BG100350A - Phenyl heterocycles as cox-2 inhibitors - Google Patents

Abstract

The compounds have the formula wherein the radical substituents R1 and R2 have the meanings defined in the description. They are used for the treatment of cyclooxygenase-2-mediated diseases. The invention also relates to certain pharmaceutical preparations containing said compound.

Description

Phenyl Heterocyclic Compounds As Cyclooxygenase Inhibitors - 2

BACKGROUND OF THE INVENTION

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 synthase, also known as cyclooxygen. Until recently, only one form of cyclooxygenase corresponding to cyclooxygenase - I or the constitutive enzyme originally identified in bovine semina - vesicles was characterized. Recently, the gene of a 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 efficiently induced by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors

A-511/96-PC 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 that of a conventional, non-steroidal anti-inflammatory drug, and would also suppress hormone-induced uterine contractions and would have a potentiated effect and would have anti-inflammatory effects 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 renal effects, a reduced ability to influence bleeding time, and possibly a reduced ability to induce asthmatic attacks in aspirin-sensitive asthmatics.

I 3

A-511/96-PC

B.

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 comprising 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 for the treatment of diseases caused by cyclooxygenase-2

I

A-511/96-PC 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 ^s ') -OC (O) -, (e) -C (O) -O-CR ⁵ (R ⁵ ) -, (f) -ch ₂ -nr ³ -ch ₂ -, (g) -CR ^S (R ^S ) -NR ³ -C (O) -, (h) -cr ⁴ = cr ⁴ '-s-, (i) -s-cr ⁴ = cr ⁴ '-, (j) -S-N = CH-, (k) -CH = N-S-, (I) -n = cr ⁴ -o-, (m) -o-cr ⁴ = n-, (n) -N = CR4-NH-, (o) -N = CR ⁴ -S-, h (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 is a double bond and sides 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) = N-S-CH =, (d) = CH-S-N =,

A-511/96-PC (e) = NO-CH =, (f) = CH-ON =, (g) = NSN =, (h) = NON = when sides a and c represent double bonds and side b represents a single connection;

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 1-4 alkyl, (b) C ₃ , C ₄ C ₅ , C ₆ , and C ₇ cycloalkyl (c) mono-, di- or 3-substituted phenyl or naphthyl, wherein the substituent is selected from the group consisting of by:

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

A-511/96-PC (8) N ₃ , (9) -CO ₂ H, (10) -CO ₂ -C ⁶ alkyl, (11) -C (R ⁵ ) (R ⁶ ) -OH, (12) -C (R ⁵⁾ (R ⁶⁾ -OC ₁ _ ₄ anKnn, and (13) -Ct-eanKun-CC ^ -R ^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) C1-6alkyl, (4) C1-6alkoxy, (8) C1-6alkyl, (6) CN, (7) CF ( 8) N (9) - (CR ⁵ ) (R (R)) -OH, and (10 HOR 4 -R 10 -C 10 alkyl);

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

A-511/96-PC

R ³ is selected from the group consisting of:

(a) hydrogen, (b) CF _3, (c) CN, (d ) d-, (e) hidroksiSTs.ealkil, (f) -C (O) -Sweet, (g) optionally substituted ⁽¹⁾ -C N-alkyl-Q, (2) -C 4 -alkyl-O-C 6 -alkyl-Q, (3) -C 4 -alkyl-3-C 6 -alkyl-O, (4) -C 4 -alkyl-O-Q, or (5) -C1-6 alkyl-3-O, wherein the substituent is on the alkyl group and the substituent is Sweet;

(h) -Q;

R ⁴ and R ^{4 are} independently selected from the group,

consisting of:

(a) hydrogen, (b) CF ₃ , (c) CN, (d) Sweet, (e) -Q, (f) -OQ;

(g) -SQ, and (h) optionally substituted ( ¹ ) -C 1-4 alkyl-Q, (2) -O-C 1-4 alkyl-O, (3) -S-C 1-6 alkyl-O, (4) -C 1-4 alkyl-O-C 1-4 alkyl-O,

