residue. The mixture was then extracted with EtOAc (2 × 100 ml), the organic layers were collected, combined, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Then the crude product is treated with MeOH (2 × 20 ml) and filtered, which gives 5.6 g of the title compound in 85% yield as an off-white powder. Mp 160-162 ° C.

¹ H NMR (CDCl ₃ , 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).

The compounds of examples 2-93 receive using the methods described in example 1

Example 97:

1- (4-Fluorophenyl) -4- (3-methyl-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-1H-2-azolone

To a solution of N ¹ - (4-Fluorophenyl) -N ¹ - [2- (3-methyl-4-methylsulfonylphenyl) -2-oxoethyl] -2-phenylacetamide (1 g, 2.27 mmol) in acetonitrile (15 ml) was added DBU (0.346 g, 2.27 mmol) in a nitrogen atmosphere at 0-5 ° C. The mixture was stirred for 4 hours, poured into water (50 ml) and extracted with EtOAc (3 × 15 ml). The organic layers were separated, combined together, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The precipitate isolated is purified using a chromatographic column using EtOAc - petroleum ether (1: 3) as an eluent, which affords 0.2 g of the title compound in 21% yield. Mp 207-209 ° C.

¹ H NMR (CDCl ₃ , 200 MHz): δ 7.9-7.7 (m, 3H), 7.4-7.0 (m, 9H), 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-methylsulfonylphenyl) -1- (4-fluorophenyl) -4-phenyl-2,5-dihydro-1H-2,5-azoldione

The title compound was obtained in 7% yield from N ¹ - (4-fluorophenyl) -N ¹ - [2- (2-fluoro-4-methylsulfonylphenyl) -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. So pl. 198-200 ° C.

¹ H NMR (200 MHz CDCl ₃ ,): δ 7.8-7.1 (m, 12H), 3.1 (s, 3H). Mass (Cl, isobutane) m / e 439 (M ⁺ , 100).

The compounds of the present invention are tested in vitro for their COX-1 and COX-2 inhibitory activity using the test methods described in the prior art. In vivo efficacy of the compound was tested on male Sprague-Dawley rats using a rat carrageenan edema test on the legs of a rat (Proc. Soc. Exp. Biol. Med. 111, 544 (1962); Laboratory models for testing NSAIDs for non-steroidal anti-inflammatory drugs (J. Lombardino ed., 1985).

Biochemical tests In Vitro

1. Spectrophotometric tests for COX-1 and COX-2:

The microsomal fraction of lamb testes is used as a source of COX-1 enzyme (Hemler et al., 1976) and microsomes from sf-9 cells infected with baculovirus containing human COX-2 k-DNA are used as COX-2 enzyme (Wanda and et al. 1994). The enzyme activity is measured by chromogenic tests based on the oxidation of N, N, N ¹ , N ¹ -tetramethyl-p-phenylenediamine (TMPD) during the reduction of PGG2 to PGH ₂ , as for the method described by Copeland et al., 1994 with the following modifications. The test mixture (1000 μl) contains 100 μM TRIS, pH 8.0, 3 μM EDTA, 15 μm hematin, 150 enzyme units and 8% DMSO. The mixture is incubated at 25 ° C for 15 minutes until the initiation of the enzymatic reaction in the presence of a compound / binder. The reaction is initiated by the addition of 100 μM arachidonic acid and 120 μM TMPD. Enzyme activity is measured by determining the initial oxidation rate of TMPD during the first 25 seconds of the reaction, followed by an increase in absorption at 603 nM. IC ₅₀ values are calculated by non-linear regression analysis of percent inhibition.

Example Concentration Inhibition percentage SOX-1 SOX-2 one 100 μM 33 one hundred 6 100 μM 0 82 52 100 μM 12 one hundred 53 100 μM 44 one hundred 55 100 μM thirty one hundred 58 100 μM 19 93 68 100 μM 0 one hundred 69 100 μM 10 93 70 100 μM 49 92 71 100 μM 3 99 89 10 μM 0 95

2) Tests on human whole blood:

COX-1 inhibitory tests

Fresh heparinized human whole blood is incubated with E. coli lipopolysaccharide (LPS) at 100 μg / ml and with 2.5 μl binder (DMSO) or test compound for 24 hours at 37 ° C. PGE ₂ plasma levels are measured by EIA equipment (Cayman chemicals, USA) after deproteinization.

COX-2 inhibitory tests

An aliquot of fresh blood is mixed with either DMSO or test compounds and allowed to clot for 1 hour at 37 ° C. Serum TXB ₂ levels are measured by EIA equipment (Cayman chemicals, USA) after deproteinization.

