BG63082B1 - Phenyl heterocyclic compounds as cyclooxygenase-2 inhibitors - Google Patents

Abstract

The compounds have the formula wherein the substituents of radical R1 and R2 have the meanings given in the description. They are administered for the treatment of diseases determined by cyclooxygenase-2. The invention also relates to certain pharmaceutical preparations containing the said compound. 27 claims

Description

The present invention relates to compounds and pharmaceutical preparations for the treatment of diseases caused by cyclooxygenase and methods of treating them.

Nonsteroidal anti-inflammatory drugs exert their anti-inflammatory, analgesic and antipyretic activity and suppress hormone-induced uterine contractions, as well as certain types of malignancies mainly by inhibiting prostaglandin G / H synthesis, also known as cyclooxygen. Until recently, only one form of cyclooxygenase corresponding to cyclooxygenase-I or the constitutive enzyme initially identified in bovine seminal vesicles was characterized. Recently, the gene of the second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized by chicken, mouse and human. This enzyme is different from cyclooxygenase - I, which is now also cloned, sequenced and characterized by sheep, mouse and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and effectively induced by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. Because prostaglandins play both physiological and pathological roles, we conclude that the constitutive enzyme, cyclooxygenase-1, is responsible, to a large extent, for endogenous basal secretion of prostaglandins and is therefore relevant for their physiological needs, such as maintenance gastrointestinal integrity and renal blood flow. On the contrary, we have come to the conclusion that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins, where rapid enzyme induction occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. Therefore, a selective cyclooxygenase -2 inhibitor would have anti-inflammatory, antipyretic and analgesic properties similar to a conventional, non-steroidal anti-inflammatory drug, and would also inhibit hormone-induced uterine potentiations, and would have uterine potentiations ability to induce some side effects associated with the underlying mechanism. In particular, such a compound would have a reduced ability to induce gastrointestinal toxicity and adverse renal effects, a reduced ability to influence bleeding time, and possibly a reduced ability to induce asthma attacks in aspirin-sensitive asthmatics.

SUMMARY OF THE INVENTION

The invention encompasses new compounds of formula I useful in the treatment of diseases caused by cyclooxygenase-2

The invention also encompasses certain pharmaceutical preparations and methods, including the use of compounds of formula I for the treatment of diseases caused by cyclooxygenase-2.

Detailed description of the invention

The invention encompasses a novel compound of formula I useful in the treatment of diseases caused by cyclooxygenase-2 of formula

or pharmaceutically acceptable salts thereof, where:

X-Y-Z is selected from the group consisting of:

(a) -CH ₂ CH ₂ CH ₂ -, (b) -C (O) CH ₂ CH ₂ -, (c) -CH ₂ CH ₂ C (O) -, (d) -CR ⁵ (R ⁵ ' ) -OC (O) -, (e) -C (O) -O-CR ⁵ (R ⁵ ') -, (f) -CH ₂ -NR ³ -CH ₂ -, (g) -CR ⁵ (R ⁵ ') -NR ³ -C (O) -, (h) -CR ⁴ = CR ⁴ ' -S-, (i) -S-CR ⁴ = GR ⁴ '-, (j) -SN = CH-, (k) -CH = NS-, (l) -N = CR ⁴ -O-, (m) -O-CR ⁴ = N-, (n) -N = CR4-NH-, (o) -N = CR ⁴ -S-, and (p) -S-CR ⁴ = N-;

(q) -C (O) -NR ³ -CR ⁵ (R ⁵ ') -, (r) -R ³ N-CH = CH-, provided that R ¹ is not S (O) ₂ Me, ( s) -CH = CH-NR ³ -, provided that R ¹ is not S (O) ₂ Me when side b represents a double bond and sides a and c represent single bonds; and

X-Y-Z is selected from the group consisting of:

(a) = CH-O-CH =, and (b) = CH-NR ³ -CH =, (c) = NS-CH =, (d) = CH-SN =, '1 · * (e) = NO-CH =, (f) = CH-ON =, (g) = NSN =, (h) = NON = when sides a and c represent double bonds and side b represents a single bond;

R ¹ is selected from the group consisting of:

(a) S (O) ₂ CH ₃ , (b) S (O) ₂ NH ₂ , (c) S (O) ₂ NHC (O) CF ₃ , (d) S (O) (NH) CH ₃ , (e) S (O) (NH) NH ₂ , (f) S (O) (NH) NHC (O) CF ₃ , (g) P (O) (CH ₃ ) OH, and (h) P (O ) (CH ₃ ) NH ₂ ,

R ² is selected from the group consisting of:

(a) C 1-6 alkyl, (B) C ₃ , C ₄ C ₅ , C ₆ , and C ₇ cycloalkyl (c) mono-, di- or 3- substituted phenyl, or naphthyl, where the substituent is selected from the group,

consisting of:

(1) hydrogen, (2) hapo (halogen), (3) C 1-4 alkoxy, (4) C 1-6 alkylthio, (5) CN, (6) CF ₃ , (7) C 1-6 alkyl,

(8) N ₃ , (9) -CO ₂ H, (Yu) -CO ₂ -C ₁ _ ₄ alkyl, (11) -C (R ⁵ ) (R ⁶ ) -OH, (12) -C (R ⁵ ) (R ⁶ ) -OC ₁ _ ₄ anKnn, and (13) -C 4 -bapyl-CO 4 -P ⁵ ;

(d) mono-, di- or tri-substituted heteroallyl, wherein the heteroaryl is a monocyclic aromatic ring of five atoms, which ring has one heteroatom which is S, O, or N and optionally contains 1, 2 or 3 additional N- atom; or the heteroaryl represents a monocyclic ring of six atoms, which ring has one hetero atom which is N and optionally contains 1, 2, 3 or 4 additional N atoms; the alternates are selected from the group consisting of:

(1) hydrogen, (2) halogen, including fluorine, chlorine, bromine and iodine, (3) C 1-6 alkyl, (4) C 1-6 alkoxy, (5) C 1-6 alkylthio, (6) CN, (7) CF ( 8) N (9) - (CR ^S ) (R ⁶ ) -OH, and (10) - (CH ⁵ ) (P ⁶ ) -O-C. ₄ alkyl;

(f) benzoheteroaryl, which includes the analogs of (d) attached to the benzo group;

R ³ is selected from the group consisting of:

(a) hydrogen, (b) CF _3, (c) CN, (d ) C ^ alkyl, (e) hydroxyC ^ eapkil, (f) -C (O) -C ₁ _ ₆ alkyl, (g) optionally substituted ( ¹ ) -C 1-4 alkyl-O.

(2) -C 1-6 alkyl-O-C 1-4 alkyl-O, (3) -C 1-6 alkyl-6- C 1-6 alkyl-O, (4) -C 1-4 alkyl-O-O, or (5) -C N -dapyl-3-O, wherein the substituent is in the alkyl group and the substituent is C 1-6 alkyl;

(h) -Q;

R ⁴ and R ⁴ independently of one another are selected from the group consisting of:

(a) hydrogen, (b) CF (c) CN, (d) C 1-6 alkyl, (e) -Q, (f) -O-Q;

(G) -SQ, and (h) optionally substituted (1) -C ^ alkyl-O, (2) -O-C ^ alkyl-O, (3) -S-C _b5 alkyl-O-, (4) -C ^ alkyl-O-C ^ alkyl-Q, (5) -C ^ alkyl-S-C ^ alkyl-O, (6) -C ^ alkyl-O-O (7) -C ₁ _ ₅ alkyl -8-O, where the substituent is in the alkyl group and the substituent is C 1-6 alkyl, and

R ⁵ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of:

(a) hydrogen, (b) C 1-6 alkyl, or R ⁵ and R ⁶ or R ⁷ and R ⁸ together with the carbon atom to which they are attached form a monocyclic saturated carbon ring of 3, 4, 5, 6 or 7 atoms ;

Q is CO ₂ H, CO-C ^ alkyl, tetrazolyl-5-yl, C (R ⁷⁾ (R ⁸⁾ (OH), or C (R ⁷⁾ (R ⁸⁾ (O-C ₁ _ ₄ alkyl) ;

provided that when XYZ is -S-CR ⁴ = CR ⁴ then R ⁴ and R ⁴ are different from CF ₃ .

Another aspect of this application of the invention is the compounds of formula I

I or their pharmaceutically acceptable salts, wherein: XYZ is selected from the group consisting of -C (O) -OCR ⁵ (R ⁵ ) - when side b represents a double bond and sides a and c represent single bonds; and R ¹ is selected from the group consisting of:

(a) S (O) ₂ CH ₃ , (b) S (O) ₂ NH ₂ ,

R ² is selected from the group consisting of:

(a) C 1-6 alkyl, (b) C ₃ , C ₄ C ₅ , C ₆ , and C ₇ cycloalkyl (c) heteroaryl, (d) benzoheteroaryl, (e) mono- or di-substituted phenyl, where the substituent is selected from the group consisting of:

(1) hydrogen, (2) halo (halogen), (3) C 1-4 alkoxy, (4) C 1-6 alkylthio, (5) CN, (6) CF (7) C 5 -alkyl, (8) N (9 ) -CO ₂ H, (10) -CO ₂ -C! _ ₄ alkyl, (11) -C (R ⁵ ) (R ⁶ ) -OH, (12) -C (R ⁵ ) (R ⁶ ) -OC ₁ _4 ^{anKI / l} - ⁿ > ^and (13) -C N-alkyl-CO 2 -I ⁵ ;

R ⁵ , R ⁵ and R ⁶ are independently selected from the group consisting of:

(a) hydrogen, (b) C 1-6 alkyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.

For the purposes of this specification, alkyl is defined as including straight, branched or cyclic structures with C 1-6 alkyl. including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-d and methyl ethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, alkoxy is intended to include alkoxy groups of 1 to 6 carbon atoms with a straight, branched or cyclic configuration. Examples of smaller alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Similarly, it is contemplated that C 1-6 alkyltyl includes alkyl groups having 1 to 6 carbon atoms of straight, branched or cyclic configuration. Examples of smaller alkyl groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. To illustrate, the propylthio group represents - SCH ₂ CH ₂ CH ₃ .

Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1, 2, 3-oxadiazole, 1, 2, 3-thiadiazole, 1, 2, 3 triazole, 1, 3, 4-oxadiazole 1, 3, 4-thiadiazole, 1, 3, 4triazole, 1, 2, 5-oxadiazole, 1, 2, 5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2, 4-triazine, 1,3, 5triazine, 1,2, 4, 5-tetrazine and the like.

Benzoheteroaryl includes the heteroaryl rings described above to which a benzene ring may be attached.