JIM

A-511/96-PC (5) -C 1-4 alkyl-3-C 1-4 alkyl-Q, (6) -C 1-6 alkyl-O-O, (7) -C 1-6 alkyl-3-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 ₂ -C ₁ _ ₄ alkyl, tetrazolyl-5-yl, C (R ⁷⁾ (R ⁸⁾ (OH), or C ^^ IS-C ^ 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

XI or pharmaceutically acceptable salts thereof, wherein: XYZ is selected from the group consisting of -C (O) -OCR ⁵ (R ⁵ ) - when country b is a double bond,

A-511/96-PC 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 element), (3) C 1-6 alkoxy, (4) C 1-4 alkyl, (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 ^s ) (R ^e ) -OH, (12) -C (R ⁵ ) (R ⁶ ) _{-OClJt anKnn} , and (13) -C _1-6 alkyl-CO 2 -R ⁵ ;

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

(a) hydrogen, (b) sreapil,

A-511/96-PC 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 the present specification alkylene is defined to include straight, branched or cyclic structures with C, _ _b alkyl including methyl, ethyl, propyl, 2-propyl, s- and t- butyl, butyl, pentyl, hexyl, 1, 1 -dimethylethyl, 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 intended that Ο _ν6 apkyltyl includes alkyl groups of 1 to 6 carbon atoms with a straight, branched or cyclic configuration. Examples of smaller alkyl groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. For illustration, the propylthio group represents - SCH ₂ CH ₂ CH ₃ .

Heteroaryl includes furan, thiophene, pyrrole, isoxazap, 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.

A-511/96-PC

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) -2cyclohexylthiophener (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, (ί) 3- (4-fluorophenyl) ) -4- (4 (methylsulfonyl) phenyl) -2- (5H) furanone, (j) 3- (4-fluorophenyl) -4- (4 (aminosulfonyl) phenyl) -2- (5H) furanone,

A-511/96-PC (k) (l) (m) (η) (ο) (Ρ) (q) (r) (s) (t) (u)

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

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

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

3- (4-Trifluoroacetylaminosulfonyl) phenyl) -2- (4-fluorophenyl) thiophene,

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

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

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

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

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

5.5-d and methyl -3- (3,4-dichlorophenyl-4 (4-methylsulfonyl) phenyl-2- (5H) furanone,

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

A-511/96-PC

I (V) ί

(w) (x)

(B)

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

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

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

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

Some of the compounds described herein contain one or more asymmetric centers and may therefore give 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 pharmaceutically acceptable carriers

A-511/96-PC is 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 for inhibiting cyclooxygenase and for treating diseases caused by cyclooxygenase successfully treated with an active agent that selectively inhibits 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 specifically inhibit COX-2, preferably COX-1, if the ratio of its IC50 concentration of COX -1 inhibition to IC50 concentration of COX-2 inhibition is 100 or more than 100.

The pharmaceutical compositions of the present invention contain, as active ingredient, a compound of formula I or its pharmaceutically acceptable salts may also contain

A-511/96-PC is 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 divalent 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.

A-511/96-PC

The compound of formula I is useful for soothing pain, fever, and inflammation in a variety of conditions, including rheumatic fever, flu-related symptoms or other viral infections, common cold, neck and back pain, dysmenorrhea, headache, toothache, sprains, and stretching myositis, neuralgia, synovitis, arthritis, including diseases of rheumatoid arthritis, degenerative joints (osteoarthritis), gout and

ankylosing spondylitis, bursitis, burns, injuries, conditions after surgical and dental 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 can also be used to treat dementia, including presenil and senile dementia, and in particular dementia associated with Alzheimer's disease (i.e., Alzheimer's dementia).