Example IC ₅₀ (nM) COX-I COX-II one 194.5 ± 27.5 2.72 + 0.425 6 > 500 5.7 52 1220 ± 20 0.578 ± 0.011 53 247 ± 24 0.368 55 > 100 one 58 357 ± 7.45 0.524 ± 0.062 68 296.5 1.248 69 > 500 0.318 ± 0.013 70 115 0.913 89 > 1000 6.13

In vivo screening methods

1. Carrageen-induced edema of rat paws

Male Wistar rats (120-140 g) were not fed for 16 hours before the experiment. Compounds are suspended in 0.25% CMC (CMC) and administered orally in a volume of 10 ml / kg 2 hours before carrageenan injection. Swelling of the hind paw is induced in rats by subcutaneous injection of 50 μl of 1% lambda-carrageenan in saline into the surface of the right paw. The paw volume is measured before and 3 hours after the carrageen injection using a plethysmometer (Ugo-Basile, Italy). Paw edema is compared with the control group of the binder, and percent inhibition is calculated taking the values for the control group as 0%.

Example Dose Inhibition percentage 6 thirty 23 52 thirty 62 53 thirty 39 55 10 48 58 thirty 44 68 thirty 44 69 thirty 51 70 thirty 51 71 thirty 17 89 thirty 31

Claims (11)