Examples of the invention are:

(a) 3- (4- (aminosulfonyl) phenyl) -2- (4fluorophenyl) -5- (2-hydroxy-2propyl) thiophene, (b) 3- (4- (aminosulfonyl) phenyl) -2- (4fluorophenyl) thiophene, (c) 3- (4- (aminosulfonyl) phenyl) -2- (4fluorophenyl) -5- (2-propyl) thiophene, (d) 3- (4- (aminosulfonyl) phenyl) -2cyclohexylthiophene _? (e) 5- (4- (carboxyphenyl) -4- (4 (methylsulfonyl) thiophene-2carboxylic acid, (f) 4- (4-fluorophenyl) -2-methyl-5- (4 (methylsulfonyl) phenyl) thiazole, (g) 2- (4-fluorophenyl) -3- (4-methylsulfonyl) phenyl) -2-cyclopenten-one, (h) 4- (4- (methylsulfonyl) phenyl) -5- (4-fluorophenyl) -isothiazole, (i) 3- (4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) furanone, (j) 3- (4-fluorophenyl) -4- (4 (aminosulfonyl) phenyl) -2- (5H) furanone , (k) 3- (4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) furan, (I) 5,5-dimethyl-3- (4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) - 2- (5H) furanone, (m) 2- (4- (aminosulfonyl) phenyl) -3- (4fluorophenyl) thiophene, and (η) 3- (4-trifluoroacetylaminosulfonyl) phenyl) -2- ( 4-fluorophenyl) thiophene, (o) 3- (3-fluorophenyl) -4- (4 (methylsulfonyl) -2- (5H) -furanone, (p) 5,5-dimethyl-3- (3-fluorophenyl) - 4- (4 (methylsulfonyl) phenyl-2- (5H) furanone, (q) 5,5-dimethyl-3- (3-chlorophenyl) -4- (4 (methylsulfonyl) phenyl-2- (5H) furanone, ( d) 3- (3,4-difluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) furanone, (s) 3- (3,4-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) ) -2- (5H) furanone, (t) 5,5-dimethyl-3- (3,4-difluorophenyl-4 (4-methylsulfonyl) phenyl-2- (5H) furanone, (i) 5,5-dimethyl -3- (3,4-Dichlorophenyl-4- (4methylsulfonyl) phenyl-2- (5H) furanone, (ν) 5,5-dimethyl-3- (4-chlorophenyl-4- (4methylsulfonyl) phenyl-2- ( 5H) furanone, (w) 3- (2-naphthyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) furan one, (x) 5,5-dimethyl-3- (2-naphthyl) -4- (4methylsulfonyl) phenyl-2- (5H) furanone, (y) 3-phenyl-4- (4- (methylsulfonyl) phenyl-

2- (5H) -Furanone.

Some of the compounds described herein contain one or more asymmetric centers and may therefore yield diastereoisomers and optical isomers. The present invention is intended to encompass such possible diastereoisomers as well as their racemic and separated, enantiometrically pure forms and their pharmaceutically acceptable salts.

Some of the compounds described herein contain olefinic double bonds and, unless otherwise specified, are considered to include both E and Z geometric isomers.

In a second application, the invention encompasses pharmaceutical preparations for the inhibition of cyclooxygenase and for the treatment of diseases caused by cyclooxygenase, as set forth herein, comprising a pharmaceutically acceptable carrier, a non-toxic therapeutically effective amount of a compound of formula I, as described above.

Within the scope of this application, the invention encompasses pharmaceutical preparations for the suppression of cyclooxygenase-2 and for the treatment of diseases caused by cyclooxygenase-2, as set forth herein, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula I as is described above.

In a third application, the invention encompasses a method of inhibiting cyclooxygenase and treating diseases caused by cyclooxygenase successfully treated with an active agent that selectively suppresses COX-2 (cyclooxygenase-2), preferably COX-1 (cyclooxygenase-1), as described herein, which comprises: administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of formula I as described herein.

For the purposes of this description, a compound is said to be sex-specific for COX-2, preferably COX-1, if the ratio of its IC50 concentration to inhibit COX-1 to IC50 concentration is to inhibit COX-2. is 100 or more than 100.

the pharmaceutical compositions of the present invention contain, as active ingredient, a compound of formula I or a pharmaceutically acceptable salt thereof, and may also contain

a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. The term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable non-toxic bases that include inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese salts containing biphasic manganese, manganese, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organically non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline,

Ν, Ν'-dibenzylethylenediamine, diethylamine,

2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrobamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamines, triamines, triamines, triamines , trimethylamine, tripropylamine, tromethamine and the like.

It should be understood that the discussion of the methods of treatment that follows below also includes pharmaceutically acceptable salts in the data for the compounds of formula I.

The compound of formula I is useful for soothing pain, fever and inflammation in a variety of conditions, including rheumatic fever, symptoms? associated with influenza or other viral infections, common cold, neck and back pain, dysmenorrhea, headache, toothache, sprains and stretch marks, myositis, neuralgia, synovitis, arthritis, including ankylosing rheumatoid arthritis, degenerative joints, degenerative joints, degenerative joints, degenerative joints bursitis, spondylitis, burns, injuries, dental conditions after surgery and procedures. In addition, such a compound can suppress neoplastic cellular transformations and tumor metastasis growth and, therefore, can be used to treat cancer. Compounds of formula I may also be administered for the treatment of dementia, including presenile and senile dementia, and in particular dementia associated with Alzheimer's disease (i.e., Alzheimer's dementia).

Compounds of formula I may also inhibit prostanoid-induced smooth muscle contraction by preventing contraction-inducing prostanoids (prostaglandins), and can therefore be used to treat dysmenorrhea, preterm birth and asthma.

Due to their high COX -2 activity and / or their selectivity for COX - 2 compared to COX -1 as defined above,

,. ..., .. ... - .. 'the compounds of formula I may be useful as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDS), especially where such non-steroidal anti-inflammatory drugs are contraindicated, as is the case in patients with gastric ulcers , gastritis, limited enteritis, ulcerative colitis, diverticolitis, or with a history of recurrent gastrointestinal lesions; gastrointestinal bleeding, clotting disorders, including anemia such as hypoprothrombinemia, hemophilia, or other bleeding problems (including those associated with impaired or impaired platelet function); kidney disease (eg impaired renal function); patients in preoperative preparation or taking anticoagulants; and patients susceptible to asthma when taking non-steroidal anti-inflammatory drugs.

Similarly, compounds of formula I can be used as partial or complete substituents of t

traditional NSAIDS formulations where you are co-administered with other agents or ingredients. Thus, in further embodiments, the invention encompasses pharmaceutical preparations for the treatment of COX-2-related diseases as defined above, the compositions comprising a non-toxic therapeutically effective amount of a compound of formula I as defined above, and one or more ingredients as another painkiller including acetaminophen or phenacetin; potentiating agent such as caffeine; H2 is an antagonist, aluminum or magnesium hydroxide; simethicone, an anti-hyperemic agent including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylxedrine or levodeoxyephedrine; an antitussive agent comprising codeine, hydrocodone, caramifene, carbetapentan or dextramethorphan; diuretic; a sedative or anti-anxiety antihistamine. In addition, the invention encompasses a method of treating diseases caused by cyclooxygenase, comprising: administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of formula I, optionally in association with one or more of the above above ingredients.

The compounds of the present invention are inhibitors of cyclooxygenase-2 and are therefore suitable for the treatment of the diseases caused by cyclooxygenase-2 listed above. This activity is illustrated by their ability to selectively suppress cyclooxygenase-2 compared to cyclooxygenase-1. Accordingly, in one of the tests, the ability of the compounds of this invention to treat the diseases caused by cyclooxygenase can be demonstrated by measuring the amount of prostaglandin E ₂ (PGE ₂ ) synthesized in the presence of arachidonic acid, cyclooxygenase -1 or cyclooxygenase-2 and compound of formula I. IC50 values represent the concentration of inhibitor required to reduce PGE ₂ synthesis by up to 50% over that of the uninhibited control. Illustrating this aspect, we have found that the compounds of the examples are more than 100 times more effective in inhibiting COX -2 than suppressing COX -1. In addition, for all compounds the IC50 for COX -2 is from 1nM to 1µΜ. For comparison, ibuprofen has an IC ₅₀ for COX -2 of 1µΜ and indomethacin has an IC ₅₀ for COX -2 of approximately 100 nM. For the treatment of all diseases caused by cyclooxygenase, the compounds of formula I can be administered orally, topically, parenterally, by inhalation spray or rectally in dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, potency enhancers and vehicles. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, intrasternal, injectable or infusion routes. In addition to treating warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is also effective in treating humans.

As indicated above, pharmaceutical preparations for the treatment of diseases caused by cyclooxygenase -2 may optionally include one or more of the above ingredients.

Pharmaceutical preparations containing the active ingredient may be in a form suitable for oral administration, for example as tablets, pills, dragees, aqueous or oily suspensions, powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Preparations for oral use may be prepared according to any known, professionally practiced method of manufacturing pharmaceutical preparations and such preparations may contain one or more agents selected from the group of sweetening agents, flavoring and flavoring agents, coloring agents and preservatives , in order to obtain pharmaceutically attractive and palatable preparations. The tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or degrading agents, for example maize starch or alginic acid; binders, for example, starch, gelatin or gum; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated according to accepted technologies in order to delay their digestion and absorption in the gastrointestinal tract and thus to produce a longer lasting effect. For example, glyceryl monostearate or glyceryl distearate may be used as a material for prolonging the action time. The tablets may also be coated according to the technology described in US patents 4256108; 4166452; and 4265874 to obtain tablets with an osmotically controlled release of the drug component.

Oral preparations may also be 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 as soft gelatin capsules in which the active ingredients are mixed with water. or they are in an oily environment, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, propyl methylcellulose, sodium alginate, hydroxypolyvinyl pyrrolidone, tragacanth or arabic gum;

dispersing or wetting agents may be natural phosphatides, for example lecithin or condensation products of fatty acid apalkylene oxide, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. fatty acids and hexitol _? such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or η-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin or aspartate.

Oily suspensions can be prepared by suspending the active ingredient in vegetable oil, for example, peanut oil, olive oil, sesame oil, coconut oil or in mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as the aforementioned flavoring agents may be added to produce a pleasant and odorant preparation for oral administration. The formulations can be preserved by adding an antioxidant such as ascorbic acid.

Powders and granules suitable for the preparation of an aqueous suspension after addition of water contain the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents were already present

given above. Additional excipients, for example, sweetening, flavoring and coloring agents may also be present.

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

Syrups and elixirs may be prepared with sweeteners, for example, glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a softener, preservative, flavoring agents and colorants, the pharmaceutical preparations may be in the form of a sterile, injectable aqueous or oleaginous suspension. This suspension can be prepared according to known techniques using the aforementioned suitable dispersing or wetting and suspending agents. The sterile injectable preparation may also be a sterile injectable form or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in

1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile stable oils are conventionally applied as a solvent or suspending medium. For this purpose, any fixed non-irritating oil, including synthetic mono - or diglycerides, may be used. In addition, some fatty acids, such as oleic acid, are used in the preparation of injection forms.

Compounds of formula I may also be administered in the form of suppositories for rectal administration of the therapeutic agent. These preparations can be prepared by mixing the drug with a suitable non-irritating excipient that is of a solid consistency at ordinary temperatures but is liquid at rectal temperature and will therefore dissolve in the rectum, releasing the drug. Such materials are cocoa butter and polyethylene glycols.

For topical application, creams, ointments, jellies, solutions or suspensions, etc., containing a compound of formula I are used (for the purposes of this application, topical application may include a mouth and gargle swab).

For the treatment of the above conditions and processes, suitable dosages are in the range of about 0.01 mg to about 140 mg per kilogram body weight daily, or alternatively, about 0.5 mg to about 7 g daily for adult patients. For example, inflammation can be effectively treated by administering about 0.01 to 50 mg of the compound per day per kilogram of body weight, or alternatively, about 0.5 to about 3.5 g per patient per day.