Compounds of formula I can also suppress 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 A-511/96-PC compounds of formula I may prove useful as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDs), especially where such non-steroids

anti-inflammatory drugs are contraindicated, as is the case in patients with gastric ulcer, gastritis, limited enteritis, ulcerative colitis, diverticolitis, or with a history of recurrent gastrointestinal lesions; gastrointestinal bleeding, clotting disorders, including anemia such as hypoprotrombinemia, 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 substitutes for conventional NSAIDs S, where they are co-administered with other agents or ingredients. Thus, in further directions, the invention encompasses pharmaceutical preparations for treating diseases caused by COX-2 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,

A-511/96-PC including acetaminophen or phenacetin; potentiating agent such as caffeine; H2 is an antagonist, aluminum or magnesium hydroxide; simethicone, an anti-hyperemic agent comprising phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylxedrine or levodeoxyephedrine; an antitussive agent comprising codeine, hydrocodone, caramifene, carbetapentan, or dextromethorphan; diuretic; a sedative or anti-anxiety antihistamine. In addition, the invention encompasses a method of treating diseases caused by cyclooxygenase, which comprises: administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of formula I, optionally in conjunction with one or more of the above - ingredients above.

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. IC 50 values

A-511/96-PC 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, IC50 for COX -2 is from 1nM to 1mM. For comparison, Ibuprofen has IC ₅₀ for COX-2 1dM and indomethacin has 1C ₅₀ for COX-2 of approximately 100 nM. For the treatment of all diseases caused by cyclooxygenase, the compounds of formula I may 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.

A-511/96-PC pharmaceutical preparations containing the active ingredient may be in a form suitable for oral administration, such 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, corn starch or apginic 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 thereby achieve

A-511/96-PC 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 carboxymethylcellulose, methyl cellulose, propyl methylcellulose, sodium alginate, hydroxypolyvinyl pyrrolidone, tragacanth or arabic gum; dispersing or wetting agents may be natural phosphatides, for example lecithin or fatty acid alkylene oxide condensation products, for example, polyoxyethylene stearate, or long-chain epiphatic alcohol condensation products, for example, heptadecatylene ethylene acetate

A-511/96-PC partial ethylene oxide products derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products ethylene oxide partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monoethylene sorbitan. 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 aspartan.

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 those mentioned above and 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.

Powder granules suitable for the preparation of an aqueous suspension after the 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

A-511/96-PC 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

mineral oil, for example 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, as well as condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan. 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. A sterile, injectable preparation may also be a sterile injectable form or suspension in a non-toxic,

A-511/96-PC is a parenterally acceptable diluent or solvent, for example, as a solution in

1,3-butanediol. Among the acceptable vehicles and solvents that may 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 a 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 order of

A-511/96-PC 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 preparation. The unit dosage forms typically contain from about 1 mg to about 500 mg of the 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.

- <, · r

A-511/96-PC

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 was prepared from III 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 obtained by the method of Kharash (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 hapogenizing agent, for example bromine in acetic acid, to give 5bromothiophene (VII, R ⁴ = Br). When it is desired to have a nitrile group at C-5, this can be achieved by VI by amidation using the HaWeinreb 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 Friedel-Crafts reaction on VII

A-511/96-PC (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 derived from ketone VIII

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Method A

Hs-γ ⁰

OMe

Py / Et ₃ N IV (R ⁴ = -CO ₂ Me)

R ^a = SO ₂ Me

- R ² = PhCO ₂ H

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Method A - continued • t

VII

R ⁴ ·. Br __________ '

VII R ⁴ = C 1 -C _is alkyl r ⁴ = cf ₃

VI

1.amidation ^

R ⁴ = CN ·.

2.TFAA (

MeMgBr VI ----------

c

R

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.

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Method B

2. Me (C1) ₂ PO

3. Η ₂ ΟλμΝΗ3

4. 4 *

1.n-BuLi

Method C: Bromination which afterwards

of ketone II gives

- bromine is converted to thiazole ketone XV,

XVI after thioamide treatment. Similarly, ketone VIII can be converted to thiazole XVII.

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Method C

Br?

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

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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 group of the pyrrole may be acylated with Cl-CO-lower alkyl in the presence of a base such as Et ₃ N. Alkylated products can also be obtained by using apkyl halides as base reagents such as for example NaH.