1. The compound of formula (I)

where R ¹ represents alkyl; R ² represents halogen, formyl, substituted or unsubstituted alkyl, hydroxyl, (C ₁ -C ₆ ) alkoxy, halogenated, or R ¹ and R ² together with the atom to which they are attached form an unsubstituted 5-7 membered structure of the formula —CH ₂ - (CH ₂ ) _n S—, where n = 1 or 2; R ³ represents hydrogen, a halogen atom or an alkyl; R ⁴ is alkoxy or aryl unsubstituted or substituted with halogen, (C ₁ -C ₆ ) alkyl, halogenated (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylsulfonyl; R ⁵ represents hydrogen, hydroxyl, alkyl alkenyl or alkoxy; R ⁶ represents hydrogen or alkyl or R ⁵ and R ⁶ together represent = O; X represents oxygen or NR ⁸ , where R ⁸ represents aryl substituted with halogen; m is an integer from 0 to 2, its pharmaceutically acceptable salts. 2. The compound according to claim 1, which is selected from such compounds as: 4- (1,1-dioxo-2,3-dihydrobenzo [b] thiophen-5-yl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3- (4-isobutylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 3-phenyl-4- (3-methoxy-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-isobutylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfanylphenyl) -3- (4-trifluoromethylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-trifluorophenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfanylphenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-chlorophenyl) -3-phenyl-2,5-dihydro-2-furanone; 3- (4-methylsulfanylphenyl) -4- (3-chloro-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-chlorophenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-fluorophenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-fluorophenyl) -3- (4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-3-chlorophenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-chlorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-fluorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-3-fluorophenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-3-chlorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-3-fluorophenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfanylphenyl) -3- (4-trifluoromethylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-trifluoromethylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-methylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfanylphenyl) -3- (4-isobutylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-isobutylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-3-fluorophenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-3-fluorophenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-2-chlorophenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfanylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfonyl-3-chlorophenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone; 4- (4-methylsulfanyl-2-chlorophenyl) -3- (4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone; 4- (2,3-dimethyl-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfanylphenyl) -3- (3-methyl-4-sulfanylphenyl) -2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (3-fluoro-4-methylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (4-ethylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (3,4-dimethylphenyl) -2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (3-bromo-4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (1-naphthyl) -2,5-dihydro-2-furanone; 3- (3-methyl-4-methoxyphenyl) -4- (3-methyl-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methoxyphenyl) -5,5-dimethyl-2,5-dihydro-2-furanone; 4- (3-methyl-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone; 4- (3-bromomethyl-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5,5-dimethyl-2,5-dihydro-2-furanone; 2- {5- [4- (4-fluorophenyl) -2,2-dimethyl-5-oxo-2,5-dihydro-3-furanyl] -2-methylsulfonylbenzyl} -2,3-dihydrobenzo [d] isothiazole- 3-oxo-1,1-dioxide; 4- (2-fluoro-4-methylsulfonylphenyl) -5,5-dimethyl-3- (3-methyl-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -2,5-dihydro-2-furanone; 3- (4-fluorophenyl) -5,5-dimethyl-4- (4-methylsulfonyl-3-morpholinomethylphenyl) -2,5-dihydro-2-furanone; 5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -2,5-dihydro-2-furanone; 3- (3,4-difluorophenyl) -4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 3- (3,5-difluorophenyl) -4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfanylphenyl) -2,5-dihydro-2-furanone; 3-isopropoxy-5,5-dimethyl-4- (3-methyl-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 4- (3-hydroxymethyl-4-methylsulfonylphenyl) -3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone; 5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfanylphenyl) -5-hydroxy-2,5-dihydro-2-furanone; 5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-methoxy-3-methylphenyl) -2,5-dihydro-2-furanone; 5-ethyl-4- (3-fluoro-4-methylsulfonylphenyl) -3- (3,4-difluorophenyl) -2,5-dihydro-2-furanone; 3- (3,4-difluorophenyl) -5-ethyl-4- (2-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 3- (3,4-difluorophenyl) -5-ethyl-4- (2-fluoro-4-methylsulfonylphenyl) -5-hydroxy-2,5-dihydro-2-furanone; 4- (3-fluoromethyl-4-methylsulfonylphenyl) -3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone; 3-isopropoxy-5,5-dimethyl-4- (3-fluoro-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 3-isopropoxy-5,5-dimethyl-4- (3-methylsulfanyl-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 3-isopropoxy-4- (3-methoxymethyl-4-methylsulfonylphenyl) -5,5-dimethyl-2,5-dihydro-2-furanone; 4- (3-formyl-4-methylsulfonylphenyl) -3-isopropoxy-5,5-dimethyl-2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methylsulfonylphenyl) -2,5-dihydro-2-furanone; 5-ethyl-4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5-hydroxy-2,5-dihydro-2-furanone; 5-ethylidene-4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -2,5-dihydro-2-furanone; 5-ethylidene-4- (2-fluoro-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-2-furanone; 5-ethylidene-4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-methyl-4-methoxyphenyl) -2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5-methyl-2,5-dihydro-2-furanone; 4- (3-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5-methyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5-methyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5-methyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3,4-difluorophenyl) -5-methyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (3-fluorophenyl) -5-methoxy-5-methyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-methylphenyl) -5-methyl-2,5-dihydro-2-furanone; 4- (2-fluoro-4-methylsulfonylphenyl) -3- (4-fluorophenyl) -5-methoxy-5-methyl-2,5-dihydro-2-furanone; 1- (4-fluorophenyl) -4- (3-methyl-4-methylsulfonylphenyl) -3-phenyl-2,5-dihydro-1H-2-azolone and 3- (2-fluoro-4-methylsulfonylphenyl) -1- (4-fluorophenyl) -4-phenyl-2,5-dihydro-1H-2,5-azoldione. 3. The compound according to claim 1, for which the pharmaceutically acceptable salt is selected 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, hydrabamine, isopropylamine, methylglucamine, piperzine, morphine procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trimethamine, diethanolamine, meglumine, ethylenediamine, N, N'-diphenylethylenediamine, N, N'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, cholinehydroxylamine, dicyclogene dialkylamine, trialk ylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine; chiral bases, such as alkylphenylamine, 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, alkynyl, ammonium or substituted ammonium salts and aluminum salts; salts may include acid addition salts, among which sulfates, nitrates, phosphates, perchlorates, borates, halides, acetate, tartrates, maleates, citrates, succinates, palmates, methanesulfonates, benzoates, salicylates, hydroxy naphthoates, benzosulfonates, ascorbates or glycates, are suitable, ketoglutarates. 4. A pharmaceutical composition for the treatment of diseases mediated by cyclooxygenase, which comprises an effective amount of a compound of formula (I)

as defined in claim 1, or a compound according to claim 2 and a pharmaceutically acceptable carrier, diluent, excipient or solvate. 5. The pharmaceutical composition according to claim 4, which is in the form of a tablet, capsule, powder, syrup, solution or suspension. 6. A method of treating diseases mediated by cyclooxygenase, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound 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 of claim 6, wherein said disease is inflammation, arthritis, or pain. 8. A method of inhibiting cyclooxygenase in cells, comprising treating the cells with an effective amount of a compound 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 of claim 8, in which the processing of cells is performed in vitro. 10. The method of claim 8, in which the processing of cells is performed in vivo. 11. The method according to paragraph 8, in which cyclooxygenase-2 (COX-2) is more strongly inhibited than cyclooxygenase-1 (COX-1).