The amount of active ingredient that can be combined with the carrier to form a single dose will vary depending on the patient being treated and the particular route of administration. For example, a preparation for oral administration to humans may contain from 0.5 mg to 5 g of the active agent, combined with an appropriate amount of carrier, which may vary from about 5 to 95% of the total amount of the formulation. per unit dose usually contain from about 1 mg to about 500 mg of active ingredient, typically 25 mg, 50mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

However, it is understandable that the specific dose level for each individual patient will depend on a variety of factors including age, body weight, overall health, gender, diet, duration of administration, route of administration, rate of excretion, combination with other medications, as well as the severity of the particular disease being treated.

Methods of synthesis

The compounds of the present invention can be prepared according to the following methods.

Method A.

β-Chlorovinylaldehyde III can be obtained from ketone II and the Vilsmeier reagent (DMF-POCI ₃ ) _? using the general method described by Weissenfels (Z. Chem. 1966, 6, 471). Thiophene compound IV is obtained from II 1 _; using the general method described by Weissenfels (Z. Chem. 1973, 13, 57). The thiol compound V can be obtained after oxidation of compound IV (R ^a = -SMe) with one equivalent of m-CPBA, after which the resulting sulfoxide is treated with reflux TFAA. The sulfonamide group (VI) can then be prepared by the Kharash method (J. Amer. Chem. Soc. 1951, 73, 3240). Hydrolysis of compound VI and decarboxylation with Cu - bronze in phenolin yields compound VII. Compound VII (R ⁴ = H) can be treated with a halogenating agent, for example bromine in acetic acid, to give 5bromothiophene (VII, R ⁴ = Br). Where a nitrile group is desired at C-5, this can be achieved by VI by amidation using the Weinreb methodology (Tetrahedron Letters, 1977, 4171) followed by dehydration with TFAA. The CF ₃ group can be introduced to the fifth place (C-5) of compound VII by the Girard method (J. Org. Chem. 1983, 48, 3220).

The introduction of an alkyl group at C-5 can be achieved by the reaction of Friedel - Crafts on VII (R ⁴ = H) and acyl chloride, CI-CO lower alkyl and a catalyst such as TiCI4 with subsequent reduction. For R ⁴ = Me, this can be achieved from the ester (R ⁴ = CO2Me) by DIBAL-Reduction followed by deoxygenation using the Lau method (J. Org. Chem. 1986, 51, 3038). Tertiary alcohols (R ⁴ = -C (CH ₃ ) ₂ OH) can be obtained from VI and MeMgBr. Sixth tertiary alcohols can also be deoxygenated using the Lau method. Similarly, thiophene IX can be obtained from ketone VIII,

Method A

II R ^a = -SMeHAu * SO ₂ Me

III

HS ^ °

OMe

IV (R ⁴ = -CO ₂ Me)

Py / Et ₃ N

R ^a = SO ₂ Me

R ² = PhCO ₂ H

R ⁴ = CO ₂ H

VI (R ⁴ = CO ₂ Me)

Method A - Continued νιι ρψ

R <= No.

VII R ⁴ = C 1 -C 6 ^alkyl R ⁴ = CF ₃

VI .amidation

- VI

2. TFAA.

r ⁴ = cn ·.

MeMgBr

Method B,

Ketone X can be converted to thiophene compound XI using the general methods already described in method A. ThiopheneXP can be obtained by attaching metal to XI with n-BuLi, abrupt cooling with methylphosphonium dichloride and adding water or ammonia (X = OH or NH ₂ ). Similarly, the other positional isomer XIV may be derived from ketone XIII.

Method B,

.n-BuLi

2. Me (CI) ₂ PO

3. H ₂ 0ma «NH ₃

Method C.

Bromination of ketone II gives a - bromine ketone XV, which is then converted to thiazole XVI after treatment with stioamide. Similarly, ketone VIII can be converted to thiazole XVII.

Method C.

II Br? o ^ R ² with X r ^4x ^ nh _? ⁴ R ^a XV I In R ² · • XVI

s ^Ra n VIII. No. ₂ In r ^{4 / x} nh ₂ R ² - ^ si-R ⁴ XVII

Method D.

Ketone XV can be converted to the imidazole compound XVIII after treatment with formamide using the method of Brederick et al, Chem. Ber. 1953, p. 88.

Method D,

XV

Method E.

Pyrrole compound XX can be obtained from diketone XIX using the general methods of Friedman et al; J. Org. Chem. 1965, p. 854, K. Dimroth et al; Ber. 1956, 56, 2602, K. Dimroth et al; Ann. 1961.634, 102. The free NH of the pyrole can be acylated with Cl -CO - lower alkyl in the presence of a base such as _g Et ₃ N. They can also be prepared alkylated products using alkyl halides as reagents with the base for example NaH.

Method E,

^{th e0} γ ° o MeO '' ^ ^x ~ ^xN ''' ^/ MeO.

NaH / DMF 0 ° C go room temperature

180 ° C

Method F.

Compounds of type XXV may be prepared from readily available 4-substituted phenylacetyl chlorides XX1a. The reaction of di (3-butenyl) cadmium with 4-substituted phenylacetyl chloride gives ketone XXI. Ozonolysis of XXI gives ketoaldehyde XXIb, which cyclizes through a base and gives cyclopentenone XXII. The addition of arylmagnesium bromide or aryl lithium to XXII gives allyl alcohol XXIV. Oxidation of XXIV with pyridine chlorchromate is desirable

2,3-Disubstituted cyclopentenone XXV. To obtain compound XXV (R ¹ = SO ₂ Me) was used

4-Methylthiophenyllithium, followed by oxidation by the magnesium salt of monperoxyphthalic acid (MMPP) or t-chloroperoxybenzoic acid (mCPA) to introduce the desired methylsulfonyl group into the XXV.

Method F

RCC

Method G.

The sequence for method G is the same as for method F ₃ except that acid chloride containing R ¹ is used as starting material. R ² is introduced at a later stage by the addition reaction of a carbonyl group followed by PCC oxidation.

Method G:

RCC> -

Method H:

4,5-Disubstituted isothiazoles and isothiazole-3 (2H) mono-1,1-dioxides can be prepared by the general method described by B. Schulze et al; Helvetica Chimica Acta, 1991, 74, 1059. Thus, aldehyde III (R ^a = SO ₂ Me) or XVII is treated with excess NH ₄ SCN in acetone under reflux to obtain the corresponding 4,5-disubstituted isothiazoles XXX and

XXVIII, the oxidation of which with hydrogen peroxide gives XXXI and XXIX.

Method H,

SO ₂ Me νιιι hA, < ^CI 1 [NH ₄ SCN r ^2Z (R ^a = SO ₂ Me) CHO RK <As Vn XXVII XXVIII

H ₂ O ₂ , AsON

III (Ra = SO ₂ Me)

XXIX

XXX

XXXI

Method I,

A suitably substituted aryl-bromomethyl ketone is reacted with an appropriately substituted arylacetic acid in a solvent such as acetonitrile in the presence of an alkaline substance such as triethylamine and then treated with 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU) ) to obtain lactone XXXIII or XXXV.

Method L

NOGS

XXXIV (R ² is mono- or di-substituted heteroaryl)

Similarly

receive 5,5-dimethyl-2 (5H) furanone derivatives.

Method J.

Lactones XXXIII or XXXV in a solvent such as THF are reacted with a reducing agent such as diisobutidaluminum hydride or lithium borohydride at -78 ° C to obtain furan XXXVI.

Method J

R ¹ XXXIII 1. DIBAL-H. · (Γί IAM. XXXV 2. H ⁺ .-. R XXXVI

Method K.

The preparation of lactams XXXVII and XXXIX can be achieved by the same reaction as described in method I, except that a suitable amide is used.

R ^2X ^ CONHR ³

---—- The basis of Fr.

_R2 A ^ r

--———-- ►

The basics

Method L.

Methyl 2-hydroxyisobutyrate is silylated with TMSCI to give TMS ether XLI, which is treated with

4-methylthiophenyllithium to give ketone XLII. Distillation followed by acylation gives the keto ester XLIV, which can be cleaved to lactone XLV by alkaline catapysis. Oxidation of XLV with MMPP or mCBA gives the desired product XLVI.

Method L.

Method Μ:

XLIII

An alternative method for the preparation of hydroxyketone XLIII is the oxidation of the known from the literature (J. Org. Chem. 1991 56,5955-8; Sulfur Lett. 1991, 12, 123-32) ketone XLIV. A mixture of XLIV, a water-soluble base such as NaOH, organic solvents such as carbon tetrachloride / tuber, and a phase conversion catalyst such as ALIQUAT 336, were stirred in air at room temperature to obtain XLIII. Compound XLIII is also described in US 4321118 and in Org. Coat. 1986, 6,175-95.

Representative compounds

Tables I and II illustrate the compounds of formula I.

Table 1.

Example Method

Table 1 (continued)

Example Method

Table! (continued)

Example Method

ϋ ^ ί *

Table 1 (continued)

Example Method

SO ₂ Me

I

I

SO ₂ Me

Table ! (continued)

Example Method

SO ₂ Me

Table 1 (continued)

Example Method

I

SO ₂ Me

Table 1 (continued)

Example Method

SO ₂ Me

Table 1 (continued)

Example Method

SO ₂ Me

Table 1 (continued)

Example Method

SO ₂ Me

Table 1 (continued)

Example Method

I

SO ₂ Me

Table 1 (continued)

Example Method

SO ₂ NH ₂

Table! (continued)

Example Method

Table 1 (continued)

Example Method

L + M

L + M

Table II

SO ₂ NH ₂

And ⁴ s \\

OMe

OMe

Table II (continued)

Table II (continued)

OH

Tablia || (continued!

HE

he

are ₂ nh ₂

are ₂ nh ₂

Table II (continued)

Table II (continued)

Table II (continued)

Table II (continued)

Table II (continued)

Table II (continued)

Cl

SO ₂ Me

Cl

Cl

Cl

SO ₂ NH ₂

Table II (continued)

Table II (continued)

Tests for determining biological activity

The compounds of general formula I can be tested using the following methods to determine their cyclooxygenase-2 inhibitory activity.

Suppression of cyclooxygenase activity

The compounds were tested as inhibitors of cyclooxygenase activity by analysis of whole-cell cyclooxygenase and microsomal fraction. Both tests measure the synthesis of prostaglandins E ₂ (PGE ₂ ) in response to arachidonic acid by radioimmunoassay. The cells used in the whole-cell test from which the microsomes for the microsomal test were obtained were human osteosarcoma 143 cells (which specifically express cyclooxygenase-2) and human U-937 cells (which specifically express cyclooxygenase-1). In these tests, 100% activity was defined as the difference between the synthesis of prostaglandin E ₂ in the absence and with the addition of arachidonate. IC ₅₀ values represent the concentration of the putative inhibitor required to restore the synthesis of PGE ₂ to 50% relative to that of the uninhibited control. Representative results are shown in Table III.