Method E

MeO and ^e0 γ ° o ^aXa

NaH / DMF 0 ° C to room temperature

180 ° C

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Method F:

Compounds of type XXV can be prepared from readily available 4- substituted phenylacetyl chlorides XXIa. 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 m-chloroperoxybenzoic acid (mCPA) to introduce the desired methylsulfonyl group into the XXV.

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Method F

Cl

XXIa

XXI /

(¢ -

NaOMe

XXII

XXIII

PCC

XXV

Method G:

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

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Method G

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

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

Method N.

MeO ₂ S

VIII (R ^a = SO ₂ Me)

Cl

CHO

XXVII

NH ₄ SCN

H ₂ O ₂ , AsON

XXVIII

III (Ra = SO ₂ Me)

NH ₄ SCN

XXIX

H ₂ O ₂ , AsON

XXX

XXXI

Method I

A suitably substituted aryl-bromo methyl ketone is reacted with a suitably 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 I

R

but ₂

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.

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Method J

XXXIII or

XXXV

1. DIBAL-H —---: --- ►2: n ⁺

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.

Method K

XXXII r ^{2 / x} conhr ³

Fundamentals ©

Fr.

-------: ---- ►

Basis

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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 cyclized to lactone XLV by alkaline catalysis. Oxidation of XLV with MMPP or mCBA gives the desired product XLVI.

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Method L

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Method Μ:

SMe

Water Base opr. solvent

------------>

phase conversion catalyst

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.

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Table 1

Example Method

SOgMe

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

and me

Table 1 (continued)

Example Method

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SO ₂ Me

zo

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Table 1 (continued)

Example Method

SO ₂ Me

zo

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

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Table 1 (continued)

Example Method

V

SO ₂ Me

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Table 1 (continued)

Example Method

L + M

L + M

zo

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Table II

are ₂ nh

OMe

OMe

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OH

SO ₂ NH _{2 are 2} nh ₂

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Table II (continued)

© zo

HE

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Table II (continued)

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Table II (continued)

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Table II (continued)

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Table II (continued)

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Table II (continued)

SO ₂ Me

SO ₂ NH ₂ ^ \. SO ₂ Me

JT zo

OMe

SO ₂ Me

SO ₂ NH ₂

OMe

Cl

Cl

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Table II (continued)

Me

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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 cyclooxygenase in whole cells and in a 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.

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Representative test - rat paw edema - protocol

Sprague-Dawley male rats (150-200 g) were allowed to fast 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 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. A 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. The values for paw edema were compared with the control group (injected vehicle) and the percentage suppression was eliminated, assuming 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 treated groups

A-511/96-PCs were coded to eliminate the subjectivity of the observer in the reading. In this protocol, ED ₃₀ for indomethacin is 1.0 mg / kg. Representative results are shown in Table IV.

Table III *

Targets' cells of Microsomes

Silent Conc. (nm) COX-2. % inhibition. COX-1% and n 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

...................'......

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An example Horses · COX-2 COX-1 Horses. COX-2 COX-1 < <nm) % inhibition. % inhibition. (nm) % inhi6. % inH6. 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

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The printer Coma. (nm) COX-2 COX-1 Conc. (nm) COX-2 COX-1 % inhibition. % inhibition. % inhi5. % inhibition. 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 10 .17 •

Ί

.72

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. An example Conc. (nm) COX-2 COX-1 Conc. (nm) COX-2 COX-1 % inhib. % inhibition. % inhib. % inhi £. 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

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An example Conc. (nm) CO-2 COX-1 Conc. <nm) COX-2 COX-1 ί % 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, IbnproFen has IC50 for COX-1 1000 nM and IC50 for COX-2 3000 nM. Similarly, Indomethacin has IC50 for COX-1 100 nM and IC50 for COX-2 10 nM.

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Table IV

ED30 (nr / kr) STRUCTURE -3.00 El ^ SO ₂ Me /. rt ^s ΓΊ F > 10.00 E> .SO ₂ Me Mr. with J jl F

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-3.00 are ₂ nh ₂ n 1 | x \ j HC / S || II > 3.00 3.00 V SO ₂ NH ₂ 4 | sj! || II > 1.10 n SO ₂ Me J) |] II F

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<0.30 CL s' F SO ₂ NH ₂ 0.42 _.SO ₂ Me I ° 0 J 0 l ( F 0.034 are ₂ nh ₂ JU 0 j ( F

·? . · · '>

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2.03 opl o XJ Υί _with SO ₂ Me ⁴ F f ' 1.49 XX _with SO ₂ Me ° 0 F 0 f ' ό 0.35 XX _with SO ₂ Me ° 0 M o 9 F ⁴ F

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zo

SO ₂ Me

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zo

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zo

I

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zo

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zo

0.68 ° o ο X _SO ₂ Me J Cl J OMe 0.16 -SO ₂ Me I Ax J 0 4-x II 1 Ί [I -1.00 .SO ₂ Me 1 ° 0 A, II 0 ^ 4x SMe

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Yu

0.33 ° vX 0 jO P F ^ S0 ₂ Me 0.46 _x S0 ₂ Me AJ ° CX 0 CHg Nr 0.76 _x S0 ₂ Me AJ ° vX Nr 0 in Nr -

.........- ίι ·.

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0.1-.3 θθ2 ^ ® Ό -0.10 ^ x.SO ₂ Me ° yX ^ f F

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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 (<5) 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. single; d. doublet; t. triplet; multiplet; no. wide; etc.; in addition Ar means aromatic signal; chemical symbols have a common meaning; The following abbreviations are also used: v (volume), w (weight), bp (boiling point), etc. (melting point), L (liter, and), mL (milliliter), g (gram, ov), mg (milligram, and), mol (moles), mmol (millimoles), eq (equivalent, and).

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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-dimethylformamide Et ₃ N = triethylamine LDA = lithium diisopropylamide m-CPBA = metachloroperbenzoic acid MMPP = monoperoxyphthapic acid MPPM - monoperoxyphthalic acid, magnesium salt 6 H ₂ O Ms = methanesul phonyl = mesyl = SO 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

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TFAA = Trifluoroacetic anhydride

THF

Thi

TLC

TMS-CN =

Tz with ₃ n ₅ tetrahydrofuran thiophendiyl thin layer chromatography trimethylsilyl cyanide 1H (or 2H) - tetrazol-5-yl apyl

Abbreviations of apkyl groups

Me = methyl Et = ethyl p-Rg = normal prop i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-H ex = cyclohexyl

EXAMPLES Example 1

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

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Step 1: 1- (4-fluorophenyl) -2- (4-methylthio) phenyl) ethanone

TNS-CN (4.32g) and Znl ₂ (44mg) were added to 4-fluorobenzapdehyde (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.O.sub.3) 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):? 52.45 (3H, s), 4.34 (2H, s), 7.197.29 (6H, m), 8.14 (2H, 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 (27.0mb) were included 3.M (11.6mL) from the Vilsmeier reagent (Aldrich catalog, 1992-1993) and

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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 under vacuum and drying for several hours, the title product was used in the next step. ¹ H NMR (CD ₃ COCD ₃ ): 02.40 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).

'H NMR (CD ₃ COCD _3): <52.48 (3H, s ), 3.88 (3H, s), 7.11 (2H, t),

7.21 (4H, s), 7.37 (24, q), 7.80 (1Hs).

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

A-511/96-PC was added 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: Carboxylic acid 4- (4- (aminosulfonyl) phenyl) -5- (4fluorophenyl) thiophene-2-methyl ester

The 5- (4-fluorophenyl) -4- (4- (methylsulfinyl) phenyl) thiophene-2-methyl carboxylic acid ester (0.500g) was dissolved in TFAA (10.0mL) and heated to reflux. refrigerate for half an hour. The solvent was then removed in vacuo and the resulting residue was evaporated 10 times with a solution of Et ₃ N-MeOH (1: 1) (100mL) to give a 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 flame i

A-511/96-PC 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).

Calculated for C ₁₉ H ₁₈ FNO ₃ S ₂

C, 58.31; Η, 4.60; N, 3.58. .

Found C, 57.94; Η, 4.66; N, 3.44.