Representative test - rat paw edema - protocol

Sprague-Dawley male rats (150-200 g) were allowed to starve overnight and between 9-10 h in the morning were given per os both test compound and vehicle (5% tween 80 or 1% methocel). An hour later, a line was marked with a marker at the level above the fold of one of the hind paws in order to determine the area of the paw to be monitored. Paw volume (V _oh ) was measured using a plethysmometer (Ugo - Basile, Italy) based on the principle of water displacement. The animals were then injected subplantally into the paw with 50 μl. 1% solution of carrageenan (Irish lichen carrageenan vegetable gelatin) in saline (FMC Corp. Maine) with an insulin syringe / needle caliber 25 (ie 500 μg paw gelatin). The paw volume was measured three hours later (V _3h ) and its increase (V _3h -V _oh ) was calculated. Animals were eftanized by CO ₂ suffocation and the presence or absence of gastric lesions was recorded. Gastric lesions were expressed as the sum of all lesions in mm. Paw edema values were compared with the control group (injected vehicle) and percent inhibition was calculated taking 100% of the values in the control group. Because a maximum of 60 to 70% suppression (paw edema) was obtained with standard NSAIDs, ED ₃₀ values were used for comparison. All treatment groups were coded to eliminate observer subjectivity in reporting. In this protocol, ED ₃₀ for indomethacin is 1.0 mg / kg. Representative results are shown in Table IV.

Table 111 *

Whole Cells Microscopes

At trans Conc. (nm) COX-2. % inhibition. COX-1% AND Η X And b. Conc. (nm) · - COX-2 % inhibition. COX-1 _% inhibition. 1 100 96 12 100 53 8 2 10 69 0 10 49 25 3 10 ' 42 10 33 19 3 100 100 100 76 12 4 10 47 2 5 10 0 0 10 43 31 6 100 78 100 19 16 7 100 74 0 1000 58 16 8 10 41 8 100 89 9 100 83 100 37 9 10 100 95 100 71 12 11 100 39 100 46 7 12 100 54 13 10 41 10 52 ' 7 13 100 84 10 58 10 14 10 73 10 45. 29 14 100 89 100 .63 0 14 1000 101 1000 69 0

Example Horses. COX-2 COX-1 Conc. COX-2 COX-1 y (nm) % inhibition. % inhib. (nm) % inhib. % .and n X iB - 15 20 39 15 80 76 15 160 95 • 16 20 41 16 40 50 16 160 85 17 40 41 17 160 77 18 40 24 18 160 58 19 40 21 19 160 59 20 10 70 20 40 91 21 10 50 21 40 94 22 20 39 22 160 98 23 20 50 23 160 88 24 40 43 24 160 78 25 160 40 26 80 27 26 160 39 27 20 38 27 160 97

Example Conc. (nm) COX-2 COX-1 Conc. (nm) COX-2 COX-1 % inhib. % inhib. % inhib. % inhib. 28 · 20 48 28 160 .69 29 20 78 29 160 85 30 160 30 31 20 49 31 160 87 32 5 43 32 · 10 73 - 32 40 92 32 80 99 33 160 6 '34 10 30 34 40 80 34 160 102 · 35 20 32 35 40 57 35 160 83 36 10 11 . 36 40 50 36 160 89 37 10 53 37 40 82 37 160 93 • 38 10 25 38 40 63 38 160 88 39 Yu .17 •

. 72

For example Koits. (nm) COX-2 COX-1 Conc. (nm) COX-2 COX-1 % inhib. % inhib. % inhib. % inhi6. 39 160 84 40 10 43 40 40 72 40 160 96 41 41 42 20 10 42 160 44. 43 10 78 43 40 101 - 44 20 14 44 40 55 44 160 106 45 10 16 45 40 61 45 160 101 46 10 76 46 40 94 -46 160 97 47 10 61 47 • 40 74 47 . 160 101 48 10 7 48 160 47 49 10 53 49 40 91 49 80 99 50 80 42

Example Conc. (nm) COX-2 COX-1 Conc. (nm) COX-2 COX-1 1 % inhibition. % inhibition. % inhibition. % inhibition. 51 5 49 51 20 95 51 40 102 52 10 50 52 40 82 52 160 102 53 10 54 53 40 96 53 160 102 - • 54 10 81 54 80 91 54 160 99 55 10 48 55 80 59 55 160 65

* In the whole-cell test, Ibaproene was IC50 for COX-1 1000 nM and IC50 for COX-2 3000 nM. Similarly, Indomethacin needle IC50 for COX-1 100 nM and IC50 for COX-2 10 nM.

Table IV

BD3Q (^ r / kr) STRUCTURE -3.00 ^^ x ^ SO ₂ Me ^ F > 10.00 ^ x.SO ₂ Me OD s] F

<0.30 / Ί s ^x F ζΟ Υ) SO ₂ NH ₂ 0.42 .SO ₂ Me ° 0 0 F 0.034 SO ₂ NH ₂ ° o JU 0 V ^ F

2.03 3Q F F 1.49 ^ x, SO ₂ Me ^c QOz F 0.35 ^ x _x ^ SO ₂ Me ° V \ Yf F

0.88 _x SO ₂ Me M ° \ X 0 T Nr Cl 0.47 _x SO ₂ Me Ar ° cx 0 Xj F ' Cl 0.71 _x SO ₂ Me M ° \ X 0 ν ' Cl

-1.00 . SO ₂ Me m ° c Nr 0 ( F 1.85 .SO ₂ Me m ° c 0 sg Cl 0.22 0.23 _x SO ₂ Me ° axis Cl 0 Cl

0.43 of} 0 Ό .SO ₂ Me Cl F 2.17 _x SO ₂ Me of} AJ 0 CF ₃ 0.81 .SO ₂ Me of} 0 F ( OMe

0.33

0.46

0.76

0.48 _{x are 2} nh ₂ oQ AJ 0 A F F 0.46 _x SO ₂ NH ₂ ° Q JU 0 A Cl Cl 0.26 A .SO ₂ Me ° 0 AJ 0 F Cl

0.55 ° 0 0 X) F ^ SOgMe Nr 0.25 _x SO ₂ Me 0 A Cl ED ₃ 0 <0-30 ΓΊϊ _x SO ₂ Me ED50 = 1.47 AJ 0 A F

0.1-.3 .SC ^ Me ° o AJ 0 Sr II A I -0.10 .SO ₂ Me ° o AJ 0 F F •

The invention will be illustrated by the following examples, which do not limit its scope, unless otherwise stated:

(i) all procedures were performed at room temperature or ambient temperature, ie at a temperature of 18-25 ° C; evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600

4000 pascals: 4.5 - 30 mm Hg) at a water bath temperature of 60 ° C; the progress of the reactions was monitored by thin layer chromatography (TLC) and the reaction time given for illustration only; melting points are uncorrected and d means decomposition; represented melting points are those obtained for the substances synthesized. as described; polymorphism may lead to the isolation in some preparations of substances with different melting points; the structure and purity of all the end products was provided by at least one of the following methods: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or macroanalytical data; yields are given for illustrative purposes only; when given, NMR data are in the form of (ό) values for major diagnostic protons, presented in parts per million (ppm) versus tetramethylsilane (TMS) as an internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; The common abbreviations used for signal format are: s. singlet ;; d. doublet; t. triplet; multiplet; Bg. wide; etc.; in addition Ar means aromatic signal; chemical symbols have a common meaning; The following abbreviations are also used: ν (volume), w (weight), bp (boiling point), etc. (melting point), L (liter, and), mL (milliliter), g (gram, s), mg (milligram, s), mol (moles), mmol (millimoles), eq (equivalent, s) ).

Abbreviations below have the meanings indicated:

Ass = acetyl Cf. = benzyl DBU = 1,8 diazabicyclo (5.4.0) undec - 7 - ene DIBAL = diisobutylaluminum hydride DMAP = 4- (dimethylamino) pyridine DMF = Ν, Ν is dimethylformamide Et ₃ N - triethylamine LDA - lithium diisopropylamide m-CPBA - metachloroperbenzoic acid MMPP - monoperoxyphthalic acid MPPM - monoperoxyphthalic acid, magnesium salt 6 H ₂ O Ms = methanesulfonyl = mesyl = 8O ₂ Me MsO = methanesulfonate = mesylate NSAID non-steroidal anti-inflammatory drug OXONE ^r = 2 KHSO ₅ * KHSO ₄ * K ₂ SO ₄ PCC = pyridine chlorchromate PDC = pyridine dichromate Ph = phenyl Phe = benzenediyl Pye == pyridinediyl r.t. = room temperature rac. = racemic SAM - aminosulfonyl or sulfonamide or SO ₂ NH ₂ TBA = tetra-p-butylammonium fluoride Th = 2- or 3-thianyl

TFAA = Trifluoroacetic anhydride

THF = tetrahydrofuran

Thi = thiophendiyl

TLC = thin layer chromatography

TMS-CN = trimethylsilyl cyanide

Tz = 1H (or 2H) - tetrazol-5-yl

C ₃ H ₅ = allyl

Acronyms of alkyl groups

Methyl

Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Vi = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl

Examples of carrying out the invention

Example 1.

3- (4- (aminosulfonyl) phenyl) -2- (4-fluorophenyl) -5- (2-hydroxy-2-propyl) thiophene

Step 1. 1- (4-Fluorophenyl) -2- (4-methylthio) phenyl) ethanone

TNS-CN (4.32g) and Znl ₂ (44mg) were added to 4-fluorobenzaldehyde (5.40g) in 1,2-dichloroethane (43.50mL). After 0.5 hours at room temperature, the solvent was removed in vacuo. To the resulting TMS-cyanhydrin (9.20g) in THF (42.0mL) at 78 ° C was added dropwise 0.51 M solution of LDA in THF (88.9mL). After a period of 0.5 hours, a THF solution (30.0mL) of 4- (chloromethyl) thioanisole (9.93g) was added dropwise over half an hour. After 18 hours at + 5 ° C, the resulting mixture was treated with TBAF (57.5 mL), then with 25% aqueous NH ₄ OAc (100ml_) and extracted with EtOAc (2x150mL). After evaporation, a 10: 1 ratio of Et ₂ O and hexane (200mL) was added to the crude ketone. After stirring for 10 hours and filtration, the title product was obtained by filtration as a solid (2.40g).

¹ H NMR (CD 3 COCD 3): d2.45 (3H, s), 4.34 (2H, s), 7.197.29 (6H, m), 8.14 (24, q).

Step 2. Cis, trans-3-chloro-3- (4-fluorophenyl) -2- (4 (methylthio) -phenyl) propenap

To a solution of 1- (4-fluorophenyl) -2- (4 (methylthio) phenyl) ethanone (2.50g) in 1,2dichloroethane (27.0m1_) were added 3,3M (11.6m1_) from the Vilsmeier reagent (Aldrich catalog, 1992-1993) and

DMAP (1.17g). After standing for 4 hours at 80 ° C, the reaction mixture was extracted with EtOAc and 25% aqueous NH ₄ OAc. After evaporation in vacuo and drying for several hours, the title product was used in the next step. ¹ H NMR (CD 3 COCD 3):? 52.40 and 2.48 (3H, 2s), 6.907.80 (8H, m), 9.55 (1H, s).

Step 3. 5- (4-Fluorophenyl) -4- (4-methylthio) phenyl) thiophen-

Carboxylic acid 2-methyl ester

To a solution of cis, trans 3-chloro-3- (4-fluorophenyl) -

2- (4- (methylthio) phenyl) propenal (3Od) in pyridine (12.0mL) were added methyl thioglycolate (1.16mL) and Et ₃ N (4.09mL). The resulting mixture was then heated at 80 ° C for two hours. After extraction with EtOAc and washing with 3N HCl, the title product was purified by flash chromatography (30% EtOAc in hexane) (2.00g).