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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): ό 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- (4fluorophenyl) 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 substance (0.180g).

A-511/96-PC ¹ H NMR (CD ₃ COCD ₃ ): δ 6 = 60 (2H, bs), 7.15 (2H, t), 7.29 (1 H, d),

7.35 (2H, q), 7.45 (2H, d), 7.60 (1H, d), 7.83 (2H, d).

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

C, 57.65; H.3.60; N, 4.20

Found: C, 57.62; H, 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

C, 60.80; H, 4.80; N, 3.73

Found: C, 60.59; H.4.45; N, 3.60

Example 4:

3- (4- (aminosulfonyl) phenyl) -2-cyclohexylthiophene ⁽ 1H NMR (CD3) 2) CO): δ 1.24-1.40 (3H, m), 1.40-1.56 (2H, m).

C 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: Benzoic acid 4- (2- (4- (methylthio) phenyl) -1-oxo-ethyl) methyl ester

A-511/96-PC

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, a 0.87 M solution of LDA in TFA (26.2 mL) was added dropwise. After a half hour, a THF solution (10.0 mL) was added dropwise over a half hour.

4- (chloromethyl) thioanisole was then 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, 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 as 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

A-511/96-PC (50 to 100% EtOAc in hexane), the title product was obtained as a white solid (3.20 g).

¹ H NMR (CD 3 COCD 3):? 5 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 (2H, d), 7.90 (2H, d), 7.92 (1H. s), 7.92 (2H, d).

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Step 5: 5- (4- (Carboxyphenip) -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; H.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

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A-511/96-PC filtered, which was followed by solvent evaporation, 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 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

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Analysis:

A-511/96-PC 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 H NMR (CD 3 COCD 3): δ 2.72 (3H, s), 3.15 (3H, s), 7.09 (2H, t), 7.52 (2H, dd), 7.60 (2H, d), 7.92 (2H, d).

Calculated for C ₁₇ H ₁₄ FNO ₂ S ₂

C, 58.78; H, 4.03; N, 4.03

C, 58.71; H, 4.17; N, 3.85

Example 7:

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

Found:

Step 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

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

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A-511/96-PC 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 (2H, t), 2.53 (2H, t), 3.63 (2H, s), 4.90-4.98 (2H, 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 obtain 8g of ketoaldehyde from the title product.

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

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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 sharply cooled with 50 mL of a saturated solution of 1 H ₄ Cl. 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 ) δ 2.12 (1 H, s), 2.34 (2H, m), 2.44 (3H, s), 2.422.52 (1 H, m), 2.56-2.65 (1 H, m). 6.37 (1H, m),

6.84 (2H, 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 PCCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4-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

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A-511/96-PC was subjected to flash chromatography with hexane / EtOAc (2: 1) to give 1.5 g of the title product.

¹ H NMR (CDCl ₃ ) ≤ 5 2.45 (3H, S), 2.68 (2H, m), 3.00 (24, 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 ) <5 2.67 (2H, m), 3.14 (3H, s0, 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 of acetone were added 230 mg (3 mmol) of NH ₄ SCN.

The reaction mixture was refluxed

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A-511/96-PC hours 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 (2H, t), 7.08 (2H, t).

C 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 n 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 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

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A-511/96-PC treated with 1.5 L 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) was added Et ₃ N (0.26mL) 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): ό 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):? 5 5.34 (2H, s), 6.67 (2H, bd).

7.18 (24, m), 7.46 (2H, m), 7.61 (2H, m), 7.90 (2H, m).

mp 187 -188 ° C (d).

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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 a cooled aqueous solution of 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 (CDCl ₃ ): δ 3.1 (3H, s), 7.02 (2H, J = 8.9, t), 7.18 (2H, m), 7.4 (2H, J = 8.8Hz, d), 7.58 (1H , 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

Step 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

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A-511/96-PC 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.

NMR (CD3COCD3): d 0.08 (9H, S), 1.38 (6H, S), 3.67 (3H, S).

With Stage 2:

2-trimethylsilyloxy-4 '- (methylthio) isobutyrophenone

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.Ί) 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

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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):? 5 1.50 (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):? 5 1.62 (3H, s), 1.67 (3H, s), 2.48 (3H, s),

3.79 (2H, s), 7.0 - 7.3 (6H, m), 7.78 (2H, d).

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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.

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A-511/96-PC ¹ H NMR (CD3COGD3): δ 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 ):? 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- (trifluoroacetylaminosulfonyl) phenyl) -2- (4 fluorophenyl) thiophene NMR (300 (, CD ₃ COCD ₃ ): δ 7.15 (24, t), 7.30 (3H, m), 7.45 (2H, d ), 7.65 (1H, d), 7.95 (2H, d).

Example 15

3- (2,4-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, 3.50; S, 9.27

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Example 16

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

To a solution of 3,4-difluorophenylacetic acid (ALDRICH CHIMICAL) (10g) 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. 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

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Example 18

3- (2,5-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, 58.89; 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 (300MH, CDCl ₃ ): δ 7.93 (2H, d), 7.49 (2H, d),

7.35 (4H, m), 5.16 (2H, s), 3.06 (3H, s).

Example 22

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

In ·

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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

A-511/96-PC ethyl acetate gave 36.6g (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- (metipsulfonyl) 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 NMR (300Mg, acetone- ₆ ): &lt; 5 7.95 (2H, d). 7.85 (1H, d), 7.63 (2H, dd), 7.55 (1H, dd), 7.45 (1H, d), 5.50 (2H, s), 3.15 (3H, S).

Example 27

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

117

A-511/96-PC ¹ H NMR (300 MHz, acetone-de): δ 8.0 (2H, d), 7.70 (2H, d), 7.50 7.30 (3H, m), 5.35 (24, 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) -2H (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

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Example 32 3- (3,4-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, 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 Cl 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 ¹ H NMR (300 MH, acetone-O ₆ ): d 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): δ 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

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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

Analysis:

Example 39

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

Ci ₇ 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 (300MHZ, acetone-de): d 8.0 (2H, d), 7.70 (2H, d) ,

7.35 (2H, d), 7.2S (2H, d), 5.35 (2H, s), 3.15 (3H, S), 2.55 (3H, S).

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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 (300MH, acetone-de): d 8.0 (2H, d), 7.70 ( 2H, d), 7.55 7.65 (1 Hm), 7.40 (1 Hd), 7.30 (1 H, m), 5.60 (2H, s), 3.15 (3H, S).

Example 43 3- (3-Bromo-4-methylphenyl) -4- (4- (methylsulfonyl) 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

A-511/96-PC ¹ H NMR (300MHZ, acetone-c1 _6): δ 8.0 (2H, d ), 7.80 ( 1 Η, d),

7.75 (3H, m), 7.25 (1H, 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) -2C (5H) -furanone

Analysis calculated for C ₁₇ H ₁₂ BrClO 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

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Example 50 3- (7-quinolinyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone

Analysis calculated for C2oH ₁₅ N0 ₄ S

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 NMR (400 MHz CD3COCD3): &lt; 5 7.92 (2H, dd), 7.64 (3H, dm ), 7.60 (1H, dd), 7.32 (1H, dd), 6.70 (1Hbs), 5.38 (24, s).

Example 52

3- (3,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone NMR (400 MHz CD3COCD3): < 5 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 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

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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

M.8 (OC1, CH ₄ ) calculated for M ⁺ , 423 found for M ⁺ +1,424

Claims (3)