¹ H NMR (CD 3 COCD 3): d2.48 (3H, S), 3.88 (3H, s), 7.11 (2H, t), 7.21 (4H, s), 7.37 (2H, q), 7.80 (1H, s) ).

Step 4: 5- (4-Fluorophenyl) -4- (4 (methylsulfinyl) phenyl) thiophene-2-methyl carboxylic acid ester

To a solution of 5- (4-fluorophenyl) -4- (4- (methylthio) phenyl) thiophene-2-methyl carboxylic acid ester (5.60g) in CH ₂ Cl ₂ (84mL) at 0 ° C was added portionwise 50 to 60% m-CPBA (5.39g). After thin layer chromatography showed that the reaction was complete (50% EtOAc in hexane), the reaction mixture was extracted with saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound as a white foam (5.00g).

1 H NMR (CD ₃ COCD ₃ ): δ 2.75 (3H, s), 3.92 (3H, s), 7.15 (2H, t), 7.40 (2H, q), 7.52 (2H, d), 7.66 (2H. d), 7.90 (1H, s).

Step 5. 4- (4- (Aminosulfonyl) phenyl) -5- (4fluorophenyl) thiophene-2-methyl carboxylic acid ester

The carboxylic acid 5- (4-fluorophenyl) -4- (4- (methylsulfinyl) phenyl) thiophene-2-methyl ester (0.500g) was dissolved in TFAA (10.0mL) and refluxed for half an hour. The solvent was then removed in vacuo and the resulting residue was evaporated 10 times with a solution of EtgN-MeOH (1: 1) (100 mL) _; to obtain viscous oil after pumping for several hours. The oil was dissolved in HOAc (10ml_) and treated at + 10 ° C with Cl ₂ in HOAc (1.9M) (3.5mL). After 20 minutes, the solvent was removed under reduced pressure and THF (20.0mL) was added to the resulting mass of the product. After several minutes of purging with NH ₃ at 0 ° C, the reaction mixture was stirred at room temperature for half an hour. After extraction with EtOAc solution - 25% NH ₄ OAc and flash chromatography (30 to 40% EtOAc in hexane), the title product was obtained as a white solid (0.210g).

1 H NMR (CD 3 COCD 3): δ 3.90 (3H, s), 6.55 (2H, bs), 7.13 (2H, t), 7.40 (2H, q), 7.46 (2H, d), 7.83 (2H, d). 7.90 (1H, s).

Step 6. 3- (4- (Aminosulfonyl) phenyl) -2- (4fluorophenyl) -5- (2-hydroxy-2-propyl) thiophene

To 4- (4- (aminosulfonyl) phenyl) -5- (4-fluorophenyl) thiophene-2-methyl carboxylic acid ester (0.460g) in THF (5.70mL) at 0 ° C was added MeMgBr (1.4M) in toluene - THF solution (5.00mL). The mixture was then stirred for several hours at room temperature. The reaction mixture was sharply cooled by the addition of 25% NH ₄ OAc solution, extracted with EtOAc and dried over Na ₂ SO ₄ . The title compound was purified by flash chromatography (40 to 50% EtOAc in hexane) (O, 30).

¹ H NMR (CD 3 COCD 3): δ 1.65 (6H, s), 4.52 (1H, S), 6.55 (2H, bs), 7.09 (3H, m), 7.34 (2H, dd), 7.30 (2H, m). 7.43 (2H, d), 7.82 (2H, d).

Calcd for C _1g H ₁₈ FNO ₃ S ₂ '·

C, 58.31; H.4.60; N, 3.58.

Found; C.57.94; H, 4.66; N, 3.44.

Example 2.

3- (4- (aminosulfonyl) phenyl) -2- (4-fluorophenyl) thiophene

Step 1.4- (4- (Aminosulfonyl) phenyl) -5- (4-fluorophenyl) thiophene-2-carboxylic acid

To a solution of 4- (4- (aminosulfonyl) phenyl) -5 (fluorophenyl) thiophene-2-methyl carboxylic acid ester (example 1, step 5) (0.210 g) in THF (2.0 mL) was added MeOH (1.0 mL) ), 1N NaOH (1.0 mL) and a few drops of 10N NaOH. The resulting mixture was heated at 45 ° C for 2 hours and then the reaction was partitioned between EtOAc and HCl (3N) to give the title product as a white solid (0.200g).

¹ H NMR (CD 3 COCD 3): δ 6.60 (2H, s), 7.15 (2H, t), 7.35 (2H, q), 7.45 (2H, d), 7.82 (2H, d), 7.87 (1H, s) .

Step 2. 3- (4- (Aminosulfonyl) phenyl) -2- (4-fluorophenyl) thiophene

To a solution of 3- (4- (aminosulfonyl) phenyl) -2- (4fluorophenyl) thiophene-2-carboxylic acid (0.280g) in quinoline (4.0mL) was added Cu-bronze (O.30g). After a half hour incubation at 180 ° C under nitrogen, the reaction mixture was extracted with EtOAc and 3N HCl, dried over Na ₂ SO ₄ and purified by flash chromatography (30% EtOAc in hexane). to give the title compound as a white solid (0.180g).

¹ H NMR (CD 3 COCD 3): <5 6 = 60 (2H, bs), 7.15 (2H, t), 7.29 (1H, d), 7.35 (24, q), 7.45 (2H, d), 7.60 (1 H, d), 7.83 (2H, d).

Analysis: Calculated for C ₁₆ H ₁₂ FNO ₂ S ₂

0,57.65; Η, 3.60; N, 4.20 Found: 0.57.62; Η, 3.59; N, 4.15

Example 3.

3- (4- (aminosulfonyl) phenyl) -2- (4-fluorophenyl) -5- (2-propyl) thiophene ¹ H NMR (CD ³ COCD 3): δ 1.40 (6H, d), 3.25 (1H, septaplet), 6.58 ( 2H, bs), 7.05 (1H, S), 7.15 (2H, t), 7.32 (2H, dd), 7.46 (2H, d), 7.80 (2H, d).

Analysis: Calculated for C ₁₉ H ₁₈ FNO ₂ S ₂

0.60.80; Η, 4.80; N, 3.73 Found: 0.60.59; 4., 4.45; N, 3.60

Example 4.

3- (4- (aminosulfonyl) phenyl) -2-cyclohexylthiophene ¹ H NMR (CD 3) 2 CO): < 5 1.24-1.40 (3H, m), 1.40-1.56 (2H, m), 1.65-1,85 (3H, m), 1.90-2.0 (2H, m), 3.18 (1H, m), 6.58 (2H, bs), 7.05 (1H, d), 7.37 (1H, d), 7.58 (2H, d) ), 7.97 (2H, d).

Example 5.

5- (4-Carboxyphenyl) -4- (4- (methylsulfonyl) phenyl) thiophene-2-carboxylic acid

Step 1. 4- (2- (4- (Methylthio) phenyl) -1-oxo-ethyl) benzoic acid methyl ester

To methyl 4-formylbenzoate (10.30 g) in 1,2 dichloroethane at room temperature were added TMS-CN (6.58 ml_) and Znl ₂ (2.00g) and after half an hour at room temperature the solvent was removed in vacuo. To the resulting TMS-cyanhydrin (5.00g) in THF (22.0 mL) at -78 ° C was added dropwise a 0.87 M solution of LDA in TFA (26.2 mL). After a half hour, a THF solution (10.0 mL) was added dropwise over a half hour.

4- (chloromethyl) thioanisole? Then the temperature was slowly brought to -20 ° C, then to 5 ° C for 2 hours and a 1N solution of TBAF in THF (50.0 mL) was added. After the addition of 25% aqueous NH ₄ OAc solution, the reaction mixture was extracted with EtOAc, dried over Na ₂ SO ₄ , evaporated in vacuo and purified by flash chromatography (20 to 30% EtOAc in hexane) to give the title compound under the form of a white solid (7l00g).

Step 2. 4- (1-Oxo-2- (4 (methylsulfonyl) phenyl) ethyl) benzoic acid methyl ester

To 7.10 g of 4- (2- (4-methylthio) phenyl) -1-oxoethyl) benzoic acid methyl ester in MeOH (100mL) at 0 ° C was added oxone (21.0 g) in water (20.0 mL). After several hours at room temperature, the reaction mixture was extracted with EtOAc and water for flash chromatography

T - ... ·.

(50 to 100% EtOAc in hexane) to give the title product as a white solid (3.20 g).

¹ H NMR (CD 3 COCD 3): δ 3.10 (3H, S), 3.95 (3H, S), 4.65 (2H, s), 7.60 (2H, d), 7.96 (2H, d), 8.20 (4H, q).

Step 3: Cis, Trans 4- (1-Chloro-3-oxo-2- (4 (methylsulfonyl) phenyl) -1-propenyl) benzoic acid methyl ester

To a solution of 4- (1 oxo-2 - ((4-methylsulfonyl) phenyl) ethyl) benzoic acid (1.70g) in 1,2-dichloroethane (15.0 mL) was added 3.3 M Vilsmeier reagent (6.2mL) and DMAP (0.624 g). The resulting mixture was heated at 80 ° C for 4 hours. The reaction mixture was then extracted with 25% aqueous NH ₄ OAc and EtOAc. After drying over Na ₂ SO ₄ and evaporating, the title compound was obtained in the form of an oil and used as such in the next step.

Step 4. 5- (4-Methoxycarbonyl) phenyl-4- (4 (methylsulfonyl) -phenyl) thiophene-2-methyl carboxylic acid ester

Prepared from 4- (1-chloro-3-oxo-2- (4-methylsulfonyl) phenyl) -1-propenyl) benzoic acid methyl ester as in Example 1, Step 3.

¹ H NMR (CD 3 COCD 3): δ 3.13 (3H, s), 3.85 and 3.92 (6H, 2s), 7.50 (2H, d), 7.55 (24, d), 7.90 (2H, d), 7.92 (1H. s), 7.92 (2H, d).

100

Step 5. 5- (4- (Carboxyphenyl) -4- (4 (methylsulfonyl) phenyl) -thiophene-2-carboxylic acid

Prepared from 5- (4- (methoxycarbonyl) phenyl) -4- (4 (methyl) sulfonyl) phenyl) thiophene-2-methyl carboxylic acid ester, as in Example 2, Step 1.

¹ H NMR (CD ₃ COCD ₃ ): δ 3.15 (3H, s), 7.50 (2H, d), 7.62 (2H, d), 7.95 (2H, d), 7.98 (1H, s), 8.05 (2H , d).

Analysis calculated for C ₁₉ H ₁₄ O ₆ S ₂ * 0–1 H ₂ O

C, 56.46; 3., 3.51

Found: C, 56.18; H, 3.51

Example 6

4- (4-fluorophenyl) -2-methyl-5- (4 (methylsulfonyl) phenyl) thiazole

Step 1. 1- (4-Fluorophenyl) -2- (4- (methylsulfonyl) phenyl) ethanone

To 1- (4-fluorophenyl) -2- (4- (methylthio) phenyl) ethanone from Example 1, step 1 (17.9 g) in a solution of CH ₂ Cl ₂ MeOH (272.0 mL / 27.0mL) at 0 ° C was added

MTORM (28.0 g). The cooling bath was then removed and the reaction mixture was stirred for 1 hour at room temperature. At 0 ° C an additional amount of MPPM (28.0 g) was added and the reaction mixture was allowed to stand at room temperature for 1.5 hours. The undissolved material was

101 filtered, which was followed by evaporation of the solvents, then the residue was extracted with CH ₂ Cl ₂ -NaHCO ₃ . After evaporation in vacuo, the resulting solid was washed with ether hexane (1: 1) and filtered to give the title compound (16.8g).