Patent Claims 1. A compound selected from the group consisting of: (a) 3- (2,4-difluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (b) 3- (3,4-difluorophenyl) -4- (4- ( methylsulfonyl) phenyl) -2- (5H) -furanone, (c) 3- (2,6-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (d) 3- (2,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (e) 3- (3,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -Furanone, (f) 3- (4-bromophenyl) -4- (4- (methylsulfonyl) phenyl) 2- (5H) -furanone, (e) 3- (4-methoxyphenyl) -4 - (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (h) 3- (phenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) furanone, (i) 3- ( 2-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (j) 3- (2-bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (k) 3- (2-bromo-4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (l) 3- (4-chloro-2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, A-511/96-PC (m) 3- (3-bromo-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (η) 3- (3-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (o) 3- (2-chloro-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) - furanone, (p) 3- (2,4-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (q) 3- (3,4-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2 (5H) -furanone, (d) 3- (2,6-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (s) 3- ( 3-chloro-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (t) 3- (4-trifluoromethylphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -Furanone, (i) 3- (3-fluoro-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (v) 3- (3-chloro) p-4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (w) 3- (3-bromo-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -Furanone, (x) 3- (2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) - 2- (5H) -Furanone, (y) 3- (4-methylthiophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (z) 3- (3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) - 2- (5H) -Furanone, A-511/96-PC (aa) 3- (2-chloro-6-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (bb) 3- (3-bromo- 4-methylphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (cc) 3- (4-bromo-2-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -Furanone, (dd) 3- (3,4-dibromophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (ee) 3- (4-chloro-3-fluorophenyl) ) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (ff) 3- (4-bromo-3-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (gg) 3- (4-bromo-2 ~ chlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (hh) 3- (2-naphthyl) -4- ( 4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (ii) 3- (7-quinolinyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (jj) 3- ( 3,4-dichl orphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) -furanone, (kk) 3- (3,4-difluorophenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) - furanone, (II) 3- (3-chloro-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) -furanone, and (mm) 3- (3-bromo-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) -furanone, or a pharmaceutically acceptable salt thereof. A-511/96-PC 2. A compound selected from the group consisting of: (a) 3- (2,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (b) 3- (3,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (c) 3- (2,6-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (d) 3 - (2,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (e) 3- (3,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl ) -2- (5H) -furanone, (f) 3- (4-bromophenyl) -4- (4- (methylsulfonyl) phenyl) - 2- (5H) -Furanone, (e) 3- (4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (h) 3- (phenyl) -4- (4 - (methylsulfonyl) phenyl) -2- (5H) furanone, (i) 3- (2-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (j) 3- (2 -bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (k) 3- (2-bromo-4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (1) 3- (4-chloro-2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (m) 3- (3-bromo-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, A-511/96-PC (n) 3- (3-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (o) 3- (2-chloro-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (p) 3- (2,4-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (q) 3- (3,4-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2 (5H) -furanone, (d) 3- (2,6-dichlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (s) 3- (3-chloro-4-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (t) 3- ( 4-Trifluoromethylphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (i) 3- (3-fluoro-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (v) 3- (3-chloro-4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (w) 3 - (3-bromo-4-methoxyphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (x) 3- (2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) - 2- (5H) -Furanone, (y) 3- (4-methylthiophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (z) 3- (3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) - 2- (5H) -Furanone, (aa) 3- (2-chloro-6-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, A-511/96-PC (bb) 3- (3-bromo-4-methylphenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (cc) 3- (4-bromo- 2-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (dd) 3- (3,4-dibromophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) ) -furanone, (ee) 3- (4-chloro-3-fluorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (ft) 3- (4-bromo-3-fluorophenyl) ) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (gg) 3- (4-bromo-2-chlorophenyl) -4- (4 (methylsulfonyl) phenyl) -2- (5H) -furanone, (hh) 3- (2-naphthyl) -4- (4- (methylsulfonyl) phenyl) -2 (5H) -furanone, (ii) 3- (7-quinolinyl) -4- (4- (methylsulfonyl) ) phenyl) -2 (5H) -furanone, (jj) 3- (3,4-dichlorophenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) -furanone, (kk) 3- (3, 4-Difluorf enyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) -furanone, (II) 3- (3-chloro-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) ) -furanone, (mm) 3- (3-bromo-4-methoxyphenyl) -4- (4 (aminosulfonyl) phenyl) -2- (2H) -furanone, and (dp) 5,5-dimethyl-3- ( 3-fluorophenyl) -4- (4methylsulfonylphenyl) -2- (5H) -furanone, or a pharmaceutically acceptable salt thereof. 3. Compound selected from the group consisting of