¹ H NMR (CD 3 COCD 3):? 5 3.13 (3H, s), 3.58 (2H, s), 7.29 (2H, t), 7.55 (2H, d), 7.88 (2H, d), 8.20 (2H, dd) .

Step 2. 2-Bromo-1- (4-fluorophenyl) -2- (4 (methylsulfonyl) phenyl) -ethanone

To 1- (4-fluorophenyl-2- (4-methylsulfonyl) phenyl) ethanone (1.00g) in CH ₂ Cl ₂ containing CHCl ₃ (1.0 mL) and Ccl ₄ (1.0 mL) was added bromine (0.614 g). After 1 hour of direct sunlight, the reaction mixture was sharply cooled with Na ₂ S ₂ O ₄ extracted with CH ₂ Cl ₂ , the product dried over Na ₂ SO ₄ and evaporated to give the title compound, which was used as the such in the next step (1.10e).

¹ H NMR (CD ₃ COCD ₃ ):? 5 3.10 (3H, s), 7.05 (1H, s), 7.30 (2H, t), 7.87 (2H, d), 7.95 (2H, d), 8.25 (2H , dd).

Step 3. 4- (4-Fluorophenyl) -2-methyl-5- (4-methylsulfonyl) phenyl) -thiazole

Thioacetamide (0.266g) and pyridine (0.300mL) were added to 2-bromo-1- (4-fluorophenyl) -2- (4- (methylsulfonyl) -phenyl) -ethanone (1.10g) in ethanol (15.0mL). After 2 hours of reflux, the reaction mixture was

102 was extracted with EtOAc, 25% NH ₄ OAc and purified by flash chromatography (50% EtOAc in hexane then 90% Et ₂ O in hexane) to give the title compound (0.320g).

< 1 &gt; H NMR (CD3COCD3): &lt; 5 2.72 (3H, S), 3.15 (3H, s), 7.09 (2H, t), 7.52 (2H, dd), 7.60 (2H, d), 7.92 (2H, d) .

Analysis: Calculated for C ₁₇ H ₁₄ FNO ₂ S ₂ C, 58.78; H, 4.03; N, 4.03 Found: C, 58.71; H, 4.17; N, 3.85

Example 7:

2- (4-fluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one

Stage 1. 1- (4-fluorophenyl) -5-hexen-2-one

To a suspension of 14.6 g (80 mmol) of CdCl ₂ in 200 mL of ether cooled to 0 ° C was added dropwise 115 mL of a 1.3 M solution of 3-butene-1-magnesium bromide. The mixture was refluxed for 1 hour, then the ether was removed by distillation. Benzene (500 mL) was added, followed by a solution of 17.5 g (100 mmol) of 4-fluorophenylacetyl chloride. After 1 hour at reflux, the reaction mixture was sharply cooled with 200 mL of saturated aqueous NH 4 Cl, 50 mL of 1N HCl and extracted with 200 mL of hexane / EtOAc in a 1: 1 ratio. The organic phase was dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography such as

103 elution was performed with hexane / EtOAc (4: 1) to give 15 g of the title product at this step.

¹ H NMR (CDCl ₃ ): δ 2.40 (24, t), 2.53 (2H, t), 3.63 (24, s), 4.90-4.98 (24, m), 5.67-5.78 (1H, m), 6.98 (2H, t), 7.13 (2H, m).

Step 2. 1- (4-Fluorophenyl) -5-oxo-2-pentanone

A solution of 14 g of 1- (4-fluorophenyl-5-hexen-2-one in 200 mL of CH ₂ Cl ₂ / MeOH (3: 1) was cooled to -78 ° C and treated with an excess of ozone. with 15 g of triphenylphosphine and stirred for 1 hour at room temperature The reaction mixture was concentrated and flash chromatography with hexane / EtOAc (3: 1) was obtained to give 8 g of ketoapdehyde from the title product.

¹ H NMR (CDCl ₃ ) δ 2.72 (4H.S), 3.71 (24, S), 6.99 (2H, t), 7.14 (24, m), 9.73 (14, s).

Step 3. 2- (4-Fluorophenyl) -2-cyclopenten-1-one

A solution of 8g of 1- (4-fluorophenyl) -5-oxo-2-pentanone in 300 mL of MeOH was treated with 2g of NaOMe. The mixture was stirred for 2 hours and then sharply cooled with 5 mL of HOAc. The solvent was evaporated and the residue purified by flash chromatography eluting with hexane / EtOAc (3: 1) to give 7g of the title product.

¹ H NMR (CDCl ₃ ) ≤ 5 2.57 (2H, m), 2.68 (2H, m),

7.04 (2H, J = 8.8Hz, t), 7.67 (2H, J = 8.8, 5.5Hz, dd), 7.77 (1H, m).

104

Step 4. 1- (4-Methylthio) phenyl) -2- (4-fluorophenyl) -2-cyclopenten-1-ol

To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et ₂ O, cooled to -78 ° C, was added dropwise 22mL of a 1.7 M solution of t-BuLi in pentane (38 mmol). The reaction mixture was stirred for 15 minutes at 78 ° C and 2.23 g of 2- (4fluorophenyl) -2-cyclopenten-1-one in 10 mL Et ₂ O was added to it. After stirring for 15 minutes at -78 ° C, the reaction was the mixture was warmed to 0 ° C and quenched with 50 mL saturated NH ₄ Cl solution. The product was extracted with 100 mL EtOAc, dried over Na ₂ SO ₄ and purified by flash chromatography eluting with hexane / EtOAc (4: 1) to give 3.4 g of the desired product.

¹ H NMR (CDCl ₃ ) d 2.12 (1H, s), 2.34 (2H, m), 2.44 (3H, s), 2.422.52 (1H, m), 2.56-2.65 (1H, m). 6.37 (1H, m),

6.84 (24, J = 8.7Hz, t), 7.17 (2H, J = 8.3Hz, d), 7.24-7.33 (4H, m).

Step 5. 2- (4-Fluorophenyl) -3- (4- (methylthio) phenyl) -2-cyclopenten-1-one

A solution of 2.2 g (7.3 mmol) 1- (4methylthio) phenyl) -2- (4-fluorophenyl ₎ was added to a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4A molecular sieve in 150 mL of CH ₂ Cl _2. ) -2-cyclopenten-1-ol in 20 mL of CH ₂ Cl ₂ . The mixture was stirred for 1 hour at room temperature and then diluted with 300 mL Et ₂ O. After filtration and concentration, the residue

105 was subjected to flash chromatography with hexane / EtOAc (2: 1) to give 1.5 g of the title product.

1 H NMR (CDCl ₃ ) δ 2.45 (3H, s), 2.68 (2H, m), 3.00 (2H, m), 7.02 (2H, J = 8.6Hz, t), 7.11 (2H, J = 8.6Hz, d), 7.15-7.23 (4H, m).

Step 6. 2- (4-Fluorophenyl) -3- (4- (methylsulfonyl) phenyl) -

2-cyclopenten-1-one

To a solution of 50 mg (0.17 mmol) of 2- (4-fluorophenyl) -3- (4-methylthio) phenyl-2-cyclopenten-1-one in 8 mL of CH ₂ Cl ₂ / MeOH (10: 1) was added 124 mg ( 0.2 mmol) MPPM. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 10 mL hexane / EtOAc (1 :). After filtration and concentration, the residue was purified by flash chromatography eluting with EtOAc / hexane (2: 1) to give 45 mg of the title product.

¹ H NMR (acetone-C1 ₆ ) ό 2.67 (2H, m), 3.14 (3H, sO, 3.16 (2H, m), 7.05-7.10 (2H, m), 7.20-7.25 (2H, m), 7.63 ( 2H, d), 7.93 (2H, d).

Example 8.

4- (4- (methylsulfonyl) phenyl) -5- (4-fluorophenyl) isothiazole

To a solution of 338 mg (1 mmol) of cis, trans 3-chloro-

3- (4-fluorophenyl-2- (4- (methylsulfonyl) phenyl) propenyl in 5 mL acetone 230 mg (3 mmol) NH ₄ SCN was added. The reaction mixture was heated to reflux.

106 h and then sharply cooled with 20 mL of saturated NaHCO ₃ solution. The product was extracted with 100 mL EtOAc, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography eluting with hexane / EtOAc (3: 2) to give 250 mg of the title product.

¹ H NMR (CDCl ₃ ) δ 8.57 (1H, s), 7.93 (3H, d), 7.50 (2H, d), 7.30 (21-1, t), 7.08 (2H, t).

Example 9.

3- (4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Step 1. 2-Bromo-1- (4- (methylsulfonyl) phenyl) ethanone

To a solution of 197 g of 4- (methylthio) acetophenone (JACS 1952, 74, p. 5475) in 700 mL of MeOH and 3500 mL of CH ₂ Cl ₂ were added 881 g of MMPR for 30 minutes. After staying at room temperature for 3 hours, the reaction mixture was filtered and the filtrate was washed with 2 L saturated aqueous NaHCO ₃ and 1L brine. The aqueous phase was further extracted with 2 L CH ₂ Cl ₂ . The combined extracts were dried over Na ₂ SO ₄ and concentrated to give 240 g of 4- (methylsulfonyl) acetophenone as a white solid.

To a cooled (-5 ° C) solution of 174 g 4 (methylsulfonyl) acetophenone in 2.5 L CHCl ₃ was added 20 mg AICI ₃ followed by a solution of 40 mL Br ₂ in 300 mL CHCl ₃ . Then the reaction mixture was

107 was treated with 1.5 L of water and chloroform was separated. The aqueous layer was extracted with 1 L EtOAc. The combined extracts were dried over Na ₂ SO ₄ and concentrated. The crude product was recrystallized from EtOAc / hexane (50/50) to give 210 g of 2-bromo-1- (4-methylsulfonyl) phenyl) ethanone as a white solid.

Stage 2.

To the product of step 1 (216 mG) _; dissolved in acetonitrile (4 mL), Et ₃ N (0.26mL) was added. followed by 4-fluorophenylacetic acid (102 mG). After 1.5 hours at room temperature, 0.23 mL of DBU was added. The reaction mixture was stirred for an additional 45 minutes and then treated with 5 mL of 1N HCl. The product was extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (40% EtOAc in hexane) to give 150 mG of the title compound as a solid.

¹ H NMR (CD ₃ COCD ₃ ): δ 3.15 (3H, s), 5.36 (3H, s),

7.18 (2H, J = 8.9Hz, t), 7.46 (2H, m), 7.7 (2H, J = 8.65Hz, d),

7.97 (2H, J = 8.68, d).

Example 10.

3- (4-fluorophenyl) -4- (4- (aminosulfonyl) phenyl) -2 (2H) furanone ¹ H NMR (CD ₃ COCD ₃ ): δ 5.34 (2H, s), 6.67 (2H, bd).

7.18 (2H, m), 7.46 (2H, m), 7.61 (2H, m), 7.90 (2H, m).

mp 187-188 ° C (d).

108

Example 11.

3- (4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) furan

Stage 1.

To the product of Example 10 (0.2g) in THF (5mL) and toluene (3mL) at -78 ° C was slowly added a solution of DIBAL (0.72mL, 1M in toluene). After 15 minutes, the solution was heated to 0 ° C for another 15 minutes. The mixture was then poured into cooled aqueous sodium potassium tartrate and EtOAc. The organic layer was stirred for half an hour with several crystals of camphor sulfonic acid. This solution was then concentrated and purified by flash chromatography to give the title product.

¹ H NMR (CDCI ₃ ):? 5 3.1 (3H, s), 7.02 (2H, J = 8.9, t), 7.18 (2H, m), 7.4 (2H, J = 8.8Hz, d), 7.58 (1 H, S), 7.68 (1H, s),

7.85 (2H, J = 8.8 Hz, d).

Example 12. 5,5 dimethyl-3- (4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone

Stage 1.

Methyl 2-trimethylsilyloxyisobutyrate

To a 1.2mL (10.4mmol) solution of methyl 2hydroxyisobutyrate in 50mL CH ₂ CH ₂ were added 1.2g (17.6mmol) imidazole and 2.1 mL (16.6mmol) TMSCI. The mixture was stirred at room temperature at

109 for one and a half hours and cooled sharply by adding 20 mL of water. The organic layer was dried over MgSO _4> concentrated and passed through a short silica gel column eluting with hexane / EtOAc (9: 1). Evaporation of the solvent gave 1.27g of the title compound as a colorless oil. ¹ H NMR (CD 3 COCD 3): δ O.O8 (9H, S), 1.38 (6H, s), 3.67 (34, s).

Stage 2.

2-tri methylphenyl or-4 '- (methylthio) isobutyl rofeno n

A solution of 204mg (1mmol) of 4-bromothioanisole in 2.5mL of THF was cooled to -78 ° C and treated with a solution of 0.42mL of 2.5M n-BuLi in hexane. After stirring at 78 ° C for one hour, a solution of 380mg (2.Ommol) methyl 2-trimethylsilyloxyisobutyrate in 2mL THF was added. The mixture was stirred for 2 hours at -78 ° C and then sharply cooled with NH ₄ OAc buffer. The product was extracted with EtOAc, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography eluting with hexane / EtOAc (19: 1) to give 95mg of the title product.

&Lt; ¹ &gt; H NMR (CD3COCD3): &lt; 5 O.O5 (9H, S), 1.52 (6H, s), 2.53 (3H, s), 7.33 (2H, d), 8.12 (2H, d).

Stage 3.

2-hydroxy-4 '- (methylthio) isobutyrophenone

110

To a solution of 40mg (0.14mmol) 2methylsilyloxy-4 '- (methylthio) isobutyrophenone in 2mL THF were added 0.2mL 1M n-Bu ₄ NF in THF. The resulting mixture was stirred for 30 minutes and then sharply cooled with 10mL NH ₄ OAc buffer. The product was extracted with EtOAc, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography eluting with hexane / EtOAc (4: 1) to afford 25mg of the title product.

¹ H NMR (CD 3 COCD 3): (3 1.5O (6H, S), 2.54 (3H, S), 4.68 (1H, s), 7.30 (2H, d), 8.15 (2H, d).

Stage 4.

2- (4-fluorophenylacetoxy) -4 '- (methylthio) isobutyrophenone

To a solution of 72mg (0.34mmol) of 2-hydroxy-4 '(methylthio) isobutyrophenone in 1.7mL of CH ₂ Cl ₂ were added 0.2mL of pyridine and 140mg (0.81mmol)

4-fluorophenylacetyl chloride. The mixture was stirred at room temperature overnight and then sharply cooled with NH ₄ OAc buffer. The product was extracted with EtOAc, dried over MgSO ₄ and concentrated. The crude product was purified by flash chromatography eluting with hexane / EtOAc (8: 1) to give 95mg of the title product.

¹ H NMR (CD 3 COCD 3): δ 1.62 (3H, S), 1.67 (3H, S), 2.48 (3H, s), 3.79 (24, s), 7.0 - 7.3 (6H, m), 7.78 (2H, d) ).

111

Stage 5.

5,5-dimethyl-3- (4-fluorophenyl-4- (4- (methylthio) phenyl) -2 (5H) furanone

To a solution of 95mg of 2- (4-fluorophenylacetoxy) -4 '(methylthio) isobutyrophenone in 4mL of CH ₂ Cl ₂ was added 0.2mL of 1,8-diazabicyclo (5.4.0) undec-7-ene. The mixture was stirred for 4 hours and diluted with NH ₄ OAc buffer. The product was extracted with EtOAc, dried over MgSO ₄ and concentrated. The residue was purified by flash chromatography eluting with toluene / EtOAc (20: 1) to afford 75mg of the title product.

¹ H NMR (CD 3 COCD 3): d 1.58 (6H, s), 2.50 (3H, S), 7.03 (2H, dd),

7.25 - 7.35 (4H, m), 7.41 (2H, dd).

Stage 6.

5,5-dimethyl-3- (4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

To a solution of 81 mg of 5,5-dimethyl-3- (4fluorophenyl) -4- (methylthio) phenyl) -2-oxo-2Hdihydrofuran in 1.8mL CH ₂ Cl ₂ and 0.2mL MeOH were added 250mg MPPM. The reaction mixture was stirred at room temperature for 1 hour and then sharply cooled with aqueous NaHCO ₃ . The product was extracted with EtOAc, dried over MgSO ₄ and concentrated. The crude product was purified by flash chromatography eluting with hexane / EtOAc (1: 1) to give 73mg of the title product.

112 ¹ H NMR (CD 3 COCD 3):? 3 1.62 (6H, s), 3 15 (3H, s), 7.02 (2H, dd), 7.40 (2H, dd), 7.65 (2H, d), 8.03 (2H. d).

5,5-Dimethyl-3- (3-fluorophenyl) -4- (4 (methylsulfonyl) -phenyl) -2- (5H) furanone was obtained in an analogous manner (mp 172.7 ° C).

Analysis: Calculated: C, 63.32; H, 4.75; found: C, 63.50; H, 4.79;

Example 13.

2- ((4-aminosulfonyl) phenyl-3- (4-fluorophenyl) thiophene ¹ H NMR (CD 3 COCD 3): δ 6.60 (2H, bs), 7.12 (2H, t), 7.25 (1H, d), 7.35 ( 2H, m), 7.45 (2H, d), 7.65 (1H, d), 7.85 (2H, d).

Analysis calculated for C ₁₆ H ₁₂ FNS ₂ O ₂ * = C, 57.65; H, 3.60; N, 4.20 found: C, 57.55; H, 3.79; N, 4.03

Example 14.

3- (4- (trifluoroacetyl amine and nosulphonyl) phenyl) -2- (4fluorophenyl) thiophene ¹ H NMR (300MHZ, CD3COCD3): δ 7.15 (2H, t), 7.30 (3H, m) , 7.45 (2H, d), 7.65 (1H, d), 7.95 (2H, d).

Example 15.

3- (2,4-dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ F ₂ O ₄ S:

C, 58.28; H, 3.45; S, 9.15 Found: C, 58.27; H, 3.50; S, 9.27

113

Example 16.

3- (3,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

To a solution of 3,4-difluorophenylacetic acid (ALDRICH CHIMICAL) (1 Og) and 2-bromo-1- (4 (methylsulfonyl) phenyl) ethanone (Example 9, step 1) (17.3g) in acetonitrile (200mL) at room temperature triethylamine (20.2mL) was slowly added to the temperature. After one hour at room temperature, the mixture was cooled in an ice bath and treated with 17.4mL DBU. After 2 hours at 0 ° C, the mixture was treated with 200mL 1N HCl and the product was extracted with EtOAc, dried over Na ₂ SO ₄ and concentrated. The residue was applied to the upper end of a silica gel column (porous glass funnel) eluted with 75% EtOAc / hexane, which after evaporation of the solvent and transfer to ethyl acetate gave 10g of the title compound.

Analysis calculated for C ₁₇ H ₁₂ F ₂ O ₄ S;

C, 58.28; H, 3.45; S, 9.15 found: C, 58.02; H, 3.51; S, 9.35

Example 17,

3- (2,6-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ F ₂ O ₄ S:

C, 58.28; H, 3.45; S, 9.15 Found: C, 58.18; H, 3.50; S, 9.44

114

Example 18

3- (2,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ Hi ₂ F ₂ O ₄ S '

C, 58.28; H, 3.45; S, 9.15 Found: C, 58.89; H, 3.51; S, 9.11

Example 19,

3- (3,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ F ₂ O ₄ S;

C, 58.28; H, 3.45; S, 9.15 Found: C, 58.27; H, 3.62; S, 9.32

Example 20,

3- (4-bromophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₁₇ H ₁₃ BrO ₄ S

C, 51.94; H, 3.33; S, 8.16 found: C, 51.76; H, 3.42; S, 8.21

Example 21.

3- (4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone ¹ H NMR (30MH, CDCl ₃ ):? 5 7.93 (2H, d), 7.49 (2H, d) ,

7.35 (44, m), 5.16 (2H, s), 3.06 (3H, s).

Example 22,

3- (4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

115

Analysis calculated for C ₁₈ H ₁₆ O ₅ S;

C, 62.78; H, 4.68; S, 9.31 Found: C, 62.75; H, 4.72; S, 9.39

Example 23.

3- (phenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

To a solution of phenylacetic acid (27.4 g, 201 mmol) and 2-bromo-1- (4- (methylsulfonyl) phenyl) ethanone (Example 9, step 1) (60 g, 216 mmol, 1.075 equivalents) in acetonitrile (630 mL ) at 25 ° C triethylamine (30.8 mL, 1.1 equivalents) was slowly added. The mixture was stirred for 20 minutes at room temperature and then cooled in an ice bath. DBU (60.1 mL, 3 equivalents) was slowly added. After stirring for 20 minutes in an ice bath, the reaction was complete and the mixture was acidified with 1N HCl (discoloration from dark brown to yellow). 2.4 L of water and ice were then added, stirred for several minutes, then the precipitate was filtered off and washed with water (yielding 64 g of crude moist product). The solid was dissolved in 750 mL of dichloromethane (dried over MgSO ₄ , filtered) and 300 g of silica gel were added. The solvent was evaporated almost to dryness (until the silica gel was adhered) and the residue was applied to the upper end of the silica gel column (porous glass funnel) eluted with 10% EtOAc / CH ₂ CI ₂ , which after evaporation of the solvent and replacement with

116 ethyl acetate gave 3bd (58%) of the title compound.

Analysis calculated for C ₁₇ H ₁₄ O ₄ S:

C, 64.95; H, 4.49; S, 10.20 Found: C, 64.63; H, 4.65; S, 10.44

Example 24

3- (2-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis: calculated for C ₁₇ H ₁₃ CIO ₄ S>

C, 58.54; H, 3.76; S, 9.19 Found: C, 58.59; H, 3.80; S, 9.37

Example 25

3- (2-bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis: calculated for C ₁₇ H ₁₂ BrFO ₄ S '

C, 49.75; H, 2.93 found: C, 49.75; H, 3.01

Example 26.

3- (2-bromo-4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone ¹ H NMR (300 MHz, acetone-de): < 5 7.95 (2H, d), 7.85 (1H, d),

7.63 (2H, dd), 7.55 (1H, dd), 7.45 (1Η, d), 5.50 (2H, s), 3.15 (3H, s).

Example 27,

3- (4-chloro-2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

117 ¹ H NMR (300MHZ, acetone-de): δ 8.0 (2H, d), 7.70 (2H, d), 7.50 7.30 (3H, m), 5.35 (2H, S), 3.15 (3H, S).

Example 28.

3- (3-bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ BrFO ₄ S:

C, 49.75; H, 2.93 found: C, 49.44; H, 2.98

Example 29.

3- (3-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₁₇ H ₁₃ CIO ₄ S:

C, 58.54; H, 3.76 found: C, 58.29; H, 3.76

Example 30.

3- (2-chloro-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ CIFO ₄ S:

C, 55.67; H, 3.30 found: C, 55.67; H, 3.26

Example 31

3- (2,4-dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₁₇ H ₁₂ Cl ₂ O ₄ S;

C, 53.28; H, 3.16; S, 8.37 found: C, 52.89; H, 3.23; S, 8.58

118

Example 32,

3- (3,4-dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₁₇ H ₁₂ CI ₂ O ₄ S:

C, 53.28; H, 3.16; S, 8.37 found: C, 53.07; H, 3.32; S, 8.51

Example 33.

3- (2,6-dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis: calculated for C ₁₇ H ₁₂ CI ₂ O ₄ S '

C, 53.28; H, 3.16; S, 8.37 found: C, 52.99; H, 3.22; S, 8.54

Example 34 "

3- (3-chloro-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone NMR (30OMH, acetone-de): δ 8.0 (2H, d), 7.70 ( 2H, d),

7.60 (1H, d), 7.25 - 7.40 (2H, m), 5.35 (2H, S), 3.15 (3H, S).

Example 35

3- (4-Trifluoromethylphenyl) -4- (4- (methylsulfonyl) phenyl) 2- (5H) -furanone ¹ H NMR (CD 3 COCD 3):? 5 8.10 (2H, d), 7.82 - 7.93 (4H, m). 7.75 (2H, d), 5.55 (2H, s), 3.30 (3H, s).

Example 36 »

3- (3-fluoro-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone

119

Analysis: calculated for C ₁₈ H ₁₅ FO ₅ S '

C, 59.66; H, 4.17 found: C, 59.92; H, 4.37

Example 37,

3- (3-chloro-4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) 2- (5H) -furanone

Analysis calculated for C ₁₈ H ₁₅ CIO ₅ S;

C, 57.07; H, 3.99 found: C, 57.29; H, 4.15

Example 38:

3- (3-bromo-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis: calculated for C ₁₈ H ₁₅ BrO ₅ S · '

C, 51.08; H, 3.57 ^% found: C, 51.38; H, 3.62

Example 39>

3- (2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₁₇ H ₁₃ FO ₄ S>

C, 61.44; H, 3.94 found: C, 61.13; H, 3.85

Example 40

3- (4-methylthiophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone ¹ H NMR (300MN, acetone-C1 ₆ ): d 8.0 (2H, d), 7.70 (2H, d ),

7.35 (2H, d), 7.25 (2H, d), 5.35 (2H, s), 3.15 (3H, s), 2.55 (3H, s).

120

Example 41

3- (3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone 1 H NMR (300MH, CDCl ₃ ): d 7.93 (2H, d), 7.49 (2H, d), 7.35 (1H, m), 7.12 (3H, m), 5.18 (2H, s), 3.06 (3H, s).

Example 42, 3- (2-Chloro-6-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone ¹ H NMR (300 MH, acetone- ₆ ): d 8.0 (2H, d ), 7.70 (2H, d), 7.55 7.65 (1H, m), 7.40 (1 Η, d), 7.30 (1 m, m), 5.60 (2H, s), 3.15 (3H, s).

Example 43 ..

3- (S-6-methyl-4-methyl-phenyl) -4- (4- (methyl-sulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₈ H ₁₅ BrO ₄ S;

C, 53.08; H, 3.71 found: C, 53.06; H, 3.83

Example 44

3- (4-bromo-2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ BrFO ₄ S;

C, 49.65; H, 2.94 found: C, 49.76; H, 3.00

Example 45,

3- (3,4-dibromophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

121 ¹ H NMR (300M HZ, acetone-C1 ₆ ): δ 8.0 (2H, d), 7.80 (1 Η, d), 7.75 (3H, m), 7.25 (1 H, d), 5.35 (2H, s) ), 3.15 (sH, s).

Example 46,

3- (4-chloro-3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis: calculated for C ₁₇ H ₁₂ CIFO ₄ S>

C, 55.67; H.3.30 found: C, 55.45; H, 3.30

Example 47 »

3- (4-bromo-3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ BrFO ₄ S

C, 49.66; H, 2.94; S.7.80 Found: C, 49.79; H, 3.01; S, 7.51

Example 48

3- (4-bromo-2-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone

Analysis: calculated for C ₁₇ H ₁₂ BrCIO ₄ S '

C, 47.74; H, 2.83; S.7.50 Found: C, 47.92; H, 2.84; S, 7.42

Example 49

3- (2-naphthyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₂₁ H ₁₆ O ₄ S

C, 69.22; H, 4.43 found: C, 69.22; H, 4.46

122

Example 50 '

3- (7-quinolinyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C ₂₀ H ₁₅ NO ₄ S d

C, 65.74; H, 4.14; N, 3.83 'found: C, 65.34; H, 4.40; N, 3.80

MS (DCI, CH ₄ ) calculated for M ⁺ , 365 found for M ⁺ +1,366

Example 51

3- (3,4-dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone ¹ H NMR (400 MHz CD3COCD 3): < 5 7.92 (2H, dd), 7.64 (3H, dm ), 7.60 (1H, dd), 7.32 (1H, dd), 6.70 (1H, bs), 5.38 (2H, s).

Example 52

3- (3,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone ¹ H NMR (400 MHz CD3COCD 3): δ 7.92 (2H, dd), 7.64 (2H, dd) , 7.30 - 7.45 (2H, m), 7.22 (1H, m), 6.68 (2H, bs), 5.37 (2H, s).

Example 53 _e

3- (3-chloro-4-methoxyphenyl) -4- (4- (aminosulfonyl) phenyl) 2- (5H) -furanone

Analysis: calculated for C ₁₇ H ₁₄ CINO ₅ S '

C, 53.76; H, 3.72; N, 3.69 Found: C, 53.32; H, 3.84; N, 3.59

MS (DCI, CH ₄ ) calculated for M ⁺ , 379 found for M ⁺ +1,380

123

Example 54,

3- (3-bromo-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C ₁₇ H ₁₄ BrNO ₅ S:

C, 48.13; H, 3.33; N, 3.30 Found: C, 48.26; H, 3.40; N, 3.28

MS (DCI, CH ₄ ) calculated for M ⁺ , 423 found for M ⁺ +1,424

124

Claims (14)

1. Compound _? selected from the group? consisting of: 3- (2,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone. 3- (3,4-Difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, 3- (2,6-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone. 3- (2,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, 3- (3,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, 3- (4-bromophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone. 3- (4-Methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone. 3- (phenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, 3- (2-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone, 3- (2-bromo-4-fluorophenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone, 3- (2-bromo-4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) 2- (5H) -furanone, 3- (4-chloro-2-fluorophenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone, 3- (3-bromo-4-fluorophenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone, 3- (3-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanoyl. 125 3- (2-chloro-4-fluorophenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone. 3- (2,4-dichlorophenyl) -4- (4- (methyl sulfonyl) phenyl) -2 (5H) -furanone, 3- (3,4-dichlorophenyl) -4- (4- (methyl sulfonyl) phenyl) -2 (5H) -furanone. 3- (2,6-dichlorophenyl) -4- (4- (methyl sulfonyl) phenyl) -2 (5H) -furanone, 3- (3-chloro-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone. 3- (4-Trifluoromethylphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone. 3- (3-fluoro-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone. 3- (3-chloro-4-methoxyphenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone. 3- (3-bromo-4-methoxyphenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone. 3- (2-fluorophenyl) -4- (4- (methyl sulfonyl) phenyl) -2- (5H) furanone, 3- (4-methylthiophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, 3- (3-fluorophenyl) -4- (4- (methyl sulfonyl) phenyl) -2- (5H) furanone, 3- (2-chloro-6-fluorophenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone. 3- (3-bromo-4-methylphenyl) -4- (4- (methylsulfonyl) phenyl) 2- (5H) -furanone, 3- (4-bromo-2-fluorophenyl) -4- (4126 (methylsulfonyl) phenyl) -2- (5H) -furanone, 3- (3,4-dibromophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, 3- (4-chloro-3-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, 3- (4-bromo-3-fluorophenyl) -4- (4 (methyl sulfonyl) phenyl) -2- (5H) -furanone, 3- (4-bromo-2-chlorophenyl) -4- (4- (methyl sulfonyl) phenyl) 2- (5H) -furanone, 3- (3.4-dichlorophenyl) -4- (4- (aminosulfonyl) phenyl) -2 (5H) -furanone, 3- (3,4-difluorophenyl) -4- (4- (aminosulfonyl) phenyl) -2 (5H) -furanone, 3- (3-chloro-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (5H) -furanone, 3- (3-bromo-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (5H) -furanone, or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 3- (3,4difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 3- (phenyl) - 4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating an inflammatory disease susceptible to treatment with a non-steroidal anti-inflammatory agent comprising a non-toxic therapeutically effective amount of a compound according to claim 1, 2 or 3 and a pharmaceutical composition 127 acceptable carrier. A pharmaceutical composition for treating cyclooxygenase-mediated diseases susceptible to treatment with an active agent that selectively inhibits COX-2 over COX-1, characterized in that it consists of a non-toxic therapeutically effective amount of a compound of claim 1, 2 or 3 and a pharmaceutically acceptable carrier. A method of treating an inflammatory disease amenable to treatment with a non-steroidal anti-inflammatory agent, characterized in that the patient in need of such treatment is administered a non-toxic therapeutically effective amount of a compound according to claim 1, 2 or 3 and a pharmaceutically acceptable carrier. 7. A method of treating cyclooxygenase-mediated diseases in which treatment with an active agent that selectively inhibits COX-2 over COX-1 is advantageous, wherein the patient in need of such treatment is administered non-toxic a therapeutically effective amount of a compound of claim 1, 2 or 3 and a pharmaceutically acceptable carrier. A compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, for use in the treatment of cyclooxygenase-mediated diseases in which treatment with an active agent that selectively inhibits COX-2 over COX-1 is advantageous. A compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory disease, allowing treatment with a non-steroidal anti-inflammatory agent. 128 Use of a compound according to claim 1, 2 or 3. or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an inflammatory disease, allowing treatment with a non-steroidal anti-inflammatory agent. Use of a compound according to claim 1, 2 or 3. or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cyclooxygenase-mediated diseases in which treatment with an active agent that selectively inhibits COX-2 over COX- is advantageous 1. A non-steroidal anti-inflammatory pharmaceutical composition comprising a acceptable non-toxic anti-inflammatory amount of a compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. A pharmaceutical composition as a selective COX-2 inhibitor, comprising a acceptable non-toxic therapeutically effective amount of a compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. A process for the preparation of phenylfuranone of formula XXXIII